bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–06–21
67 papers selected by
Luca Bolliger, lxBio
  1. CAR T Cell Therapy in Solid Tumors: Lessons From Early-Phase Clinical Trials and Biological Barriers to Efficacy.
  2. Next-generation CAR-NK cell therapy: engineering strategies, translational challenges, and future perspectives in cancer immunotherapy.
  3. CAR-T cell therapy for autoimmune diseases: current clinical trial landscape and the next wave of development.
  4. Bispecific CAR T and CAR NK cells in dual-threat immunotherapy: opportunities and challenges.
  5. The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.
  6. Chimeric Antigen Receptor T Cells as Living Therapeutics Targeting Senescence and Age-Related Diseases.
  7. Outcomes of Chimeric Antigen Receptor T-cell (CAR-T) Cell Therapy in Hematological Malignancies - A Systematic Review and Meta Analysis.
  8. Early Phase Dose-Finding Designs for CAR-T Cell Therapies.
  9. Recent advances in bispecific natural killer cell engagers for cancer immunotherapy.
  10. T-cell engagers in cancer immunotherapy: mechanisms, challenges, and future perspectives.
  11. Tuning the Affinity of Chimeric Antigen Receptors Enhances the Function of Human Engineered Regulatory T Cells.
  12. Breathing new life into T-cell receptor-engineered T-cell therapy in solid tumors: enhancing strategies to expand the universality of precision therapy.
  13. Chimeric antigen receptor technology: an emerging translational immunotherapy in nonneoplastic diseases.
  14. CAR-Tography of modeling approaches and opportunities in cellular therapy of cancer.
  15. Chimeric Antigen Receptor-T Cell Therapy for Pediatric and Young Adult Primary Central Nervous System Tumors: A Systematic Review of Early Phase Clinical Trials with a Focus on Diffuse Midline Glioma.
  16. Differences in evidentiary requirements for oncology drug assessments across Health Technology assessment bodies in Germany, Spain, and France, the European Medicines Agency, and the EU Health Technology assessment Regulation.
  17. NK cell-based immunotherapy.
  18. Challenges and recent advances in CAR-T cell therapy for solid tumors.
  19. Precise control of switchable chimeric antigen receptor T cells allows enhanced safety and less T cell exhaustion.
  20. Transcriptional and functional profiling reveals unique activation of Adapter CAR T cells in acute myeloid leukemia.
  21. Pharmacoeconomics of high-cost therapies: real world challenges.
  22. Cellular immunotherapy in melanoma: the next frontier in cancer treatment.
  23. Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Melanoma: A Systematic Review of Phase One Clinical Trials.
  24. Mapping the TCR landscape: computational tools empowering translational immunology and therapy design.
  25. Fertility management and outcomes after CAR T-cell therapy: an international survey from the Cellular Therapy and Immunobiology working party of the European Society for Blood and Marrow Transplantation.
  26. Photonics-Integrated and AI-Enhanced Medical Sensing: From Molecular Diagnostics to Real-Time Cell Therapy Monitoring.
  27. India's Drug Discovery and Development Industry: The Quest for Novel Therapeutic Treatments.
  28. Emerging therapeutic strategies in multiple sclerosis: a focus on innovative and targeted approaches.
  29. Secure healthcare data management using federated learning, blockchain, and explainable artificial intelligence: a systematic review.
  30. CAR cellular therapies for acute myeloid leukemia: current landscape and future directions.
  31. Cardiac Risk Without a Roadmap: Lack of Evidence-Based Guidance for Cardiovascular Toxicity of T-Cell Redirecting Therapies.
  32. [Efficacy and safety of fourth-generation CAR-T cells targeting CD19 and BCMA with anti-IL-6 antibody secretion in refractory systemic lupus erythematosus].
  33. A conditional multi-signal validation framework for cancer immunotherapy: the adaptive anti-error biological system.
  34. Linking T Cell States to T Cell Receptors in Systemic Lupus Erythematosus.
  35. Overcoming fratricide of CD86 targeting CAR-T cells by defined logic-gate CAR strategy.
  36. Knowledge mapping and research trends of chimeric antigen receptor T-cell immunotherapy in breast cancer: A bibliometric and visual analytics study.
  37. Integration of Federated Learning and Blockchain in Health Care: Tutorial on Medical Data, Architectures, Privacy, Security, and Regulatory Compliance.
  38. Designing next-generation interleukin immunotherapy: A cytokine-guided framework for precision cancer therapy.
  39. Not all personal utilities are equal: a two-tier normative framework for genomic health technology assessment.
  40. Evaluating the Impact of Different Natural History Modeling Methods on Cost-Effectiveness Decisions: A Case Study in Duchenne Muscular Dystrophy.
  41. The search for safe and effective CAR-T targets in AML.
  42. Why advanced therapy medicinal products struggle in clinical translation: an in-depth analysis of developmental challenges in the EU.
  43. T Cell Exhaustion as a Regulated Differentiation Programme.
  44. Most-Favored-Nation pricing meets Joint Clinical Assessment: early evidence of compounding pressure on European drug launches.
  45. Cytokine release syndrome in solid tumours: mechanism-based therapeutic strategies for prevention and management.
  46. Immunometabolic Reprogramming: A New Frontier in Cancer Immunotherapy.
  47. From blood draw to tumor infiltration: therapeutic variations in CAR-macrophage therapy for solid tumors.
  48. Development and Validation of an AI Tool for Automated PICO Scoping for the European Joint Clinical Assessment (JCA): A Proof of Concept.
  49. Pre-infusion quantitative EEG features associated with delayed neurocognitive impairment following CAR T-cell therapy.
  50. T cell decision-making decodes the dynamic antigenic landscape.
  51. Phenotypic response surfaces in pharmacology: Mechanistic and translational perspectives on optimizing drug combination therapies.
  52. Safety profile of chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma: A systematic review and meta-analysis of proportions from clinical trials.
  53. Computational prediction of TCR cross-reactivity: principles, challenges and translational opportunities.
  54. Rethinking health technology assessment in robotic surgery: an EFISDS-TROGSS position paper. Official position paper of the European Federation - International Society for Digestive Surgery (EFISDS) and The Robotic Global Surgical Society (TROGSS).
  55. Genetically engineered outer membrane vesicles as next-generation bionanomaterials for therapeutic and diagnostic applications.
  56. Defining seizure freedom in epilepsy: a pragmatic literature review.
  57. A symposium update on the key perspectives in systemic sclerosis and systemic lupus erythematosus.
  58. Estimation of Future Patient Populations Eligible for Radioligand Therapies in the EU and the UK: A Modelling Study.
  59. Piggybacking Towards Progress for CAR-T Cell Therapy in Prostate Cancer.
  60. Current status and challenges of TCR-T cell therapy for AML/MDS.
  61. CRISPR-screen informed engineered T cell therapies.
  62. Reprogramming the tumor microenvironment via TFF3 targeting: a potential novel avenue to boost CAR-T cell therapy in solid tumors.
  63. The landscape of cellular immune alteration in systemic lupus erythematosus.
  64. Nanomaterials for Subcellular Organelle Targeting: Unlocking New Avenues for Enhanced Therapeutic Effectiveness.
  65. Infectious toxicities associated with bispecific antibodies and CAR-T Cells in multiple myeloma: a systematic review.
  66. The impact of gut microbiota on cervical cancer and precancerous lesions: neglected status, mechanisms, challenges, and a call to action.
  67. JAK inhibitors in areas outside of inflammatory arthritis: focus on connective tissue diseases.
  1. Hematol Oncol. 2026 Jul;44(4): e70209
    CAR T Cell Therapy in Solid Tumors: Lessons From Early-Phase Clinical Trials and Biological Barriers to Efficacy.
    Kasie Liu, Vincent Truong Pham, Shaozi Fu, LuZhe Sun, Gang Huang.
      Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of select hematologic malignancies, where disease accessibility, well-defined lineage antigens, and clinically manageable target cell depletion have enabled more durable responses. However, translation to solid tumors has been far more limited due to the structural, metabolic, and immunologic barriers that are less prominent in many blood cancers. This review uses hematologic malignancies as the standard for CAR T cell therapy success while synthesizing mechanistic insights from preclinical models and emerging data from early-phase solid tumor trials. We define how antigen heterogeneity, impaired trafficking, metabolic suppression, immunosuppressive signaling, and on-target, off-tumor toxicity limit CAR T cell infiltration, persistence, and function in solid tumors. We also highlight recurring clinical patterns indicating that antitumor activity is most achievable when tumor-enriched antigens are targeted, delivery strategies overcome physical barriers, and CAR T cells are engineered to resist exhaustion and suppression within hostile microenvironments. By evaluating next-generation approaches, including cytokine armoring, multi-antigen and logic-gated recognition, regional delivery, and regulatable safety circuits, we propose a model for rational CAR T cell design tailored to solid tumor biology while informed by the principles underlying hematologic success. These insights support context-dependent engineered immunotherapies capable of extending the durability and safety achieved in blood cancers to solid malignancies.
    Keywords:  CAR T cells; chimeric antigen receptors; immunotherapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.1002/hon.70209
  2. Cancer Cell Int. 2026 Jun 18.
    Next-generation CAR-NK cell therapy: engineering strategies, translational challenges, and future perspectives in cancer immunotherapy.
    Minoo Bakhtiari, Hamid Nickho, Mahmoud Mahmoudi, Fahimeh Lavi Arab, Akram Hoseinzadeh, Rasoul Baharlou.
      Natural killer (NK) cells play a central role in innate immune surveillance and represent a promising platform for next-generation cancer immunotherapy. Recent advances in chimeric antigen receptor (CAR) engineering have accelerated the development of CAR-NK cell therapies as potentially safer and more accessible alternatives to CAR-T cell therapy. Compared with CAR-T cells, CAR-NK therapies demonstrate lower risks of cytokine release syndrome and graft-versus-host disease while offering the potential for allogeneic "off-the-shelf" applications. Preclinical and early-phase clinical studies have shown encouraging antitumor activity of CAR-NK cells in both hematological malignancies and solid tumors. However, several translational challenges remain, including limited in vivo persistence, insufficient tumor trafficking, immunosuppressive tumor immune microenvironments, manufacturing variability, and restricted long-term clinical data. To overcome these barriers, emerging strategies such as CRISPR-based gene editing, cytokine-armored CAR constructs, multiplex engineering, checkpoint blockade combinations, and oncolytic virus-based approaches are being actively investigated. This review provides an updated overview of CAR-NK cell biology, engineering strategies, current clinical progress, major translational challenges, and future therapeutic opportunities. In addition, we discuss evolving combinatorial and next-generation engineering approaches that may improve persistence, safety, and therapeutic efficacy, ultimately facilitating the broader clinical translation of CAR-NK immunotherapy.
    Keywords:  CAR-NK cells; Cancer immunotherapy; Combination therapy; Gene editing
    DOI:  https://doi.org/10.1186/s12935-026-04389-x
  3. Front Immunol. 2026 ;17 1853170
    CAR-T cell therapy for autoimmune diseases: current clinical trial landscape and the next wave of development.
    Qingyu Chen, Yuxin Zhu, Qianqi Xu, Yemeng He, Yaoyi Wang, Ziyue Wang, Weisong Dong.
      Chimeric antigen receptor T-cell (CAR-T) therapy has expanded beyond oncology and is emerging as a promising strategy for autoimmune diseases. Early clinical experience, particularly with CD19-directed CAR-T cells, has shown that deep remission can occur in refractory disorders such as systemic lupus erythematosus, inflammatory myopathies, and systemic sclerosis. These observations are consistent with an immune-reset-like process, although its durability, cellular basis, and disease-specific mechanisms remain incompletely defined. However, the clinical development landscape remains uneven. Based on an April 2026 Trialtrove snapshot, the field is growing rapidly but remains concentrated in a limited number of countries, diseases, and target classes, with most studies in early-phase development. These features suggest that autoimmune CAR-T therapy has moved beyond proof of concept, but has not yet reached a mature, indication-optimized stage of clinical translation. In this Perspective, we argue that the next phase of progress will depend less on increasing trial numbers than on improving biological precision, platform diversity, and trial design. The current pipeline is dominated by CD19-centered programs and diseases in which B-cell depletion appears biologically plausible, but this approach is unlikely to be equally informative across autoimmune disease. Key questions remain regarding remission durability, relapse after B-cell reconstitution, patient selection, toxicity management, and scalability. Looking ahead, major opportunities include plasma cell-directed approaches, dual-target strategies, chimeric autoantigen receptor platforms, tolerance-oriented cell therapies, off-the-shelf products, and in vivo engineering. The near-term readout window will be critical in determining whether autoimmune CAR-T therapy becomes broadly deployable or remains limited to selected indications and settings.
    Keywords:  BCMA; CAAR; CAR-T; CD19; autoimmune diseases; clinical trials; immune-reset-like remodeling; perspective
    DOI:  https://doi.org/10.3389/fimmu.2026.1853170
  4. Mol Biol Rep. 2026 Jun 19. pii: 963. [Epub ahead of print]53(1):
    Bispecific CAR T and CAR NK cells in dual-threat immunotherapy: opportunities and challenges.
    Ali Shahin Baher, Aya Khalid, Anahita Ganjalikhani Hakemi, Armita Ganjalikhani Hakemi, Mojdeh Soltani, Zohreh Saltanatpour, Andrey A Zamyatnin, Alessandro Parodi, Mazdak Ganjalikhani Hakemi.
      Antigen escape and intratumoral heterogeneity remain major barriers to durable responses in chimeric antigen receptor (CAR)-based cancer immunotherapies. While single-antigen CAR-T cell therapies have achieved notable success in hematologic malignancies, relapse driven by antigen loss, lineage plasticity, and tumor evolution remains common, and efficacy in solid tumors is limited. Similar antigen-dependent limitations are also observed in other targeted immunotherapies, including bispecific antibodies, underscoring the broader challenge of achieving durable immune control. To address these challenges, bispecific and combinatorial CAR strategies have emerged to broaden antigen coverage, enhance tumor selectivity, and reduce immune evasion. This review examines the biological mechanisms underlying antigen escape and critically evaluates dual-targeting CAR architectures, including tandem CARs, dual-CAR systems, logic-gated designs, and inhibitory CARs. We distinguish between mechanistic rationale and clinically validated benefit, highlighting the heterogeneity of outcomes across studies and the limited evidence supporting consistent superiority over optimized monospecific approaches. We summarize preclinical and clinical evidence supporting bispecific CAR-T strategies, particularly in B-cell malignancies, while discussing challenges related to toxicity, manufacturing complexity, and translational scalability. We further evaluate CAR-engineered natural killer (CAR-NK) cells as a complementary platform. Their innate cytotoxicity, favorable safety profile, and compatibility with allogeneic manufacturing offer important translational advantages, although limitations in persistence, tumor infiltration, and clinical validation remain. Finally, we position CAR-based therapies within the evolving immunotherapy landscape, emphasizing therapeutic sequencing, combination strategies, potential cross-resistance, and the need to align CAR design and platform selection with tumor-specific patterns of antigen expression and immune escape.
    Keywords:  Bispecific CAR; CAR NK Cell; CAR T cell; Immunotherapy; TanCAR; iCAR
    DOI:  https://doi.org/10.1007/s11033-026-12144-8
  5. Front Immunol. 2026 ;17 1847986
    The trinity of T cell engagement: navigating the molecular and clinical landscape of CAR-T, TILs, and TCEs in the war against cancer.
    Qiang Yang, Shaobin Wang, Fanlin Liu, Yongli Yu, Hai Zhao.
      The advent of cancer immunotherapy has fundamentally restructured the oncological paradigm, moving away from agents that directly target tumor cell kinetics toward strategies that empower the host immune system to recognize and eliminate malignancy. Central to this revolution is the cytotoxic T lymphocyte (CTL), now harnessed as a potent "living drug" through engineered and naturally selected modalities. This review provides a critical, in-depth examination of the three dominant pillars of T cell-driven therapies: Chimeric Antigen Receptor T-cell (CAR-T) therapy, Tumor-Infiltrating Lymphocyte (TIL) therapy, and T Cell Engagers (TCEs). We dismantle the molecular mechanisms defining each approach, contrasting the synthetic, major histocompatibility complex (MHC)-independent signaling of CAR-T cells with the diverse, MHC-restricted TCR repertoire of TILs, and the transient, pharmacologic bridging provided by bispecific TCEs. While CAR-T therapy has achieved historic success in hematologic malignancies, its translation to solid tumors is severely compromised by the hostile tumor microenvironment (TME), characterized by metabolic insulation, physical exclusion, and profound immunosuppression. Conversely, TIL therapy offers a polyclonal strategy tailored for solid tumors but is hindered by complex biomanufacturing logistics and variable tumor immunogenicity. TCEs promise off-the-shelf accessibility but face challenges regarding persistence and on-target/off-tumor toxicity. Beyond clinical outcomes, we explore the pathophysiological underpinnings of resistance, including antigen escape mechanisms and T cell exhaustion programs. Finally, we posit that the future of curative regimens lies in rational combinatorial strategies-integrating advanced genetic engineering, metabolic reprogramming, and TME-modulating agents like oncolytic viruses-to overcome the multifaceted defenses of solid tumors.
    Keywords:  CAR T-cells; adoptive cell therapy; antigen escape; bispecific T cell engagers; immunosuppression; synthetic biology; tumor microenvironment; tumor-infiltrating lymphocytes (TILs)
    DOI:  https://doi.org/10.3389/fimmu.2026.1847986
  6. Research (Wash D C). 2026 ;9 1326
    Chimeric Antigen Receptor T Cells as Living Therapeutics Targeting Senescence and Age-Related Diseases.
    Qingyi Shao, Danlei Chen, Wenxia Shao, Qing Ye.
      The aging of the global population exacerbates the burden of age-related diseases; however, therapies that can intervene in fundamental aging processes are lacking. Senescent cells drive chronic inflammation and multitissue dysfunction through the secretion of proinflammatory and profibrotic senescence-associated secretory phenotype cells, making them emerging therapeutic targets. Although first-generation senolytic drugs have entered clinical trials, they face limitations such as insufficient targeting specificity and transient efficacy. The success of chimeric antigen receptor T cell (CAR T cell) therapy in cancer immunotherapy has validated its precision clearance capabilities as a "living drug". This review systematically elaborates on the paradigm shift of extending CAR T cell therapy to aging medicine, from the discovery and validation of surface targets on senescent cells to a CAR engineering design tailored to the senescent microenvironment and from evidence of reversing fibrosis and improving metabolic function in preclinical models to the challenges of specificity, safety, and manufacturing faced in clinical translation. Finally, future directions for integrating technologies such as mRNA delivery and artificial intelligence are envisioned in this article, which proposes that CAR T cell therapy may drive the evolution of medicine from "treating single diseases" to "intervening in shared aging processes", offering transformative strategies to achieve healthy aging.
    DOI:  https://doi.org/10.34133/research.1326
  7. Curr Stem Cell Res Ther. 2026 Jun 12.
    Outcomes of Chimeric Antigen Receptor T-cell (CAR-T) Cell Therapy in Hematological Malignancies - A Systematic Review and Meta Analysis.
    Ullas Mony, Vishnu Priya Veeraraghavan, Neeraj Sidharthan.
       INTRODUCTION: CAR T therapy is used in various hematological malignancies that involve genetic modification of autologous T cells to target tumor cells. The aim of this meta-analysis was to evaluate the efficacy and safety of CAR T cell therapy in haematological malignancies with relation to response rates, survival outcomes, and treatment-related adverse events.
    METHODS: This meta-analysis followed PRISMA guidelines. 428 records were identified from Pub- Med, Embase, Web of Science, Scopus, Cochrane Library, and Google Scholar for studies between 2019 and 2024. Clinical trials and observational studies evaluating CAR T therapy in haematological malignancies were included. Study quality was assessed using the Newcastle Ottawa Scale and ROBINS I tool. Random effects models were used, and heterogeneity was measured with the I² statistic.
    RESULTS: Twelve studies met the inclusion criteria. CAR T therapy showed high ORR and CR in Bcell malignancies, with ORR reaching 90.5% in R/R B NHL and 81% remission in B ALL. CRS was common but mainly mild to moderate, while neurotoxicity and GvHD were less frequent. Metaanalysis demonstrated substantial heterogeneity for ORR, CR, and CRS. Most studies were rated good quality, though moderate bias related to missing data and design differences was observed.
    DISCUSSION: Meta-analysis shows CAR T therapy achieves high ORR and durable remission in B ALL and DLBCL. CD19-directed therapy was promising. Compared to myeloid cell malignancies, B-cell malignancies showed better response. These findings point towards optimisation of protocol and appropriate patient selection apart from the toxicity management, which is required to improve the outcomes.
    CONCLUSION: CAR T therapy shows high response rates in haematological malignancies with controllable toxicity, thus establishing its role in relapsed and refractory disease. It highlights the need for improved durability, access, and constant clinical application.
    Keywords:  Acute myeloid leukemia; B-cell acute lymphoblastic leukemia; cytokine release syndrome; graft-versus-host disease; multiple myeloma; non-hodgkin lymphoma.
    DOI:  https://doi.org/10.2174/011574888X401292260530151340
  8. Pharm Stat. 2026 Jul-Aug;25(4):25(4): e70102
    Early Phase Dose-Finding Designs for CAR-T Cell Therapies.
    Weishi Chen, Pavel Mozgunov, Jimmy Mullaert, Xavier Paoletti.
      Chimeric Antigen Receptor (CAR)-T cell is an immunotherapy which revolutionised the treatment of relapsed/refractory lymphoma and leukaemia. It is shown to have a higher response rate, higher mid-to-long term overall survival, and lower toxicity than standard treatments. However, due to a lack of dose-limiting toxicity (DLT) and unclear dose-effect relationship, traditional phase I designs of clinical trials cannot lead to accurate selections of the optimal dose (OD). Beside clinical outcomes, the CAR-T cell expansion from serial blood samples is measured at various time points. We propose a novel early phase dose-finding design for CAR-T cells, using both toxicity and activity endpoints to locate the OD. The number of CAR-T cells measured in the peripheral blood is used to indicate activity, which is more sensitive than the short-term clinical responses traditionally used. A Bi-Exponential model is used for the repeated measures of the number of cells for each patient, and is estimated under a Bayesian framework. The model is motivated by biological concerns and is flexible enough to accommodate different shapes of the cell-expansion curve. Three criteria for activity are considered: (1) the number of cells at specific time points, (2) the duration before all cells are eliminated, (3) the area under the cell-expansion curve. Simulation studies show that the OD can be selected with high accuracy even under small sample sizes.
    Keywords:  CAR‐T cells; dose finding; phase I clinical trials
    DOI:  https://doi.org/10.1002/pst.70102
  9. Immunotherapy. 2026 Jun 19. 1-21
    Recent advances in bispecific natural killer cell engagers for cancer immunotherapy.
    Mousa Thalji, Yago Nieto.
      Natural killer (NK) cells are innate cytotoxic lymphocytes capable of eliminating malignant cells independently of major histocompatibility complex (MHC) - restricted antigen recognition. This makes them particularly valuable in tumors that evade adaptive immune surveillance through MHC antigen loss or impaired processing. However, tumor-intrinsic immune evasion mechanisms and suppressive tumor microenvironments frequently impair endogenous NK cell activity, limiting the effectiveness of nontargeted autologous NK cell-based approaches.Bispecific and multispecific NK cell engagers (NKCEs) have emerged as promising immunotherapeutics designed to redirect NK cells toward tumor-associated antigens while delivering potent activating signals. These engineered molecules typically engage activating NK receptors (e.g. CD16a, NKG2D, or NKp46) to promote immune synapse formation and antigen-specific cytotoxicity. Advances in molecular engineering have enabled the development of multispecific platforms that integrate dual tumor antigen targeting, multireceptor activation, and cytokine support - particularly interleukin-15-, to enhance NK cell persistence, expansion, and functional durability.This review highlights progress in NKCE design, preclinical efficacy, and early clinical translation, while addressing safety considerations, mechanisms of resistance, and rational combination strategies, such as with adoptive NK cell therapies and checkpoint inhibitors. Collectively, NKCEs represent versatile, drug-like immunotherapies with the potential to overcome key limitations of monoclonal antibody and T cell - based therapies.
    Keywords:  Allogeneic NK cell therapy; Bispecific and multispecific antibodies; Natural killer cells; Tumor microenvironment; antibody-dependent cellular cytotoxicity; bispecific NK-cell engagers; cancer immunotherapy
    DOI:  https://doi.org/10.1080/1750743X.2026.2688683
  10. Front Immunol. 2026 ;17 1755512
    T-cell engagers in cancer immunotherapy: mechanisms, challenges, and future perspectives.
    Kaaviyaa Muthughavi, Manoj Khokhar, Hem Chandra Jha, Rajan Kumar Pandey.
      T-cell engagers (TCEs) are a rapidly evolving class of cancer immunotherapies that redirect cytotoxic T cells to tumor-associated antigens independently of MHC presentation. This review outlines the development, structural formats, and therapeutic potential of various TCE platforms, including bispecific (BiTEs) and trispecific T-cell engagers (TriTEs), dual affinity re-targeting (DART), and other emerging formats. We also highlight the clinical success in treating hematologic malignancies as demonstrated by agents such as blinatumomab and teclistamab. We also discussed the ongoing challenges in solid tumors, such as antigen heterogeneity and the immunosuppressive tumor microenvironment. A comparative analysis with CAR-T cell therapies is provided, with a focus on efficacy, safety, toxicity, resistance, and cost. Strategies to increase specificity and reduce toxicity, such as tumor-selective activation (e.g., XPATs), CD3 affinity tuning, and multifunctional constructs, are discussed. Future directions include AI-driven design, synthetic biology, and potential applications beyond oncology, including autoimmune and infectious diseases. As scalable, off-the-shelf therapeutics, T-cell engagers are poised to become essential tools in personalized and accessible cancer treatment.
    Keywords:  CAR-T-cell; T-cell engagers; bispecific antibodies; cancer immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1755512
  11. Eur J Immunol. 2026 Jun;56(6): e70226
    Tuning the Affinity of Chimeric Antigen Receptors Enhances the Function of Human Engineered Regulatory T Cells.
    Ada Sera Kurt, Marwa Elgosbi, Elisavet Kodela, Emmanuelle Landmann, Paula Ruiz, Yoh Zen, Jorge Torres-Yaguana, Alexander Puttick, Quisha Bustamante, Minahil Sharjeel, Hannan Murshid, Marc Martinez-Llordella, Alberto Sanchez-Fueyo.
      Chimeric antigen receptors (CAR) incorporating single-chain variable fragments (scFv) exhibit much higher affinity for their cognate antigens than native T cell receptors (TCR). Reducing the affinity of the CAR has been shown to improve the function of effector CAR-T cells by limiting their activation-induced exhaustion while preserving their capacity for serial killing of antigen-rich tumor cells. CAR technologies are increasingly being applied to regulatory T cell (Treg)-based immunotherapies as well. However, the impact of CAR affinity on Treg biology and function remains poorly understood. To address this question, we transduced purified human Tregs with second-generation CAR constructs bearing scFvs with varying affinities toward HLA-A2 and compared their properties both in vitro and in vivo. High-affinity (HA) CAR-Tregs displayed higher avidity and more pronounced CAR downregulation upon antigen engagement. In contrast, low-affinity (LA) CAR-Tregs exhibited enhanced antigen-specific activation and superior suppressive capacity. These differences were confirmed using human and mouse precision-cut liver slices and a xenogeneic graft-versus-host disease (GVHD) murine model. LA CAR-Tregs exhibited greater accumulation/persistence, delayed GVHD onset, and improved survival than HA CAR-Tregs. Our findings, indicating that CAR affinity strongly influences CAR-Treg function, provide important considerations for the optimization of engineered Treg therapies and the benchmarking of existing cell products.
    DOI:  https://doi.org/10.1002/eji.70226
  12. Exp Hematol Oncol. 2026 Jun 19.
    Breathing new life into T-cell receptor-engineered T-cell therapy in solid tumors: enhancing strategies to expand the universality of precision therapy.
    Yawen Li, Xiaozhen Zhang, Yan Chen, Jieru Lin, Tingbo Liang, Xueli Bai.
      Adoptive T-cell transfer therapy (ACT) has significantly propelled the advancement of tumor immunotherapy. Among various strategies targeting solid tumors, the T-cell receptor (TCR)-engineered T-cell (TCR-T cell) therapy has emerged as a highly promising approach, exhibiting an expanded therapeutic window across diverse patient populations and superior tumoricidal activity in certain solid malignancies compared with chimeric antigen receptor T cell (CAR-T) and tumor-infiltrating T cells/lymphocyte (TIL) therapies. However, its clinical efficacy remains constrained. In this paper, we introduce the limitations and challenges faced by TCR-T cells in solid tumor treatment, and summarize recent efforts overcoming these limitations and translating TCR-T cell therapies into clinical application. Furthermore, their current status and effectiveness in clinical solid tumor patients were analyzed. We expect that the precision therapies of TCR-T cells, with the support of high-affinity TCRs and a diverse array of target antigens, multimodal synergistic therapy strategies and efficient in vitro production processes, will benefit a wider patient population, thus revealing new clinical application potential.
    Keywords:  Clinical trial; Enhancing strategy; Solid cancer; TCR; TCR-T cell therapy; Tumor antigen
    DOI:  https://doi.org/10.1186/s40164-026-00793-1
  13. Front Immunol. 2026 ;17 1864256
    Chimeric antigen receptor technology: an emerging translational immunotherapy in nonneoplastic diseases.
    Sijie Zhou, Yuan Li, Jiulu Zhao, Wang Zhan, Cheng Zhou, Yanqiang Zou, Xiaohan Li, Jikai Cui, Jie Wu, Jiahong Xia.
       Background: One of the most significant recent advancements in cancer immunotherapy is the development of chimeric antigen receptor (CAR) technology. More recently, this approach has been gradually modified for the research associated with various treatment-resistant nonneoplastic diseases by engineering immune cells to provide precise targeting.
    Results: This narrative review discusses two primary therapeutic approaches the use of CAR technology in the treatment of nonneoplastic diseases. One strategy involves the elimination of specific pathogenic cell populations. Specifically, by engineering T cells, macrophages, or natural killer (NK) cells, pathogenic cells can be eliminated in autoimmune disorders, infectious diseases, and fibrotic lesions. The second approach aims to restore immune homeostasis by using engineered regulatory T cells (Tregs) to control augmented immune effector responses. This strategy has been shown to promote transplant tolerance and has therapeutic potential for inflammatory bowel disease and type 1 diabetes. Furthermore, this review addresses major issues concerning the persistence, safety, and manufacturing accessibility of CAR cells and discusses some emerging technological approaches that could be used for focused refinements of this technology.
    Conclusions: The precision medicine platform for CAR technology has advanced beyond oncology by integrating targeted cell destruction with the management of immune homeostasis. As future possibilities with frontier cell engineering and interdisciplinary approaches are explored, CAR cell therapy is likely to evolve into a more adaptable, refined, and clinically viable immunotherapy technology, with its therapeutic potential expanded to a broad range of diseases.
    Keywords:  chimeric antigen receptor (CAR) technology; engineered immune cells; immunotherapy; nonneoplastic diseases; precision targeting
    DOI:  https://doi.org/10.3389/fimmu.2026.1864256
  14. Folia Med Cracov. 2026 Mar 31. 66(1): 43-57
    CAR-Tography of modeling approaches and opportunities in cellular therapy of cancer.
    Monika Jesionek.
      Chimeric Antigen Receptor CAR-T therapy represents a potent adoptive cell immunotherapy for cancer, yet its clinical application remains constrained by pronounced interindividual variability, severe adverse events, and restricted efficacy in solid tumors. Computational modeling has emerged as a critical framework for analyzing and characterizing CAR-T cell behavior to mitigate these clinical limitations. This systematic review synthesizes 20 computational models identified through targeted bibliographic search that were developed using human clinical datasets. The reviewed studies employ a range of mathematical frameworks, including cellular kinetics and population pharmacometrics models, tumor-immune interaction models, quantitative systems pharmacology approaches, and multiscale mechanistic models. Across these frameworks, CAR-T cells are represented as dynamic populations undergoing expansion, contraction, persistence, and functional exhaustion. Many models further incorporate phenotypic stratification into functional subsets, most commonly effector and memory cells, to capture the multiphasic kinetics observed in clinical settings. Additional variables frequently include tumor burden, antigen expression, host immune cells, cytokines, and CAR-target complexes, reflecting different levels of biological detail and modeling objectives. Based on this analysis, I propose a unified set of core variables that captures the key biological processes represented across existing models while providing a consistent structure for future modeling efforts. Together, these studies demonstrate that the choice and structure of variables used to describe CAR-T cell populations and their interactions are key determinants of model interpretability and translational relevance. Improved access to longitudinal clinical datasets and phenotype-resolved measurements will be essential for developing more predictive and clinically applicable computational models of CAR-T therapy.
    Keywords:  CAR-T therapies; cancer models; computational models; immunotherapy; pharmacokinetics
    DOI:  https://doi.org/10.24425/fmc.2026.158984
  15. Target Oncol. 2026 Jun 15.
    Chimeric Antigen Receptor-T Cell Therapy for Pediatric and Young Adult Primary Central Nervous System Tumors: A Systematic Review of Early Phase Clinical Trials with a Focus on Diffuse Midline Glioma.
    Sai Sanikommu, Alejandro N Santos, Bashar Dawoud, Khushi H Shah, Sima Vazquez, Ashish H Shah, Victor M Lu.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has demonstrated substantial efficacy in hematologic malignancies; however, its application in pediatric and young adult primary central nervous system (CNS) tumors, particularly pediatric diffuse midline glioma (DMG), remains investigational. Several early phase trials have recently reported clinical experiences with CNS-directed CAR-T cell therapies, necessitating a systematic distillation to better understand the state of the field.
    OBJECTIVE: The aim of the study was to systematically review early phase clinical evidence evaluating the safety, feasibility, and preliminary efficacy of CAR-T cell therapy in pediatric and young adult patients with primary CNS tumors.
    PATIENTS AND METHODS: A systematic review was conducted on early phase clinical studies assessing CAR-T cell therapies in pediatric and young adult patients diagnosed with primary brain tumors. Data collected included information on antigen targets, route of administration, dosing strategies, patient characteristics, prior therapies, toxicity profiles, anti-inflammatory management, radiographic and clinical outcomes, biologic correlates, and survival.
    RESULTS: The search identified eight early phase trials involving 74 pediatric and young adult patients. Of the cohort, 63 received CAR-T cell infusion, targeting B7-H3, GD2, HER2, EGFR806, and PSMA-GD2 via intraventricular, intravenous, or combined routes. All patients had heavily pretreated, recurrent, or refractory disease, with all DMG cohorts receiving prior radiation. CAR-T cell therapy was feasible, with no treatment-related mortality. Immune toxicities, including cytokine release syndrome and CNS neurotoxicity, were common but reversible with corticosteroids and cytokine therapies. Among response-evaluable patients, 65% achieved disease control (stable disease or partial response), while 35% had progressive disease. Objective responses were rare, but many had disease stabilization, especially in DMG cohorts. Post-infusion, immune activation was evident, with CAR-T cell trafficking to CNS and increased cytokines in cerebrospinal fluid and plasma. Median survival ranged from 13 to over 30 months, with some patients exceeding expectations.
    CONCLUSIONS: Preliminary clinical experience indicates that CAR-T cell therapy for pediatric and young adult CNS tumors is biologically active and clinically feasible, exhibiting a distinct yet manageable toxicity profile. Although durable objective responses are currently limited, the frequent occurrence of disease stabilization and extended survival in certain patients substantiate ongoing research and the refinement of CAR-T cell strategies for CNS malignancies.
    DOI:  https://doi.org/10.1007/s11523-026-01225-0
  16. Expert Rev Pharmacoecon Outcomes Res. 2026 Jun 16.
    Differences in evidentiary requirements for oncology drug assessments across Health Technology assessment bodies in Germany, Spain, and France, the European Medicines Agency, and the EU Health Technology assessment Regulation.
    Amber Tiemens, Christophe Sauboin, Sharon Wolters, Simon James Bond, Judith Olga Maria Bentvelzen, Susana Monteiro, Seán Walsh, Maarten Jacobus Postma.
       BACKGROUND: This study compares evidentiary requirements for oncology drugs across the European Medicines Agency (EMA), the EU Health Technology Assessment Regulation (HTAR), and national Health Technology Assessment (HTA) practices. Given the heterogeneity in evidentiary requirements across EU Member States, identifying these differences is critical for navigating the EU HTAR.
    RESEARCH DESIGN AND METHODS: EMA guidelines and EU HTA guidance documents were reviewed, followed by interviews with HTA experts from Germany, Spain, and France to identify differences in oncology drug assessments and anticipated EU HTAR impact. Six recent oncology drug assessments conducted by these three HTA bodies were reviewed to substantiate the interview findings. A comparative analysis of evidence acceptability and potential alignment between organizations was conducted.
    RESULTS: The EMA and EU HTAR guidance showed higher acceptability of available evidence than national HTA bodies. The German HTA body demonstrated the highest level of acceptability, followed by Spain and France. The six assessments supported expert insights by demonstrating national variability.
    CONCLUSION: Differences in the acceptability of evidence across the EMA, EU HTAR, and HTA bodies were identified, highlighting the need for increased alignment and shared understanding of evidentiary requirements. Recommendations to reduce or manage variability include international collaborations, harmonization, and early dialogs.
    Keywords:  Evidence generation; health technology assessment; joint clinical assessment; market access; oncology drugs
    DOI:  https://doi.org/10.1080/14737167.2026.2691190
  17. Hum Vaccin Immunother. 2026 Dec;22(1): 2688610
    NK cell-based immunotherapy.
    Mark Alexander Forsberg, Yago Nieto.
      NK cells have rapidly become a leading platform for cancer immunotherapy. Unlike T cells, NK cells recognize transformed cells through integrated signals from inhibitory and activating receptors, enabling allogeneic "off-the-shelf" therapies without risk of graft-versus-host disease and low rates of cytokine release syndrome and neurotoxicity. Refinement in sourcing of allogenic NK cells, especially umbilical cord blood and induced pluripotent stem cells, ex vivo activation and expansion, CAR engineering, and combinations with novel engagers have resulted in clinically applicable products with encouraging activity and excellent safety. However, barriers remain, including limited in vivo persistence, host rejection of allogeneic cells, and inefficient trafficking into solid tumors. Venues of progress include multiantigen and logic-gated CAR platforms, inducible safety switches, cytokine armoring, and metabolic and transcriptional rewiring to improve NK fitness. As NK cell therapies progress into the clinic, exploration of rational combinations with checkpoint inhibitors, small-molecule kinase inhibitors, chemotherapy, and radiotherapy warrant study.
    Keywords:  CAR; NK cells; cellular immunotherapy; lymphomas; umbilical cord blood
    DOI:  https://doi.org/10.1080/21645515.2026.2688610
  18. Crit Rev Oncol Hematol. 2026 Jun 16. pii: S1040-8428(26)00321-5. [Epub ahead of print]226 105434
    Challenges and recent advances in CAR-T cell therapy for solid tumors.
    Zhixun Guo, Dewen Zhong, Dongxue Jiao, Jinfeng Wu, Jiawen Wang, Deng Lin, Yuanxing Fang, Yongbao Wei.
      Chimeric Antigen Receptor T-cell (CAR-T) therapy has achieved revolutionary success in hematological malignancies. However, its broad application in solid tumor treatment still faces fundamental challenges. This review explores the multiple obstacles encountered by CAR-T therapy in conquering solid tumors, including core issues such as tumor antigen heterogeneity, the immunosuppressive tumor microenvironment (TME), difficulties in T-cell infiltration, and treatment-related toxicities. Beyond merely describing these challenges, this article focuses on organizing the breakthrough strategies that have emerged in recent years. It highlights several cutting-edge directions, including the discovery of novel targets (e.g., Claudin 18.2, B7-H3), innovative CAR designs (e.g., logic-gated CARs, armored CARs), local delivery and in situ generation techniques, and combination therapies (e.g., with radiotherapy, immune checkpoint inhibitors, oncolytic viruses). Finally, this review outlines future directions of developing intelligent, controllable next-generation CAR-T technologies through multidisciplinary integration, hoping to provide a valuable perspective for advancing basic research and clinical translation in this field.
    Keywords:  CAR engineering; CAR-T cell therapy; Solid tumors; Tumor microenvironment remodeling
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105434
  19. J Transl Med. 2026 Jun 17.
    Precise control of switchable chimeric antigen receptor T cells allows enhanced safety and less T cell exhaustion.
    Zihan Anna Zhang, Logan Herring, Thuzar Hla Shwe, Yue Hu, Xiaotong Song, Wenyue Cao, Wenshe Ray Liu.
       BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success in hematologic malignancies, yet their clinical utility remains limited by safety concerns, limited persistence, and T-cell exhaustion driven by continuous receptor signaling. While switchable CAR designs provide external control, many reported systems are irreversible, strictly binary, or compromise CAR-T potency.
    METHODS: We engineered an optimized chemically switchable CAR platform (CSN CAR) that pharmacologically regulates antigen engagement by controlling the surface expression of the full-length CAR. An NS3 protease module was embedded within the CAR construct to enable drug-dependent stabilization of intact CAR on T cells. Using engineered CAR-T cells, we quantified drug-controlled activation, cytotoxicity, and cytokine release against CD19⁺ tumor cells by flow cytometry and ELISA in vitro. We further screened clinically approved NS3/4A inhibitors in CAR-HEK and CAR-T cells to identify optimal small-molecule controllers. A chronic stimulation model was established to assess CAR-T persistence and exhaustion-associated phenotypes in vitro.
    RESULTS: CSN CAR-T cells enabled precise, dose-dependent regulation of CAR surface density, cytokine production, and cytotoxicity. In the OFF state, switchable CAR-T cells showed minimal basal activity, consistent with reduced antigen-driven activation and cytokine release in the absence of drug in the experimental conditions. Upon drug addition, intact surface CAR was detectable within 1 h, reaching ~ 80% of peak observed CAR expression by 4 h. Reversible suppression of CAR expression enabled attenuation of cytotoxicity toward normal CD19⁺ B cells in vitro after target-cell reduction, supporting a potential strategy to mitigate prolonged on-target/off-tumor activity. Under chronic stimulation, switchable CAR-T cells exhibited reduced exhaustion-associated markers, more stable CAR expression, and preferential differentiation toward a central memory phenotype.
    CONCLUSION: Together, these findings establish CSN CAR as a reversible and tunable switchable CAR-T platform enabled by clinically approved NS3/4A inhibitors, supporting controllable modulation of CAR activity with potential applications for improving the precision and safety of CAR-T cell therapy.
    Keywords:  Chimeric antigen receptor (CAR); Cytokine release syndrome; Switch; T cell exhaustion; T cell therapy
    DOI:  https://doi.org/10.1186/s12967-026-08464-9
  20. J Transl Med. 2026 Jun 18.
    Transcriptional and functional profiling reveals unique activation of Adapter CAR T cells in acute myeloid leukemia.
    Nele Knelangen, Ulrika Bader, Evangelia Maniaki, Boris Engels, Luca Gattinoni, Joerg Mittelstaet.
       BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating malignant diseases, yet its efficacy is often limited by challenges such as controllability and the lack of tumor-specific antigens. Adapter CAR (AdCAR) T cells address these limitations by redirecting T cell activity through adapter molecules rather than direct interaction with tumor-associated antigens, offering an on-/off- switch mechanism and the potential for multitargeting. While functionality of AdCAR T cells has been demonstrated in various models, the underlying AdCAR T cell response to differing adapter concentration and its comparison to conventional CAR T cells remain poorly characterized.
    METHODS: In this study, we systematically examined adapter-dependent AdCAR T cell responses using functional assays and single-cell RNA sequencing in an acute myeloid leukemia model.
    RESULTS: Adapter concentration was found to determine AdCAR T cell activation dynamics, transcriptional states and metabolic reprogramming. At low adapter concentrations, an interferon-responsive state was observed, while high concentrations induced strong cytolytic activity, cytokine secretion, and metabolic shifts toward glycolysis and oxidative phosphorylation. Importantly, increasing adapter concentrations enhanced tumor control of sub-optimally activated AdCAR T cells, demonstrating the platform's tunability. A hallmark gene signature was identified across different adapters and target cells, comprising the interferon-responsive gene MX1 and activation-associated genes including ENO1, HSP90AB1, and RRM2.
    CONCLUSIONS: Our findings provide a mechanistic framework for tuning AdCAR T cell responses and offer critical insights for optimizing adapter dosing to enhance the safety and efficacy of tunable CAR T cell therapies.
    Keywords:  Adapter CAR T cell; CAR T cell; T cell activation; Universal CAR T cell
    DOI:  https://doi.org/10.1186/s12967-026-08461-y
  21. Expert Rev Pharmacoecon Outcomes Res. 2026 Jun 19.
    Pharmacoeconomics of high-cost therapies: real world challenges.
    Elvira Meni Maria Gkrinia, Andrej Belančić, Ivana Stević, Dinko Vitezić, Slobodan Janković.
       INTRODUCTION: The emergence of high-cost therapies, particularly in oncology, rare diseases, and advanced therapy medicinal products, has increased the need for robust pharmacoeconomic evaluations to support healthcare decision-making. These innovative interventions often promise substantial clinical benefits but also pose challenges due to limited long-term data, high upfront costs, and uncertain cost-effectiveness.
    AREAS COVERED: This narrative review critically examines key pharmacoeconomic frameworks, e.g. cost-effectiveness analysis and cost-utility analysis, and highlights their limitations in assessing such novel therapies. The role of real-world evidence, advanced modeling techniques, and patient-reported outcomes is explored, alongside the ethical and policy considerations that arise in pricing, access, and reimbursement. Recent literature and case studies involving gene and cell therapies are reviewed, illustrating the complexity of determining value under uncertainty.
    EXPERT OPINION: The paper advocates for a more flexible, transparent, and patient-centered approach to health technology assessment, integrating societal values and dynamic reassessment mechanisms. Such strategies are essential for achieving sustainable access to high-value therapies while maintaining health system efficiency and equity.
    Keywords:  Cost-effectiveness; Cost-utility; Real-world evidence; health technology assessment; novel therapies; pharmacoeconomic evaluation
    DOI:  https://doi.org/10.1080/14737167.2026.2691186
  22. J Exp Clin Cancer Res. 2026 Jun 18. pii: 139. [Epub ahead of print]45(1):
    Cellular immunotherapy in melanoma: the next frontier in cancer treatment.
    Anna-Lena Wien, Angeliki Stamtsis-Datsi.
      Therapy-resistant melanoma remains a major clinical challenge despite advances with immune checkpoint inhibitors and targeted therapies, as most patients ultimately exhibit primary or acquired resistance and progress through multiple toxic treatment lines with limited durable benefit. This resistance reflects not only T-cell dysfunction but also a profound quantitative deficit of tumor-reactive lymphocytes, compounded by myeloid- and Treg-mediated immunosuppression, impaired antigen presentation, and tumor dedifferentiation programs generating a cold tumor microenvironment. Cellular immunotherapies aim to overcome these barriers by supplying or priming new tumor-reactive repertoires while reshaping the tumor microenvironment and restoring durable immunity. Dendritic-cell vaccines safely induce broad, long-lived responses but show modest activity as monotherapy in advanced disease. Tumor-infiltrating lymphocyte therapy directly replaces the missing tumor-specific compartment and has demonstrated clinically meaningful response rates in checkpoint-refractory melanoma, though at the cost of complex, intensive manufacturing and conditioning requirements. Genetically engineered TCR-T and CAR T/CAR NK therapies provide programmable specificity but remain constrained by antigen selection, toxicity risks, and limited persistence in solid tumors. NK-cell platforms offer HLA-independent, off-the-shelf potential but require further optimization for trafficking, persistence, and resistance to suppression. Overall, rational combinations - particularly DC-priming integrated with adoptive cell therapy - represent the most promising path to durable tumor control in treatment-refractory melanoma.
    Keywords:  Adoptive T cell transfer; CAR NK cells; CAR T cells; Immunotherapy; Tumor-infiltrating Lymphocytes
    DOI:  https://doi.org/10.1186/s13046-026-03762-y
  23. Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261452884
    Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Melanoma: A Systematic Review of Phase One Clinical Trials.
    Pavan Shet, Prerana Ghosh, Karan Varshney, Sameen Sawdagar.
      IntroductionMelanoma is a growing health concern, with global incidence increasing annually. However, treatment for refractory disease is currently limited. Chimeric antigen receptor (CAR) T-cell therapy has shown promising results in haematological malignancies. Despite this, its utility in solid cancers, such as melanoma, is not yet established. We performed a systematic review of phase one trials to help determine and describe foundational understandings of the safety and efficacy of CAR T-cell therapy for melanoma.MethodsThis systematic review was conducted in accordance with the Cochrane Collaboration Handbook for Systematic Review of Interventions and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement Guidelines. Databases were searched to identify articles before November 18, 2025, which described the use of CAR T-cell therapy in melanoma patients with published results. Study, patient, and treatment characteristics were summarised and analysed.ResultsIn total, 2726 articles were screened. Ultimately 5 studies comprising 15 patients with melanoma treated with CAR T-cell therapy were analysed and discussed. T-cell therapies were all autologous and the targets for the CAR T-cell therapies included GD2, PD-1 and cMET antigens across a wide variety of cell doses. Across pooled data, clinical responses varied, with some patients displaying either a partial or complete clinical response. Treatment related effects were of grade one or two severity, with no serious adverse effects reported, including neurotoxicity side effects, or treatment limited related toxicity/mortality events. Peak expansion typically occurred within day 7 to 28, but persistence was limited across studies.ConclusionCAR T-cell therapy for melanoma is a novel treatment approach in its infancy. Results are preliminary, and remain largely descriptive, as findings are limited by heterogeneity and small sample sizes. Further investigation through additional phase one trials, and subsequent phase two/three trials, are required for better establishing direct clinical viability.
    Keywords:  CAR T-cell therapy; adoptive cellular immunotherapy; clinical trials; melanoma; phase one; skin cancer
    DOI:  https://doi.org/10.1177/15330338261452884
  24. J Immunother Cancer. 2026 Jun 18. pii: e014184. [Epub ahead of print]14(6):
    Mapping the TCR landscape: computational tools empowering translational immunology and therapy design.
    Pâmella Borges, Martiela Vaz de Freitas, Jinkyung Yoo, Finn Beruldsen, Jaila Lewis, Francisca Joseli Freitas de Sousa, Sae Hee Choi, Duy Bao Nguyen, Geancarlo Zanatta, Jeong Hoon Jang, Eduardo Donadi, Houda Alachkar, Steven P Wolf, Maurício Menegatti Rigo, Hyeongseon Jeon, Dinler Amaral Antunes.
      T cell receptors (TCRs) are central to adaptive immunity, yet their vast sequence and structural diversity present a significant challenge to fully understand immune responses. The application of high-throughput sequencing technologies, including bulk and single-cell approaches, generates vast datasets of TCR repertoire information, requiring advanced computational tools for meaningful analysis. Here, we provide a comprehensive overview of the state-of-the-art in silico tools developed to enable diverse TCR repertoire analyses. We categorize over 40 computational tools into six primary analytical stages creating a workflow for TCR analysis in the context of cancer immunotherapy: (1) data acquisition, including differences between TCR sequencing technologies and databases; (2) TCR reconstruction and inference, which focuses on accurately extracting from raw sequencing data the V(D)J gene usage, including complementarity-determining region sequences, and the α/β pairing; (3) TCR clustering, which groups receptors based on similarity, helping characterize repertoire shifts, therapy responses and identify cancer-associated TCR clones; (4) structural modeling of TCRs and TCR-peptide-major histocompatibility complex (MHC), which is used to predict the three-dimensional structures of TCRs with or without their targets; (5) TCR specificity prediction, which predicts whether a given TCR can bind to a given peptide-MHC complex; and finally (6) functional and clinical integration, addressing the breakthroughs and bottlenecks for wider clinical application of these methods. For each category, we discuss the underlying methodologies, representative tools and their key applications, details about usability and accessibility, and comments on their strengths and limitations. With this overview, we offer a critical perspective on the current state of the field, providing an overall framework and guidance for new users and developers of these technologies. We also highlight open challenges and key future directions, particularly regarding the integration of multi-omics data and next-generation artificial intelligence approaches to unlock the full potential of TCR repertoire analysis for clinical immunotherapy applications.
    Keywords:  Immunotherapy; Major histocompatibility complex - MHC; T cell; T cell Receptor - TCR
    DOI:  https://doi.org/10.1136/jitc-2025-014184
  25. EClinicalMedicine. 2026 Jun;96 104014
    Fertility management and outcomes after CAR T-cell therapy: an international survey from the Cellular Therapy and Immunobiology working party of the European Society for Blood and Marrow Transplantation.
    Giorgio Orofino, Isabel Sánchez-Ortega, Juana Schwartz Mota, Andrea Aroldi, Cristina Castilla-Llorente, Camille Bigenwald, Jean Hugues Dalle, Karima Yacouben, Roberta Di Blasi, Eugenio Galli, Victoria Grandage, Andrea Palasciano, Larry Bacon, Georg-Nikolaus Franke, David Fandrei, Maximilian Merz, Lindsay George, Lucía Lopez-Corral, Judith S Hecker, Daniele Mannina, Stefania Bramanti, Juan Alberto Martin Gonzalez, Núria Martínez-Cibrian, Soeren Lykke Petersen, Kamila Polgarova, Rachel Protheroe, Deborah Richardson, Ron Ram, Shlomo Elias, Bastian von Tresckow, Friedrich Stölzel, Iwona Streiss, Nicolas Vallet, Jeroen Knippenberg, Ana Alarcon Tomas, Simona Pagliuca, Florent Malard, Jürgen Kuball, Annalisa Ruggeri.
       Background: CAR T-cell therapy has become a highly effective treatment for hematological malignancies, and emerging evidence indicates promising benefits for non-oncohematological conditions. As its clinical use broadens, understanding long-term outcomes and late complications is crucial. One critical yet understudied area is fertility, for which current evidence remains limited and no formal guidelines provide direction for patients undergoing CAR T-cell therapy.
    Methods: To address this gap, we conducted a cross-sectional survey on behalf of the Cellular Therapy and Immunobiology Working Party (CTIWP) of the European Society for Blood and Marrow Transplantation (EBMT) focusing on current practices, existing challenges, and reported reproductive outcomes. Questionnaires were distributed electronically (via SurveyMonkey) between Jan 8, 2025 and April 18, 2025 to 247 EBMT-affiliated centers assessing current fertility-related practices and procedures around CAR T-cell therapy. A second, complementary questionnaire was circulated between Dec 23, 2025 and April 9, 2026 to gather detailed information on reported pregnancies following CAR T treatment.
    Findings: 99 of 247 (40%) centers answered and were included in the analysis. At data censoring, 24 pregnancies were reported in 19 patients, resulting in 18 live births, 2 ongoing pregnancy (one with twins), and 4 miscarriages. Eighteen pregnancies occurred in female CAR T-cell recipients, and six were reported by male recipients through their partners. In patients achieving pregnancy, B cell lymphoma was the most common indication for treatment. Pregnancies in the female cohort occurred naturally in 83% of cases (15/18). Among patients with data, the median time between CAR T-cell infusion and delivery or miscarriage was 3 years (range 4 months-6 years). Although both low- and high-grade Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) were reported among these patients, these events did not appear to influence pregnancy outcomes, acknowledging the small sample size. While most centers (52/63, 83%) reported offering fertility counselling before CAR T-cell infusion, 11 centers (17%) indicated that they do not routinely inform patients of the potential reproductive risks. Most centers (79%) offered fertility preservation procedures to male and female patients. The most common barriers to fertility preservation referral were the urgency of initiating bridging therapy to CAR T-cell infusions due to active or rapidly progressive disease in aggressive disease and extensive prior chemotherapy exposure, defined as more than three previous treatment lines. For female patients, the predominant approaches were oocyte cryopreservation (63%) and ovarian tissue cryopreservation (59%). Among male patients, semen collection and cryopreservation was the most frequently used method (93%). Endocrinologic follow-up practices after CAR T-cell therapy varied substantially across centers.
    Interpretation: We report the largest series of pregnancies and live births after CAR T in patients with hematological malignancies and autoimmune diseases, and the first within Europe. As CAR T-cell therapy is increasingly administered earlier in the treatment algorithms and to younger populations, integrating standardized fertility counselling and preservation strategies into routine care will be essential. The reproductive success highlights the urgent need for robust research and formalized guidelines in this evolving field.
    Funding: None.
    Keywords:  CAR-T; Fertility preservation; Pregnancies; Reproductive outcomes
    DOI:  https://doi.org/10.1016/j.eclinm.2026.104014
  26. Prog Biophys Mol Biol. 2026 Jun 19. pii: S0079-6107(26)00042-8. [Epub ahead of print]
    Photonics-Integrated and AI-Enhanced Medical Sensing: From Molecular Diagnostics to Real-Time Cell Therapy Monitoring.
    Alberto Boretti.
      Over the past two decades, photonic sensing has transitioned from laboratory concepts to clinically relevant tools for disease detection and treatment guidance, driven by the convergence of nanotechnology, artificial intelligence (AI), and advanced fabrication. Unlike recent reviews that focus narrowly on individual technologies, this Perspective synthesizes advances across silicon photonics, nanophotonics, and quantum platforms, highlighting their accelerating clinical translation. We present a unified framework showing how optical imaging, photoacoustic techniques, and quantum sensing address critical challenges in quality control, cell tracking, and toxicity monitoring-with particular emphasis on CAR-T cell therapy. The integration of microfluidics, AI-driven data analysis, and closed-loop therapeutic systems is enabling real-time, personalized interventions. However, we also provide a balanced assessment of the significant practical limitations of quantum and other emerging platforms, acknowledging that classical photonics remains sufficient and often more practical for most near-term applications. We further identify key translational barriers-including biocompatibility, regulatory pathways, system-level integration, surface fouling, reimbursement, and data integration-and propose strategies to overcome them. We conclude by defining four Grand Challenges for the next decade and presenting a technology roadmap with explicit timelines. The coming decade will likely see widespread clinical deployment of photonic sensors for point-of-care diagnostics, continuous monitoring, and image-guided interventions, including cell therapy workflows, ultimately improving patient outcomes.
    Keywords:  CAR-T cell therapy; Photonic sensors; artificial intelligence in medicine; cell therapy monitoring; closed-loop therapy; cytokine release syndrome; fiber optic sensors; immuno-PET; machine learning for biosensing; nanophotonics; optical biosensors; optical metabolic imaging; photoacoustic imaging; point-of-care diagnostics; quantum sensing; quantum-enhanced detection; silicon photonics; theranostic platforms; wearable photonics
    DOI:  https://doi.org/10.1016/j.pbiomolbio.2026.06.003
  27. ChemMedChem. 2026 Jun 15. 21(11): e70304
    India's Drug Discovery and Development Industry: The Quest for Novel Therapeutic Treatments.
    Edmond Differding.
      A comprehensive review and analysis of drug discovery efforts at Indian companies between the mid-1990s and 2025 reveals 1095 ongoing (462) or past (633) projects and molecules under investigation at 195 major pharmaceutical, biotechnology, and start-up companies, of which 128 are currently actively pursuing research. They consist mainly of small molecules (811), followed by novel biologics (189) and gene therapies (95), and cover all stages from early discovery (618), preclinical (276), and clinical development phases (Phase 1: 98; Phase 2: 63; Phase 3: 19) up to approved drugs and treatments (21). Small molecules are dominated by new chemical entities (684), followed by prodrugs, salts, and formulations (56), repurposed drugs (53), and others (18). Biologics consist largely of monoclonal antibodies or fragments (92), antibody-drug conjugates (22), various (fusion) proteins (40), enzymes (10), and others (25). Gene therapies use gene silencing (24), gene transfer (21), genome editing (7), modulation of mRNA splicing (3), and genetically modified cells based on chimeric antigen receptor technology using T and NK cells (40). Tracking companies and projects over time illustrates the dynamics and increasing diversification of drug discovery activities in India.
    DOI:  https://doi.org/10.1002/cmdc.70304
  28. Naunyn Schmiedebergs Arch Pharmacol. 2026 Jun 15.
    Emerging therapeutic strategies in multiple sclerosis: a focus on innovative and targeted approaches.
    Husna Irfan Thalib, Sariya Khan, Sanha Sideeque, Taqiyah Zaheerullah Sheriff, Aleesha Muzammil, Fatma E Hassan.
      Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system marked by damage to myelin and nerve cells. Current treatments help control inflammation but have limited success in progressive stages and repairing nerve damage. This review aims to summarize new therapies for MS that target both inflammation and neurodegeneration beyond traditional immunosuppressive drugs. We conducted a thorough literature search to summarize key findings from original studies, including clinical trials investigating novel MS treatments such as Bruton's tyrosine kinase (BTK) inhibitors, CAR T-cell therapy, vaccines targeting Epstein-Barr virus (EBV) and specific antigens, drugs promoting remyelination, monoclonal antibodies, stem cell therapy, sphingosine-1-phosphate receptor modulators, cytokine blockers, gut microbiome interventions, and nanotechnology-based drug delivery. Emerging therapeutic strategies in MS increasingly target mechanisms beyond conventional immunosuppression, including B-cell and microglial modulation, immune tolerance induction, remyelination, cytokine signaling, microbiome regulation, and enhanced central nervous system drug delivery. BTK inhibitors and S1P receptor modulators demonstrated anti-inflammatory activity in clinical trials, although some agents failed to show superiority over established therapies. Cell-based therapies, including CAR T-cell therapy and stem cell transplantation, showed early promise in refractory disease but remain limited by safety concerns and insufficient long-term data. Remyelination-promoting agents and EBV-targeted immunotherapies demonstrated encouraging preliminary findings; however, many approaches remain in preclinical or early-phase clinical stages. Nanotechnology-based delivery systems and microbiome-directed therapies represent emerging areas with potential translational relevance. Emerging therapies in MS reflect a growing shift toward mechanism-based and potentially personalized therapeutic strategies. Although several approaches demonstrate promising preclinical and early clinical results, many remain investigational, and further large-scale studies are required to establish long-term efficacy, safety, and clinical applicability.
    Keywords:  BTK inhibitors; CAR T-cell therapy; EBV vaccines; MS; Mesenchymal stem cells; Monoclonal antibodies; Remyelination
    DOI:  https://doi.org/10.1007/s00210-026-05579-0
  29. Front Digit Health. 2026 ;8 1871960
    Secure healthcare data management using federated learning, blockchain, and explainable artificial intelligence: a systematic review.
    Tanisha Bhardwaj, K Sumangali.
      Due to the rapid digitization of healthcare systems, there has been a huge collection of sensitive personal data of patients. Thus, secure, privacy-preserving, and efficient data management systems are required. Current distributed healthcare systems increasingly use centralized data processing frameworks that are prone to privacy violations, data fragmentation, and malicious attacks. Despite advances in federated learning, blockchain, explainable AI, and incremental optimization, current survey literature studies each technology separately without considering how the four technologies can be harnessed to create synergies. A systematic review of 26 peer-reviewed studies published from 2018 to 2026 indicates that an integrated architecture incorporating federated learning, blockchain, explainable AI, and incremental optimization can be designed. This review identifies ten critical issues that need to be addressed when researching the four technologies. These issues include communication costs, scalability issues, interoperability concerns, limited clinical explainability, and high computational costs when applied in real-time situations. In comparison to privacy, scalability, interpretability, and efficiency, a hybrid approach can help improve data security, boost the interpretability of the models, facilitate data sharing, and prevent data-sharing risks. Overall quality assessment based on the CASP qualitative checklist analysis of all 26 studies indicated an average score of 7.0 out of 10, implying that the quality of the methods used in the studies was acceptable.
    Keywords:  GDPR compliance; blockchain technology; differential privacy; explainable artificial intelligence; federated learning; healthcare data security; incremental learning; internet of medical things (IoMT)
    DOI:  https://doi.org/10.3389/fdgth.2026.1871960
  30. Immunotherapy. 2026 Jun 19. 1-18
    CAR cellular therapies for acute myeloid leukemia: current landscape and future directions.
    Jure Hederih, James Patrick, Isaac Gannon, Alexandros Rampotas, Claire Roddie, Rob Sellar.
      Chimeric antigen T cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, but has not seen this success replicated in acute myeloid leukemia (AML). Many antigens present on AML cells are shared with healthy hematopoietic progenitors, posing a risk of prohibitive toxicity with CAR-T therapy. Furthermore, clonal evolution of AML, antigen escape and effects of tumor microenvironment (TME) may hinder the efficacy of treatment. A number of innovative approaches to overcome these barriers have been attempted in recent years, including combinatorial and neoantigen targeting, logic-gated CARs, CAR-T armoring to overcome the effects of TME and CAR-T consolidation of engineered antigen-negative stem cell transplants. Despite this, no CAR-T treatments are currently licensed for AML. While some early trial data seems promising, it remains to be seen whether CAR-T therapy is a viable strategy for treatment of AML.
    Keywords:  AML; CAR-T; cellular therapy; immunotherapy; leukemia
    DOI:  https://doi.org/10.1080/1750743X.2026.2689849
  31. Curr Oncol Rep. 2026 Jun 17. pii: 67. [Epub ahead of print]28(1):
    Cardiac Risk Without a Roadmap: Lack of Evidence-Based Guidance for Cardiovascular Toxicity of T-Cell Redirecting Therapies.
    Serafino LaGalbo, Matthew T Foley, Anastasia E Metropulos, Kyle A Burton, Daniel R Principe.
       PURPOSE OF REVIEW: T-cell redirecting therapies have revolutionized the treatment of several hematologic malignancies. These include CAR T-cell therapy, an adoptive immunotherapy in which a patient's T-cells are engineered to express synthetic receptors against tumor surface antigens, and bispecific T-cell engagers, antibodies simultaneously targeting CD3 and a tumor-specific antigen. Both approaches redirect T-cells toward tumor cells, thereby enhancing anti-tumor immunity independent of major histocompatibility complex class restriction. With expanding indications, their use is extending into older and less fit populations than those represented in pivotal trials, raising important questions regarding toxicity profiles in patients with greater comorbidity burden.
    RECENT FINDINGS: Although cardiovascular toxicities of CAR T and bispecific T-cell engagers have been described, reported incidences are highly variable due to inconsistencies in adverse event definitions and surveillance across studies. Further, most studies have excluded patients with pre-existing heart failure or cardiomyopathy. Consequently, there is a lack of evidence-based guidance for risk stratification, peri-treatment management, or monitoring in this growing subgroup. Here, we briefly review the cardiovascular toxicities associated with T-cell redirecting therapies and highlight limitations in clinical trial inclusion criteria. We then emphasize the urgent need for uniformity in defining cardiovascular toxicities, as well as for dedicated studies in patients with pre-existing heart failure or cardiomyopathy as a distinct high-risk population.
    Keywords:  Bispecific T-cell engager; CAR T-cell therapy; Cardiomyopathy; Cardiovascular toxicity; Heart failure; Immunotherapy
    DOI:  https://doi.org/10.1007/s11912-026-01791-6
  32. Zhonghua Yi Xue Za Zhi. 2026 Jun 23. 106(23): 2378-2383
    [Efficacy and safety of fourth-generation CAR-T cells targeting CD19 and BCMA with anti-IL-6 antibody secretion in refractory systemic lupus erythematosus].
    X X Xu, Q Wang, X J Zhao, N Xiang, B L Hu, X B Wang, Z Chen.
      Clinical data of 3 patients with refractory systemic lupus erythematosus (rSLE) who received chimeric antigen receptor T-cell (CAR-T) therapy at the Department of Rheumatology and Immunology, the First Affiliated Hospital of University of Science and Technology of China, from June to September 2024 was prospectively enrolled. After lymphodepleting preconditioning with cyclophosphamide combined with fludarabine, 2 patients received a low dose (0.5×10⁶/kg) and 1 patient received a medium dose (1.0×10⁶/kg) of a 4th-generation CAR-T cells (SCAR02) targeting cluster of differentiation 19 (CD19) and B-cell maturation antigen (BCMA) and secreting interleukin-6 (IL-6) antibodies. Follow-up was conducted at day 14 and months 1, 2, 3, 6, 9, and 12 post-infusion to systematically evaluate safety (including treatment-related adverse events, cytokines, and immunoglobulin levels) and efficacy (including cellular kinetics, clinical efficacy, and serological markers). All 3 patients were females, aged 37, 25, and 41 years, respectively. During the follow-up period, no cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or other serious adverse events occurred. CAR-T cells expanded well in all patients; peripheral blood CD19⁺ B cells were completely depleted on days 9-13 and gradually recovered over 3-5 months. By month 12, the SLE Disease Activity Index 2000 (SLEDAI-2K) scores of patients 1 to 3 decreased from 8, 8, and 9 at baseline to 0, 4, and 0, respectively; anti-double-stranded DNA antibodies all turned negative, and complement levels returned to normal. Two patients achieved drug-free complete remission based on the Definitions of Remission in SLE (DORIS) criteria, and 1 patient achieved an SLE Responder Index-4 (SRI-4) response. This study demonstrates that SCAR02 exhibits a good safety profile and preliminary efficacy in rSLE patients, and its function of secreting IL-6 antibodies may help alleviate CRS.
    DOI:  https://doi.org/10.3760/cma.j.cn112137-20251226-03435
  33. Front Immunol. 2026 ;17 1845119
    A conditional multi-signal validation framework for cancer immunotherapy: the adaptive anti-error biological system.
    Emery M Kalondero.
       Background: Cancer immunotherapy faces persistent limitations due to its reliance on single-signal therapeutic architectures, which are vulnerable to antigen loss, off-tumor toxicity, and tumor heterogeneity. A fundamental contributor to therapeutic failure is the generation of biological decision errors - false-positive activation in normal tissues and false-negative missed recognition in antigen-low tumors.
    Objective: We propose the Adaptive Anti-Error Biological System (AABS), a conceptual framework designed to improve therapeutic precision through structured multi-signal validation and conditional effector activation. A simplified implementation, AABS-01, is introduced as a trimodular conditional therapeutic model integrating tumor priming, dual-signal AND-gate logic, and conditional effector engagement.
    Framework: AABS-01 operates through three coordinated layers: (1) a Tumor Priming Layer enhancing antigen visibility through tumor-restricted IFN-γ conditioning, epigenetic modulation, and TME normalization; (2) a Validation Layer implementing Boolean AND-gate logic requiring simultaneous detection of two independent tumor-associated signals; and (3) an Effector Layer triggering localized immune activation exclusively upon validated dual-signal convergence.
    Bioinformatic support: Analysis of TCGA Pan-Cancer Atlas and GTEx v8 transcriptomic data confirms that four candidate signal pairs (HER2/MUC4, EGFR/EpCAM, MSLN/HER2, PD-L1/GD2) achieve corrected Tumor Specificity Index (TSI) values of 18.3x to 46.8x across six cancer types, after correction for inter-signal correlation (r = 0.18-0.44). A revised probabilistic framework accounting for signal co-regulation demonstrates that AND-gate logic achieves 3-8x false-positive rate reduction versus single-signal approaches under empirically observed correlation conditions.
    Conclusion: AABS represents a paradigm shift from reactive to decision-based cancer immunotherapy, grounded in established immunological principles including T-cell multi-signal activation and kinetic proofreading. A five-phase experimental roadmap with quantitative endpoints is provided to guide preclinical and translational validation.
    Keywords:  AND-gate logic; bispecific antibodies; cancer immunotherapy; conditional activation; multi-signal validation; precision medicine; synthetic biology; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1845119
  34. Arthritis Rheumatol. 2026 Jun 15.
    Linking T Cell States to T Cell Receptors in Systemic Lupus Erythematosus.
    Zandra E Walton, Deepak A Rao.
      
    DOI:  https://doi.org/10.1002/art.70254
  35. Exp Hematol Oncol. 2026 Jun 18. pii: 53. [Epub ahead of print]15(1):
    Overcoming fratricide of CD86 targeting CAR-T cells by defined logic-gate CAR strategy.
    Tobias Riet, Simon Lennartz, Niklas Bösing, Lars Fabian Prinz, Luise Dähn, Christof Scheid, Michael Hallek, Markus Martin Chmielewski.
      Despite its remarkable success in the treatment of several hematological malignancies, cellular immunotherapy using chimeric antigen receptor (CAR) T cells faces significant challenges when treating refractory/relapsed or myeloid malignancies such as AML, CML or multiple myeloma. To overcome the pronounced heterogeneity of such diseases, the search for suitable tumor-associated antigens recently led to surface antigens of the B7 protein family as potential CAR-T cell targets. Using the example of CD86-targeting, we highlight a considerable pitfall of CAR-T therapy which utilizes B7-family proteins as a prominent group of T cell (activation) associated antigens. In a consistent set of in vitro and in vivo experiments we could demonstrate that fratricide among pre-activated CD86-specific CAR-T cells strongly reduces their overall survival and efficacy in tumor killing as recently shown for B7-H3/CD276-targeting CARs. Therefore, we propose a defined combinatorial antigen recognition concept via dual-chain CAR-T cells that incorporate an "AND-gate" mechanism through CD19 primary CAR activation and CD86 conditional co-stimulation to circumvent a severely limited outcome.
    Keywords:  AND gate; CAR-T cell; CD86; Cellular immunotherapy; Dual-chain CAR; Fratricide; Hematological malignancies
    DOI:  https://doi.org/10.1186/s40164-026-00791-3
  36. Hum Vaccin Immunother. 2026 Dec;22(1): 2690841
    Knowledge mapping and research trends of chimeric antigen receptor T-cell immunotherapy in breast cancer: A bibliometric and visual analytics study.
    Yuechen Xu, Yu Xu, Zhisen Wang, Qiyi Yi, Fan Wang, Po Bian.
      Chimeric antigen receptor T cell (CAR-T) immunotherapy has achieved landmark success in hematologic malignancies and is being explored for breast cancer (BC) and other solid tumors, prompting research to improve efficacy and safety. We retrieved 894 related to CAR-T immunotherapy for BC from the Web of Science Core Collection and performed bibliometric analyses using CiteSpace and VOSviewer to map the research landscape, development trajectory, and key contributors. Joinpoint regression assessed temporal trends in annual publications using R 4.4.2. The USA led publication output. Institutional co-occurrence revealed the University of London and Technische Universität Dresden as central hubs. CANCER RES and FRONT IMMUNOL were identified as core journals. Darcy PK and Morgan RA were prominent authors by output and citations. Keyword clustering and timeline visualization indicated that the terms "in vivo," "tumor microenvironment (TME)," and "targeted therapy" have remained highly active in recent years. In addition, burst detection analysis revealed that keywords including TME, "epithelial-mesenchymal transition," and "mesothelin" have gradually emerged as research frontiers, suggesting increasing attention to resistance mechanisms and tumor immune regulation. These findings provide a systematic overview of the evolving research landscape and help identify emerging hotspots and future directions. BC remains the most frequently diagnosed malignancy among women worldwide and a major cause of cancer-related death. We systematically mapped the knowledge structure and development trends of CAR-T research in BC, identifying major research contributors and emerging research hotspots, which may provide valuable insights for future basic research and clinical exploration in this field.
    Keywords:  Chimeric antigen receptor T cells; CiteSpace; Joinpoint regression analysis; VOSviewer; bibliometric study; breast cancer
    DOI:  https://doi.org/10.1080/21645515.2026.2690841
  37. J Med Internet Res. 2026 Jun 15. 28 e80178
    Integration of Federated Learning and Blockchain in Health Care: Tutorial on Medical Data, Architectures, Privacy, Security, and Regulatory Compliance.
    Yahya Shahsavari, Yaser Baseri, Abdelhakim Hafid, Oussama Abderrahmane Dambri, Dimitrios Makrakis.
       Unlabelled: The convergence of artificial intelligence (AI), blockchain technology, and health care represents one of the most transformative yet technically challenging frontiers in computational medicine. As health care systems adopt data-driven paradigms for precision medicine and clinical decision support, the need for secure, privacy-preserving, and collaborative learning frameworks has become critical. This tutorial introduces a comprehensive, clinically oriented, and compliance-aware framework integrating federated learning (FL) and blockchain for secure and privacy-preserving health care analytics. FL enables collaborative training across distributed institutions without raw data sharing, in alignment with privacy regulations such as the Health Insurance Portability and Accountability Act (HIPAA) and the General Data Protection Regulation (GDPR). However, FL remains vulnerable to model poisoning and gradient leakage. To address these risks, we introduce blockchain-based FL (BCFL), which leverages blockchain's immutable ledger and decentralized consensus to enhance trust, verifiability, and auditability. The tutorial's main contributions include (1) a taxonomy of diverse medical data types and their FL requirements; (2) three integration architectures (fully coupled, semicoupled, and loosely coupled) analyzed for security, scalability, and regulatory compliance; (3) a security analysis of health care-specific vulnerabilities and mitigation strategies using advanced cryptography, such as zero-knowledge proofs, homomorphic encryption, and differential privacy; and (4) a regulatory compliance framework addressing HIPAA, GDPR, and United States Food and Drug Administration guidelines for AI-enabled medical devices. We demonstrate BCFL's relevance across major health care applications, including disease prediction, medical imaging, patient monitoring, and drug discovery, and highlight emerging research directions such as quantum-resilient cryptography, scalable interoperability, and automated compliance. This tutorial serves as a foundational resource for advancing secure, compliant, and collaborative AI in health care; fostering privacy-preserving analytics; and improving patient outcomes.
    Keywords:  HIPAA compliance; IoT health care; blockchain technology; health care security; machine learning; medical data privacy
    DOI:  https://doi.org/10.2196/80178
  38. Cytokine Growth Factor Rev. 2026 Jun 01. pii: S1359-6101(26)00042-0. [Epub ahead of print]90 51-69
    Designing next-generation interleukin immunotherapy: A cytokine-guided framework for precision cancer therapy.
    Chunhui Wang, Wenxue Ma, Xiaohan Wang, Yimin Xu, Sanxiong Huang.
      Interleukins (ILs) are powerful regulators of anti-tumor immunity, yet their clinical impact in cancer has remained limited despite decades of therapeutic development. Although first-generation cytokines such as IL-2 established proof-of-principle for cytokine-driven cancer immunotherapy, their broader clinical translation was constrained not by insufficient immunostimulatory potency, but by imprecise deployment, including poor receptor selectivity, systemic exposure, and inadequate alignment with tumor immune context. Despite major advances in cytokine engineering, clinical benefit has continued to lag because cytokine deployment remains insufficiently matched to receptor biology, spatial pharmacology, and immune-state architecture. In this Review, we examine how next-generation interleukins, particularly IL-15, IL-21, and IL-10, are redefining cytokine therapy through functionally specialized roles in sustaining cytotoxic persistence, preserving effector competence, and rewiring suppressive immune states. We synthesize emerging strategies in receptor-biased engineering, spatially restricted delivery, and context-matched combination design, and propose a cytokine-guided framework that integrates receptor logic, delivery geometry, immune-state matching, and biomarker-informed deployment. We further argue that the principal barriers to clinical translation are no longer primarily molecular, but translational, including biomarker insufficiency, trial misalignment, tissue-level resistance, and patient heterogeneity. Overall, next-generation interleukins are best understood not as stronger cytokines, but as more precisely deployable immunotherapeutic modules for durable and rational cancer immunotherapy.
    Keywords:  Cytokine engineering; Cytokine-guided design; Interleukin immunotherapy; Precision immunotherapy; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2026.05.004
  39. J Med Ethics. 2026 Jun 17. pii: jme-2026-111969. [Epub ahead of print]
    Not all personal utilities are equal: a two-tier normative framework for genomic health technology assessment.
    Johnny Sakr.
      Health technology assessment (HTA) bodies are increasingly asked to consider the personal utility of genomic testing: the informational, practical and psychosocial value of results beyond direct changes in clinical management. Yet treating all non-clinical benefits as normatively equivalent risks obscures the distributive task of publicly funded HTA, while refusing to consider them at all ignores forms of value that may bear on rights, equity and system design. This article offers a decision-structuring framework that distinguishes between discretionary personal utility and justice-based personal utility. The framework is expressly residual: where a benefit can already be captured through conventional HTA domains, such as health-related quality of life, avoided downstream costs, caregiver effects or standard clinical utility, it should be counted there rather than relabelled as personal utility. I then identify a third category, derivative value, for constructs such as hope value and option value whose realisation depends on future scientific, institutional or policy contingencies external to the patient. The framework does not supply an algorithm for reimbursement. Instead, it clarifies burden of justification, guards against double-counting and helps HTA bodies separate patient-indexed claims from broader public-value arguments. Applied to diagnostic genomic testing for childhood hearing impairment, the framework shows how some commonly invoked benefits are better treated as discretionary, others as justice-relevant and others as requiring separate policy justification. I conclude with practical steps that analysts and policy leaders can adopt now: residual-domain mapping, non-duplication checks, structured scenario analyses and deliberative documentation of contested classifications.
    Keywords:  Distributive Justice; Ethics; Resource Allocation
    DOI:  https://doi.org/10.1136/jme-2026-111969
  40. MDM Policy Pract. 2026 Jan-Jun;11(1):11(1): 23814683261447231
    Evaluating the Impact of Different Natural History Modeling Methods on Cost-Effectiveness Decisions: A Case Study in Duchenne Muscular Dystrophy.
    Jonathan Broomfield, Keith R Abrams, Michael J Crowther, Michela Guglieri, Nicholas R Latimer, Mark J Rutherford.
      Introduction. Cost-effectiveness analyses are vital in guiding decisions on treatment reimbursement. Natural history models are central to these, enabling the estimation of long-term costs and quality-adjusted life-years (QALYs) in the absence of lifetime trial data. Rare disease data are often scarce, resulting in disease progression being estimated through clinical assumptions. This study aims to evaluate how different modeling approaches influence cost-effectiveness estimates in rare disease health technology assessments (HTAs), using Duchenne muscular dystrophy (DMD) as a case study. Methods. A published economic model was used to compare 2 approaches for estimating disease progression: an assumption-based method relying on clinical plausibility and data-driven methods using data from 1,005 patients with DMD across 8 studies. Transition probabilities were estimated assuming increasing flexibility of study heterogeneity and compared with a simulated treatment cohort. Models were evaluated by comparing incremental cost-effectiveness ratios (ICERs) across approaches. No gold standard exists, so the plausibility of predictions was evaluated by comparing survival and disease progression estimates to published milestones. Results. Results showed that although the assumption-based model was clinically plausible, it predicted higher QALY gains (0.77) and lower ICERs (£1.96M per QALY) than data-driven methods did, which estimated QALY gains of 0.25, 0.26, 0.27, and 0.28 and ICERs of £6.2M, £6.2M, £5.8M, and £5.7M per QALY for the least to most flexible models, respectively. Limitations. No covariate effects or updated cost and utility data were incorporated, as the study purpose was a methodological comparison between approaches. Analyses were deterministic not probabilistic. Conclusions and Implications. This study emphasizes the critical role of model selection for HTA in rare diseases, showing that cost-effectiveness estimates from robust data-driven approaches can differ from clinically plausible assumption-based models.
    Highlights: The choice of a natural history modeling method can drastically alter the cost-effectiveness results in rare disease evaluations.A case study in Duchenne muscular dystrophy demonstrates how different modeling approaches yield divergent cost-effectiveness outcomes.Assumption-based models, even when clinically plausible, may underestimate measures of cost-effectiveness and result in less reliable guidance for decision makers.Data-driven models using real-world patient data provide more reliable estimates for health technology assessment (HTA).This study offers practical guidance for analysts and HTA bodies on selecting robust modeling approaches in rare disease contexts.
    Keywords:  Duchenne muscular dystrophy; economic evaluation; rare diseases
    DOI:  https://doi.org/10.1177/23814683261447231
  41. Blood Cancer J. 2026 Jun 20.
    The search for safe and effective CAR-T targets in AML.
    Florian Van Oers, Donovan Flumens, Simon Haentjens, Laurens Krekelbergh, Sébastien Anguille.
      Acute myeloid leukemia (AML) remains a highly aggressive malignancy with limited therapeutic options and poor long-term survival. A major barrier to curative treatment is the persistence of leukemic stem cells (LSCs), a chemo-resistant population that drives relapse. Chimeric antigen receptor (CAR)-T-cell therapy has transformed the treatment of B-cell hematological malignancies. However, its application in AML has been met with significant challenges. Among the key challenges are the scarcity of AML-specific antigens and the risk of on-target/off-tumor toxicity due to shared antigen expression on normal hematopoietic stem cells (HSCs) and/or mature blood cells. Early clinical trials of CAR-T-cell therapy in AML -primarily targeting CD123, CD33, or CLL‑1- have demonstrated limited durable complete remissions and/or frequent myeloablation, underscoring the need for more selective targets. While other targets show more restricted expression profiles, they are often expressed only in a small subgroup of AML patients. In this review, we systematically evaluated 63 AML-associated antigens for which CAR constructs have been reported, using five criteria: (1) homogeneous expression across AML patients, (2) uniform expression on AML cells within individual patients; (3) presence on LSCs, (4) absence on normal HSCs, and (5) no or acceptable expression on mature blood cells. Applying a 20-point scoring framework, 13 novel antigens emerged as the most promising candidates for CAR-T-cell therapy in AML: ADGRE2, SIGLEC-6, IL1RAP, MUC1, CCR1, CD155, CD70, LILRB4, GRP78, CD37, ITGB2, TIM-3 and mesothelin. We discuss the advantages and limitations of each target, along with strategies to mitigate associated risks. With no CAR-T-cell therapy currently approved for AML, this comprehensive review provides a prioritized antigen landscape and a framework to guide the rational design of next-generation CARs for this challenging malignancy.
    DOI:  https://doi.org/10.1038/s41408-026-01544-5
  42. Front Med (Lausanne). 2026 ;13 1839531
    Why advanced therapy medicinal products struggle in clinical translation: an in-depth analysis of developmental challenges in the EU.
    Charlotte Van Isterdael, Edurne Mugarza, Piret Fischer, Koen Debackere, Peter Vandenberghe, Silvia Martin Lluesma, Johan Van Eldere, Isabelle Huys.
      Advanced Therapy Medicinal Products (ATMPs) can offer unprecedented therapeutic benefit for patients with limited treatment options. However, their clinical translation and early-stage clinical development remain highly complex, particularly for academic developers and small- and medium-sized enterprises (SMEs). This study presents a comprehensive analysis of the different types of challenges that ATMP developers face in initiating clinical trials, based on a scoping literature review, conducted according to the JBI methodology for scoping reviews and reported according to PRISMA-ScR. PubMed, Embase and Scopus were searched for peer-reviewed literature covering the last decade, focusing on publications discussing regulatory challenges for ATMP developers at the stage of clinical trial initiation. Our findings show that key challenges exist in four areas, comprising (a) preclinical evidence and product characteristics, (b) cell sourcing and manufacturing, (c) clinical trials and (d) regulatory landscape. Early engagement with regulators and the availability of up-to-date guidance documents emerged as key strategies to align developer efforts with regulatory expectations, while the review also identifies practical recommendations to support more efficient and harmonized clinical translation. In line with the objectives of JOIN4ATMP, these insights are valuable for developers and informative for regulators to foster more efficient and aligned ATMP development pathways.
    Keywords:  advanced therapy medicinal product (ATMP); cell and gene therapy (CGT); clinical translation; regulatory challenges; scoping review
    DOI:  https://doi.org/10.3389/fmed.2026.1839531
  43. Eur J Immunol. 2026 Jun;56(6): e70205
    T Cell Exhaustion as a Regulated Differentiation Programme.
    Marc Veldhoen, Cristina Ferreira.
      T cell exhaustion is now recognised as a structured, antigen-driven differentiation programme rather than a state of cellular fatigue. Under sustained antigen exposure, CD8+ T cells progress through distinct, hierarchically organised differentiation states, initiated by progenitor exhausted cells (TPEX), which retain self-renewal, multipotency, and responsiveness to immune checkpoint blockade. Continued stimulation drives differentiation into intermediate (TEXint) and terminally exhausted (TEX term) states, with TEXint retaining greater effector capacity than TEXterm despite both exhibiting restraint relative to functional effector T cells, alongside increasingly consolidated epigenetic architecture. Rather than reflecting immunological failure, exhaustion preserves long-term antigen surveillance while limiting tissue damage. Convergence between exhaustion-associated transcriptional modules and tissue-resident memory (TRM) programmes highlights shared mechanisms of adaptation to restrictive microenvironments. Yet TRM and TEX arise in distinct contexts and are not interchangeable. Recognising exhaustion as a context-dependent differentiation process reframes therapeutic strategies, in line with current evidence indicating that immune checkpoint blockade primarily acts by expanding and redirecting the TPEX pool rather than reversing terminal exhaustion. This framework integrates insights from chronic infection, tumour immunology, and tissue adaptation.
    DOI:  https://doi.org/10.1002/eji.70205
  44. J Comp Eff Res. 2026 Jun 19. e260110
    Most-Favored-Nation pricing meets Joint Clinical Assessment: early evidence of compounding pressure on European drug launches.
    Sreeram V Ramagopalan, Michael L Ryan.
      
    Keywords:  EU Joint Clinical Assessment; Most-Favored-Nation pricing; advanced therapy medicinal products; international reference pricing; market access; oncology; pharmaceutical launches; rare diseases
    DOI:  https://doi.org/10.57264/cer-2026-0110
  45. Ther Adv Med Oncol. 2026 ;18 17588359261457552
    Cytokine release syndrome in solid tumours: mechanism-based therapeutic strategies for prevention and management.
    Federico Monaca, Rachel Woodford, Kroopa Joshi, Fiona Thistlethwaite, Kok Haw Jonathan Lim, Igor Gomez-Randulfe.
      Cytokine release syndrome (CRS) represents a spectrum of immune hyperactivation initiated by rapid T-cell engagement and amplified through innate immune cells, particularly monocytes and macrophages, with downstream cytokine cascades driving endothelial dysfunction, capillary leak and organ impairment. CRS is a frequent, class-associated toxicity of T-cell-engaging immunotherapies and is being observed with increasing regularity as T-cell-redirecting therapies progress through clinical development in solid tumours. Although CRS is typically less severe in patients with solid tumours relative to those with haematological malignancies, phase II-III trials of these emerging agents consistently report grade 1-2 CRS in the majority of patients, highlighting the need for effective prevention and management strategies, while preserving anti-tumour activity of the primary therapy. Current grading and management algorithms have been largely extrapolated from experience with chimeric antigen receptor T-cell therapies and rely on step-up dosing, premedication, supportive care and escalation to interleukin (IL)-6/IL-6R blockade and corticosteroids. However, steroid-refractory or high-grade CRS, as well as overlapping syndromes underscore the limitations of this approach and the need for mechanism-based interventions targeting upstream mediators and signalling hubs. These include IL-1 blockade, Janus kinase-signal transducer and activator of transcription inhibition, granulocyte-macrophage colony-stimulating factor neutralisation, tumour necrosis factor-alpha inhibition and interferon gamma blockade. In this narrative review, we synthesise the mechanistic rationale and emerging clinical evidence underpinning CRS prevention and management in solid tumours, with a particular focus on T-cell engager (TCE) and other T-cell-redirecting therapies. We then outline key risk-mitigation strategies and discuss their potential implications for anti-tumour immunity. Finally, we highlight key knowledge gaps, particularly the paucity of prospective solid tumour-specific data, with current CRS prevention and management strategies therefore remaining largely extrapolated from haematological malignancies, alongside the need for biomarker-driven risk stratification, optimal sequencing and prophylactic strategies and the development of next-generation TCE designs.
    Keywords:  T-cell engagers; T-cell-redirecting therapies; cytokine release syndrome; immune-effector cell-associated toxicities; solid tumours
    DOI:  https://doi.org/10.1177/17588359261457552
  46. Curr Mol Med. 2026 Jun 10.
    Immunometabolic Reprogramming: A New Frontier in Cancer Immunotherapy.
    Saeed Mohammadi, Mahmoud Darweesh, Mina Rahmati, Moosa Al-Hamadani, Milad Ahmadaghdami, Ahmed Al-Harrasi.
      The interaction between cellular metabolism and immune function, termed immunometabolism, has been regarded as a crucial determinant of anti-tumor immunity and the efficacy of cancer immunotherapy. Understanding the metabolic dependencies and vulnerabilities of various immune cell subsets and cancer cells is enabling researchers to study novel therapeutic strategies. These strategies aim to reprogram the metabolic landscape of the TME to enhance stronger anti-tumor immune responses and overcome resistance to current immunotherapies. This review provides a comprehensive overview of the fundamental principles of immunometabolism, detailing the key metabolic pathways and regulators in immune and cancer cells. We explore the distinct metabolic profiles of various immune cell subsets and how they are altered during an anti-tumor response. Furthermore, we discuss the metabolic hallmarks of cancer cells, considering variations across different cancer types. Then, we discuss how current immunotherapies, such as checkpoint inhibitors and CAR-T cell therapy, impact and are influenced by cellular metabolism. Finally, we highlight promising therapeutic opportunities for targeting immunometabolism, including metabolic inhibitors, modulators, and combination strategies. This review aims to introduce immunometabolic reprogramming as a new frontier to enhance the efficacy of cancer immunotherapy and improve patient outcomes.
    Keywords:  CAR-T engineering; Immunometabolism; cancer heterogeneity; checkpoint blockade; metabolic reprogramming; precision oncology.; tumor microenvironment
    DOI:  https://doi.org/10.2174/0115665240435650260516221100
  47. Immunotherapy. 2026 Jun 13. 1-13
    From blood draw to tumor infiltration: therapeutic variations in CAR-macrophage therapy for solid tumors.
    Mohsen Ghasem Zadeh Soroush, Alieh Mirzaei, Mahan Ranjbar, Mobin Mohammadi, Arman Baghbanzadeh, Shayesteh Kokabi Hamidpour, Seied Asadollah Mousavi, Mostafa Rezaei-Tavirani, Babak Arjmand.
       INTRODUCTION: Engineering CAR-macrophages (CAR-Ms) has revolutionized the solid tumors immunotherapy, due to intrinsic anti-tumor capacity, phagocytosis ability, and immunomodulatory effects of macrophages in tumor microenvironment (TME) remodeling.
    METHODOLOGY: A literature review was conducted using databases including PubMed, Google Scholar, and Scopus. The data was extracted using relevant articles published from 1991 to 2026 based on key words such as Chimeric Antigen Receptor Macrophages, CAR-M, Immunotherapy Resistance, Solid Tumors, and Tumor Microenvironment.
    AREAS COVERED: CAR-Ms originate from different sources, but in turn come with distinct advantages and challenges regarding scalability, polarization capacity, phenotype shift, antigen escape, and functional stability. Genetic engineering techniques are essential to increase CAR-M efficacy. Along with intrinsic engineering, the integration of CAR-Ms with chemotherapy, radiotherapy, immune checkpoint inhibitors, and new methods, such as nanomedicine, enhances antitumor effects by modulating TME barriers and abrogation of immune evasion mechanisms.
    EXPERT OPINION/COMMENTARY: CAR-m therapy is represented as a promising next-generation treatment for solid tumors, due to its strength to overcome the challenges of lymphocyte approaches. However, TME polarization and variability in patient response should be considered to achieve optimal efficacy. Future advancements should improve signaling design, integration of novel immunologic methods, TME modulation, and biomarker-guided patient stratification.
    Keywords:  CAR-M; Chimeric antigen receptor macrophages; immunotherapy resistance; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.1080/1750743X.2026.2688710
  48. Value Health. 2026 Jun 13. pii: S1098-3015(26)02485-X. [Epub ahead of print]
    Development and Validation of an AI Tool for Automated PICO Scoping for the European Joint Clinical Assessment (JCA): A Proof of Concept.
    Bart-Jan Boverhof, Nikos Takatzoglou, Ken Redekop, Carin Uyl-de Groot, Jacob Jan Visser, Maureen Rutten-van Mölken Phd.
       OBJECTIVE: The European Union Health Technology Assessment regulation (EU-HTAR) requires laborious PICO scoping (Patient population, Intervention, Comparator, Outcome) and consolidation across member states during joint clinical assessments (JCAs). We developed a tool to automate PICO extraction from HTA documents and clinical guidelines.
    METHODS: We developed a proof-of-concept AI pipeline using retrieval-augmented generation and large language models to process documents, translate to English, extract PICOs, and consolidate findings. The system was validated using two oncology cases from non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). We curated datasets for both cases, comprising 49 reports totalling 5,463 pages from 16 unique countries. Performance was assessed using recall (sensitivity) & precision (positive predictive value) and compared against human data extraction.
    RESULTS: The AI system demonstrated strong recall performance, achieving 0.807 for NSCLC and 0.837 for HCC. The AI outperformed human extraction in the NSCLC case (0.81 versus 0.71 recall) while matching human performance in HCC (0.84 versus 0.81). Extraction of the comparator element showed high recall (0.911 NSCLC; 0.967 HCC). The AI pipeline required 96 minutes of computational time beyond translation, saving approximately 25 hours of human screening work.
    CONCLUSIONS: We showed that AI-based PICO extraction was feasible and valuable in two use-cases. The system showed good recall and had the potential to reduce workload in the JCA. It may be useful for the assessors and co-assessors in the EU-HTAR process, the industry in gaining insight into PICO expectations, and national HTA bodies in understanding the expected PICO wishes of other nations.
    Keywords:  AI; Automation; European Union HTA Regulation (EU-HTAR); Generative-AI; Joint Clinical Assessment (JCA); LLMs; PICO scoping
    DOI:  https://doi.org/10.1016/j.jval.2026.05.009
  49. J Neuroimmunol. 2026 Jun 12. pii: S0165-5728(26)00152-9. [Epub ahead of print]419 579003
    Pre-infusion quantitative EEG features associated with delayed neurocognitive impairment following CAR T-cell therapy.
    Laura Lopez-Viñas, Victoria Fernández Sánchez, Pablo Cabezudo-García, Carolina Díaz Aizpun, Marina Gómez-Villaboa, María José Postigo Pozo, Pedro J Serrano-Castro, Jose Luis Ayala Rodrigo.
      Immune effector cell-associated neurotoxicity syndrome (ICANS) is a frequent and potentially severe complication of chimeric antigen receptor (CAR) T-cell therapy, reflecting complex interactions between the immune system and the central nervous system. Reliable baseline biomarkers capable of identifying patients at increased risk of late post-infusion neurological impairment within the first 10 days after CAR T-cell therapy remain limited. We conducted a prospective single-center study to evaluate whether pre-infusion quantitative electroencephalography (qEEG) features are associated with subsequent neurological impairment following CAR T-cell therapy. Fifteen adults with relapsed or refractory lymphomas underwent baseline EEG recordings 2-5 days before infusion. Quantitative analyses included relative spectral power, slow-to-fast frequency ratios, interhemispheric symmetry, and coherence. Supervised classification models were used as exploratory analyses to assess the association between baseline qEEG parameters and neurological outcomes during early (≤5 days) and late (>5 days) post-infusion phases. Baseline qEEG features showed no relevant association with early neurological outcomes. In contrast, pre-infusion increases in delta-to-alpha and delta-to-beta ratios, predominantly in right temporoparietal regions, were associated with later neurological impairment, particularly language disturbances, numerical counting impairment and, less consistently, disorientation and reduced collaboration. Exploratory classification metrics for selected cognitive-language domains were higher than those observed for global ICANS classification or cytokine release syndrome, supporting a possible relative specificity for neurotoxicity-related processes. These findings suggest that baseline qEEG markers of regional cortical slowing may reflect underlying neuroimmune vulnerability and may be associated with later neurocognitive impairment after CAR T-cell therapy. Quantitative EEG may therefore contribute to early risk stratification and neuroimmunological monitoring strategies in patients undergoing immune effector cell therapies.
    Keywords:  CAR T-cell therapy; ICANS; Neuroinflammation; Neurotoxicity; Quantitative EEG
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.579003
  50. Front Immunol. 2026 ;17 1806850
    T cell decision-making decodes the dynamic antigenic landscape.
    Inbal Eizenberg-Magar, Lior Dayan, Benny Chain, Yaron E Antebi.
      The adaptive immune system continuously encounters antigens from a wide range of sources, including pathogens, self-tissues, tumors, and environmental agents. While extensive studies have characterized how lymphocytes respond to antigen binding, most experimental frameworks consider the antigenic environment as static. In reality, antigen levels can fluctuate dramatically across a wide range of temporal and spatial scales. In this review, we examine how the dynamics of antigen presentation, ranging from molecular binding events to organism-level exposure, affect T cell activation and fate. We discuss the cellular and molecular mechanisms that allow T cells to detect and respond to changes in antigen concentration over timescales from seconds to days. These include kinetic proofreading of TCR signaling, frequency-dependent decoding in intracellular signaling networks, and population-level feedback circuits involving effector and regulatory T cells. Theoretical and experimental evidence suggests that T cells are tuned not only to antigen quantity but also to its rate of change, with implications for tolerance, immune activation, and memory formation. We highlight how manipulating the dynamics of antigen exposure, such as through controlled vaccine delivery, can modulate immune responses and suggest that incorporating temporal features into immunological models may improve our understanding of immune decision-making and inform therapeutic strategies.
    Keywords:  T cell activation; T cell receptor signaling; antigen dynamics; immune decision; kinetic proofreading; signal decoding; systems immunology; temporal signal processing
    DOI:  https://doi.org/10.3389/fimmu.2026.1806850
  51. Biochem Pharmacol. 2026 Jun 15. pii: S0006-2952(26)00506-X. [Epub ahead of print]251(Pt 2): 118168
    Phenotypic response surfaces in pharmacology: Mechanistic and translational perspectives on optimizing drug combination therapies.
    Adnan Amin, Atif Ali Khan Khalil, Muhammad Saeed Akhtar, Sajid Ali, Wajid Zaman.
      Combination drug therapies are central to the treatment of diseases with multifactorial etiology, including cancer, infectious diseases, and autoimmune disorders. Despite their widespread use, optimizing drug combinations remains challenging because of complex pharmacokinetic and pharmacodynamic interactions and substantial inter-patient variability. Phenotypic Response Surfaces (PRS) have emerged as a computational framework for mapping multidimensional drug-dose response landscapes while accounting for patient-specific biological and clinical factors. However, current PRS-oriented approaches vary considerably in how molecular, biochemical, and clinical determinants are incorporated into response models. In this review, we critically evaluate the mechanistic foundations of PRS-based methods for optimizing drug combinations. Particular emphasis is placed on how structural biology, biomarker-defined target dependence, and pharmacokinetic/pharmacogenetic models can be linked to response-surface frameworks to improve mechanistic interpretability and patient-specific dose optimization. We also examine recent advances in artificial intelligence (AI) platforms that support phenotypic optimization across multiple therapeutic areas. Although these approaches show promise, current PRS applications remain limited by challenges in integrating multi-omics data, parameterizing drug exposure and target engagement, validating model transportability across patient populations, and translating predictive models into clinical practice. Overall, PRS represents a promising framework for combination-therapy optimization, but its clinical utility will depend on more rigorous integration of molecular mechanism, exposure-response relationships, and biomarker-constrained modeling.
    Keywords:  Autoimmune diseases; Cancer therapy; Drug dosing optimization; Personalized combination therapy; Phenotypic response surfaces; Precision medicine
    DOI:  https://doi.org/10.1016/j.bcp.2026.118168
  52. Br J Haematol. 2026 Jun 15.
    Safety profile of chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma: A systematic review and meta-analysis of proportions from clinical trials.
    Charalampos Filippatos, Ioannis Ntanasis-Stathopoulos, Areti Voulomenou, Panagiotis Malandrakis, Efstathios Kastritis, Maria Gavriatopoulou, Meletios-Athanasios Dimopoulos, Evangelos Terpos.
      
    Keywords:  CAR T; RRMM; adverse events; cilta‐cel; ide‐cel; safety
    DOI:  https://doi.org/10.1111/bjh.70624
  53. J Transl Med. 2026 Jun 18.
    Computational prediction of TCR cross-reactivity: principles, challenges and translational opportunities.
    Wenzhen Li, Yu Pan, Xu Wu, Yuting Song, Yin Wang, Lu Xie.
      T-cell receptor (TCR) cross-reactivity, whereby a single TCR recognizes multiple peptide-MHC (pMHC) ligands, is essential for immune surveillance but also represents a major safety challenge for TCR-based therapeutics because of severe off-target toxicities. Rapid advances in immune-repertoire sequencing, structural biology, and immunopeptidomics have accelerated computational efforts to characterize cross-reactive recognition at scale. However, most existing methods are adapted from conventional TCR-pMHC specificity prediction and remain insufficiently aligned with the one-to-many, structurally plastic, and context-dependent nature of cross-reactivity. Here, we review the main data resources supporting TCR cross-reactivity modeling, including sequence- and structure-centric databases, and highlight persistent limitations, such as scarce explicitly annotated cross-reactive TCRs, strong biases toward viral epitopes and common HLA alleles, limited paired αβ-chain information, and a lack of rigorously validated negative examples. We then compare the major computational paradigms-sequence-based, structure-based, machine-learning, and multimodal approaches-with emphasis on their respective strengths and limitations in interpretability, generalization, and scalability. Finally, we discuss emerging translational applications and outline key priorities for the field, including dedicated datasets, rigorous benchmarking, and biologically grounded multimodal models to enable safer and more clinically actionable TCR-based immunotherapies.
    DOI:  https://doi.org/10.1186/s12967-026-08476-5
  54. J Robot Surg. 2026 Jun 19. pii: 596. [Epub ahead of print]20(1):
    Rethinking health technology assessment in robotic surgery: an EFISDS-TROGSS position paper. Official position paper of the European Federation - International Society for Digestive Surgery (EFISDS) and The Robotic Global Surgical Society (TROGSS).
    Luigi Marano, Rodolfo J Oviedo, Gennaro Nappo, Francesco Paolo Prete, Beniamino Pascotto, Adel Abou-Mrad, Yogesh Vashist.
      Robotic-assisted surgery (RAS) has evolved from a procedural innovation into an increasingly integrated component of contemporary digital surgical ecosystems. Nevertheless, most current Health Technology Assessment (HTA) frameworks continue to evaluate robotic systems primarily through comparator-based models focused on isolated perioperative and oncological outcomes. In this EFISDS-TROGSS position paper, we critically examine the methodological limitations of conventional HTA paradigms when applied to robotic surgical platforms, using the recent Italian AGENAS appraisal as a representative case study. While the AGENAS document represents one of the most comprehensive national evaluations of RAS performed to date, its heterogeneous recommendations across procedures highlight unresolved tensions regarding perioperative benefit, real-world implementation, learning curves, organizational impact, and long-term healthcare value. We argue that RAS should increasingly be interpreted not simply as a surgical device, but as a platform technology interacting with simulation-based training, digital infrastructure, surgical data science, artificial intelligence, telecommunication systems, and institutional organization. Rather than a surgical device alone, RAS should be interpreted and regarded as a combination of technological advances and approaches that integrate various degrees of artificial intelligence autonomy, image navigation, telesurgery, and other benefits to empower the surgical team. Conventional HTA models, originally developed for relatively discrete therapeutic interventions, may incompletely capture the multidimensional interaction between robotic technologies and modern healthcare systems. Particular attention is dedicated to real-world evidence, implementation maturity, reimbursement limitations, and the growing mismatch between current Diagnosis-Related Group (DRG) structures and technologically integrated surgical care. Finally, we propose more flexible and multidimensional assessment frameworks integrating procedural outcomes with organizational sustainability, digital interoperability, workforce implications, and longitudinal healthcare value.
    Keywords:  Digital surgery; Health technology assessment; Healthcare systems integration; Real-world evidence; Robotic-assisted surgery; Surgical innovation
    DOI:  https://doi.org/10.1007/s11701-026-03562-8
  55. J Mater Chem B. 2026 Jun 04.
    Genetically engineered outer membrane vesicles as next-generation bionanomaterials for therapeutic and diagnostic applications.
    Xuyu Bian, Ziyan Huang, Chenhang Xu, Jiawei Yue, Yumin Wu.
      Outer membrane vesicles (OMVs), naturally released by Gram-negative bacteria, represent a unique class of bionanomaterials with inherent immunogenicity, efficient cellular delivery, and scalable production. However, their native toxicity, compositional heterogeneity, and lack of targeting specificity have hindered broader therapeutic translation. Advances in genetic engineering and synthetic biology have revolutionized OMV design, transforming these biological byproducts into highly programmable bionanomaterial platforms. This review systematically outlines the key engineering strategies for OMVs, including surface display for targeting and immunomodulation, cargo loading for encapsulating nucleic acids, proteins, and drugs, and membrane modulation for tuning stability and safety. We highlight the transformative applications of genetically engineered OMVs (geOMVs) in cancer immunotherapy, next-generation vaccines, targeted delivery, and diagnostic imaging. Finally, we discuss the critical challenges in the clinical translation-such as scalable manufacturing, safety profiling, and regulatory pathways-and propose future directions integrating synthetic biology, materials science, and artificial intelligence to realize the full potential of geOMVs as intelligent, precision therapeutic and diagnostic platforms.
    DOI:  https://doi.org/10.1039/d6tb00650g
  56. Seizure. 2026 Jun 05. pii: S1059-1311(26)00164-0. [Epub ahead of print]140 128-135
    Defining seizure freedom in epilepsy: a pragmatic literature review.
    P Boon, B Schmitz, P House, L M'Rabet, A Marcellusi, J Poza, F Sofia, P Tittensor, I Pavisic, C Vázquez Álvarez, S Sgarbi, E Stamuli, M Walker.
       INTRODUCTION: Epilepsy is a prevalent brain condition, affecting 50 million people worldwide. Achieving seizure freedom (SF) without intolerable adverse events should be the primary treatment goal. However, the lack of standardized definitions within clinical trials and regulatory and health technology assessment (HTA) evaluations, and uncertainty regarding how short‑term seizure freedom outcomes are interpreted within these contexts present significant challenges in framing consensus. This pragmatic literature review (PLR) aims to characterize how seizure freedom is defined and operationalized in clinical trials, regulatory evaluations, and HTA contexts, to inform the development of a Delphi panel questionnaire.
    METHODS: A pearl growing approach was applied. Searches were conducted across PubMed, Cochrane, ClinicalTrials.org (2019 - 2024), regulatory and Health Technology Assessment (HTA) reports, using terms related to epilepsy, anti-seizure medication (ASM), and SF. Articles reporting SF as an outcome in pharmacological epilepsy treatments were included. Data were screened, extracted, and narratively summarized.
    RESULTS: From 147 references, 25 articles were included for review following deduplication. Definitions of SF varied based on population (adult, pediatric, geriatric), seizure type (focal, generalized), clinical setting (trials, real-world studies), and data analysis method (intention to treat vs. per protocol). Variable requirements for defining SF in regulatory and HTA were also identified.
    CONCLUSION: No consensus exists regarding how seizure freedom is operationalized and reported within clinical trials and regulatory and HTA evaluations. This pragmatic literature review highlights substantial variability in definitions and measurement approaches across these contexts. The findings will be used to inform a Delphi panel exercise aimed at building expert consensus on how seizure freedom should be defined and applied in clinical trials, regulatory, and HTA settings.
    Keywords:  Epilepsy; Outcome definitions; Pragmatic literature review; Seizure freedom
    DOI:  https://doi.org/10.1016/j.seizure.2026.06.001
  57. J Transl Autoimmun. 2026 Jun;12 100379
    A symposium update on the key perspectives in systemic sclerosis and systemic lupus erythematosus.
    Yves Renaudineau, Christian M Hedrich, Jean-Charles Guery, Makoto Miyara, Jan Damoiseaux, Luc Mouthon, Gregory Pugnet, Stanislas Faguer, Antoine Delpuech, Julie Bellière, Laurent Sailler, Bénédicte Puissant, Mathieu Fusaro.
      The fourth LBMR-Tim (Toulouse Referral Medical Laboratory of Immunology) symposium was convened on December 15th, 2025, in Toulouse, France, to discuss recent advances in the understanding and management of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Pathophysiological mechanisms underlying SSc and SLE were discussed from a genetic perspective, with particular emphasis on the X-chromosomal TLR7/TLR8 locus and the interferon signaling pathway. Cellular aspects were explored, highlighting the critical roles of regulatory T cells (Tregs), exhausted T cells, macrophage polarization, and endothelial cells. At the translational research frontier, significant initiatives are underway within the framework of the European Autoimmunity Standardization Initiative (EASI) aimed at enhancing routine biomarker application for diagnosis, disease monitoring, and prognostic considerations. Emerging biomarker candidates promise potential for improving prognostic assessment and follow-up in lupus nephritis (e.g., urinary sCD163/creatinine ratio), cardiovascular complications and vasculopathy associated with SSc (e.g., dephosphorylated-uncarboxylated matrix Gla protein [dp-ucMGP] and endothelial progenitor cells), as well as therapeutic response evaluation (e.g., IGRA-PHA assays and proteomic methodologies). Therapeutically, a paradigm shift is underway with the development of efficacious mono- and multi-targeted antibody treatments alongside cellular therapies designed to eliminate B cells through chimeric antigen receptor (CAR) T cells or to re-establish immune regulation through Treg restoration. The integration of these therapeutic modalities necessitates further investigation to optimize individualized patient selection and management strategies. The multidisciplinary expert panel advocates for a comprehensive approach encompassing fundamental science, translational research, clinical expertise, and therapeutic innovation to advance in the management of these two complex syndromes.
    Keywords:  Biomarkers; CAR T cells; Genetics; Systemic lupus erythematosus; Systemic sclerosis; TLR7; Treg
    DOI:  https://doi.org/10.1016/j.jtauto.2026.100379
  58. Lancet Reg Health Eur. 2026 Aug;67 101733
    Estimation of Future Patient Populations Eligible for Radioligand Therapies in the EU and the UK: A Modelling Study.
    Uwe Holzwarth, Roberta Cirillo, Margarida Goulart, Diego Hernandez, Platon Peristeris, Andreas Poschenrieder, Panagiota Papaioannou, Panos Kanavos, Christian la Fougère, Leonhard Schaetz.
       Background: The eligible patient population for radioligand therapies (RLTs) has the potential to grow rapidly in the coming years. European healthcare systems may be ill-prepared to provide the additional treatment capacity required on top of current workload. To address this challenge, data on the size of the eligible patient pool and the potential utilisation of RLTs are needed.
    Methods: The maximum pool of patients theoretically eligible for RLTs over the next decade was estimated for the 27 EU member states (EU-27) using incidence data, and additionally for France, Germany, Italy, Spain (EU-4) and the UK using prevalence data. Conditions for which RLT are currently authorised, potential expansions of existing authorisations to earlier disease stages, and anticipated authorisations for products in development were analysed.
    Findings: Between 2025 and 2035 in the EU-27, the patient pool theoretically eligible for RLTs could increase from 11,000 to 13,000 to approximately 130,000-180,000. A scenario based on preliminary utilisation data suggests that, in the EU-4, 17,000-35,000 patients from this pool could be treated in 2030, increasing to approximately 37,000 patients by 2035.
    Interpretation: The expected uptake of RLTs in EU healthcare systems over the coming decade may overwhelm available treatment capacity, even in countries with well-developed nuclear medicine infrastructure. Efforts across all EU countries will be required to ensure adequate patient access to RLTs and to minimise health inequalities in cancer care.
    Funding: Research by WifOR was funded by Novartis Pharma AG. JRC research was covered by the European Commission's Research Framework Programmes budget.
    Keywords:  Cancer; Nuclear medicine; Patient numbers; Radioligand therapy; Treatment capacity
    DOI:  https://doi.org/10.1016/j.lanepe.2026.101733
  59. Clin Cancer Res. 2026 Jun 17.
    Piggybacking Towards Progress for CAR-T Cell Therapy in Prostate Cancer.
    Patrick C Lee, Michael T Schweizer, Rosa Nadal.
      P-PSMA-101 is a first-in-class, stem cell memory T cell-enriched, PSMA-targeting CAR-T therapy. This cellular therapy showed notable clinical activity in two patients; however, PSA50 responses were generally modest. While severe immune effector-related toxicities were observed in some patients, a novel iCasp9 safety switch was largely effective in mitigating toxicity.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-26-0959
  60. Int J Hematol. 2026 Jun 18.
    Current status and challenges of TCR-T cell therapy for AML/MDS.
    Yoshiki Akatsuka.
      Although novel drugs have recently been introduced in the clinic, the survival rates of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) are not yet satisfactory; thus, developing novel strategies with different modes of action is urgently needed. Immunotherapy against AML/MDS is less feasible than that for B-cell malignancies because commonly and uniformly expressed cell-surface targets are lacking, and HLA constraints further limit patient eligibility. Careful patient selection based on high and homogeneous target antigen expression in AML/MDS cells may serve as a biomarker. In this review, we first describe T-cell receptor (TCR) T-cell therapy development processes, then review recent clinical trials and future perspectives.
    Keywords:  AML; Adoptive therapy; Gene-modified T-cell; MDS; TCR-T
    DOI:  https://doi.org/10.1007/s12185-026-04239-6
  61. Front Immunol. 2026 ;17 1839064
    CRISPR-screen informed engineered T cell therapies.
    Karrie Wong, Conor Calnan, Micah J Benson.
      Adoptive T cell therapies can deliver curative responses for refractory patients with B cell malignancies, yet clinical activity in solid tumors remains inconsistent. Tumor-intrinsic barriers dominating this inconsistency include the immunosuppressive solid tumor microenvironment (TME) imposing chronic inhibitory cues to T cells and the scarcity of patient-shared and uniformly expressed tumor-restricted antigens for T cells to target. CRISPR-based forward genetics screens enable mapping of the functional genome regulating T cell anti-tumor activity. Here, we review recent insights from pooled CRISPR knockout screens in T cells to define convergent targets and pathways regulating T cell anti-tumor function and align the pharmacology of engineered T cells with sequential barriers they encounter within the TME. We additionally propose a framework for CRISPR screen-enabled target prioritization and present an example of how these principles can be applied to the functional enhancement of T cells through TIL (Tumor Infiltrating Lymphocyte) therapy, which utilizes a patient's personalized immune response against solid tumor antigens.
    Keywords:  CRISPR; T cell; TIL; adoptive cell therapy; solid tumor
    DOI:  https://doi.org/10.3389/fimmu.2026.1839064
  62. Cancer Gene Ther. 2026 Jun 16.
    Reprogramming the tumor microenvironment via TFF3 targeting: a potential novel avenue to boost CAR-T cell therapy in solid tumors.
    Arman Rahimi, Ghasem Solgi, Mehrnoush Safarzadeh, Pantea Mohammadi, Mohsen Rastegari-Pouyani.
      CAR-T cell therapy has shown great success in hematological malignancies. However, this immunotherapeutic strategy faces critical challenges in solid tumors mainly due to the key hurdles brought about by the hostile tumor microenvironment (TME). Effective CAR-T cell therapy in solid tumors is hampered by low tumor infiltration of the administered T cells due to the dense fibrotic nature of the TME and its aberrant vasculature. Also, solid tumors shape a highly immunosuppressive milieu in which the cytotoxic activity and persistence of functional CAR-T cells are abolished. Trefoil factor family (TFF) peptides, especially TFF3, have recently drawn a lot of attention due to their pro-tumor activities. Based on the recent evidence, TFF3 is upregulated in solid tumors where it plays roles in chemotherapy resistance, increased survival, and proliferation of cancer cells, expansion of the immunosuppressive cells and enhanced angiogenesis, which contributes to the aberrant tumor vasculature. In this review, we explore how TFF3 signaling contributes to tumor progression and immune escape, and how its inhibition might reshape the tumor microenvironment (TME) to better support CAR-T cell activity. Mounting evidence suggests that blocking TFF3 could help reduce immunosuppression, restore more normal blood vessel structure, and disrupt the pro-fibrotic and tumor-promoting interactions driven by cancer stem cells (CSCs). At the same time, since TFF3 plays an important role in protecting mucosal tissues and promoting repair after injury, its inhibition needs to be approached carefully. We also discuss strategies to selectively block TFF3 within tumors while minimizing unwanted effects on healthy tissues. Gaining a deeper understanding of how TFF3 contributes to therapy resistance may open up new opportunities to enhance CAR-T cell treatment in solid tumors, either through combination therapies or as a preconditioning step before CAR-T cell infusion.
    DOI:  https://doi.org/10.1038/s41417-026-01040-9
  63. Front Immunol. 2026 ;17 1755310
    The landscape of cellular immune alteration in systemic lupus erythematosus.
    Jie Xiao, Lina Duan, Jia Yang, Yulu Deng, Shuyin Pang, Hongxia Wang, Xiaofeng Yin, Haifang Wang, Yurong Qiu, Xin Li, Ying Gong, Haixia Li.
      Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by multi-organ inflammation and profound immune dysregulation. Aberrant interactions among adaptive and innate immune cells-including T cells, B cells, dendritic cells, macrophages, neutrophils, and natural killer cells-disrupt immune tolerance and perpetuate chronic inflammation. This review provides a comprehensive overview of the dysfunctional cellular immune landscape in SLE, focusing on the pathogenic crosstalk among immune cell subsets and its contribution to disease progression. We highlight the imbalance of T cell subsets (Th1, Th17, Tfh, Treg), B cell hyperactivation, and impaired regulatory cell function. Furthermore, we discuss how excessive NETosis, type I interferon signaling, and impaired apoptotic clearance amplify autoantibody production and immune complex-mediated injury. Emerging evidence positions gut microbiome dysbiosis as a critical environmental driver of immune dysregulation in SLE, characterized by depletion of beneficial butyrate-producing commensals and enrichment of pro-inflammatory taxa. This dysbiosis contributes to disease pathogenesis through gut barrier dysfunction, molecular mimicry, and short-chain fatty acid deficiency. Finally, we examine potential therapeutic strategies, including immune checkpoint modulation, metabolic interventions, and novel cellular therapies, aimed at restoring immune equilibrium in SLE.
    Keywords:  autoantibodies; autoantigen; cellular immune; gut microbiome; immune equilibrium; systemic lupus erythematosus
    DOI:  https://doi.org/10.3389/fimmu.2026.1755310
  64. J Drug Target. 2026 Jun 17. 1-51
    Nanomaterials for Subcellular Organelle Targeting: Unlocking New Avenues for Enhanced Therapeutic Effectiveness.
    Kiarash Solouki, Muhammad Sohail.
      Subcellular organelle targeting is changing the way nanomedicine is designed, moving the field beyond simple cellular entry toward more precise intracellular localization, controlled cargo release, and functional activity within disease-relevant compartments. This review critically discusses nanomaterial-based strategies for targeting the nucleus, mitochondria, lysosomes, endoplasmic reticulum, Golgi apparatus, and cytoskeleton-associated trafficking pathways. Its main novelty is the use of a cross-organelle, mechanism-based framework that links nanocarrier physicochemical properties with intracellular transport biology, rather than examining each organelle or delivery platform separately. Lipid nanoparticles, polymeric carriers, dendrimers, inorganic nanomaterials, biomimetic systems, and engineered extracellular vesicles are compared according to their targeting mechanisms, cargo compatibility, therapeutic potential, and translational limitations. Particular attention is given to nuclear import mediated by NLS-, CPP/TAT-, and aptamer-based strategies; mitochondrial delivery shaped by membrane potential, membrane fusion, and redox-responsive release; lysosomal targeting for pH- and enzyme-activated therapies; and ER/Golgi-directed delivery through retrograde trafficking, retention motifs, and modulation of stress-related pathways. The review also brings together several emerging directions, including stimuli-responsive release, biomimetic surface engineering, extracellular vesicle scalability, CRISPR/Cas delivery, base and prime editing, and targeted protein degradation, all of which may support more programmable forms of intracellular therapy. Importantly, it separates true organelle localization from transient trafficking or nonspecific perinuclear accumulation, emphasizing the need for stronger and more reliable validation methods. Key barriers remain, including inefficient endosomal escape, off-target intracellular accumulation, organelle-specific toxicity, long-term safety concerns, reproducibility, scalable manufacturing, and regulatory classification. Overall, this review frames organelle-directed nanomedicine as a rational design strategy for improving therapeutic precision, while also stressing that clinical translation will depend on clear evidence of durable, safe, and measurable therapeutic benefit at the organelle level.
    Keywords:  Subcellular organelle targeting; intracellular trafficking; organelle-directed nanomedicine; stimuli-responsive nanocarriers; translational nanomedicine
    DOI:  https://doi.org/10.1080/1061186X.2026.2691784
  65. Ann Hematol. 2026 Jun 18.
    Infectious toxicities associated with bispecific antibodies and CAR-T Cells in multiple myeloma: a systematic review.
    Magdalena Benda, Patrick Reimann, Wolfgang Willenbacher, Eberhard Gunsilius, Katja Weisel, Irene Strassl, Maria Theresa Krauth, Stefan Knop, Thomas Winder, Normann Steiner.
      T-cell-redirecting therapies have transformed the treatment of relapsed/refractory multiple myeloma (RRMM) but are associated with substantial infection risk. We systematically reviewed infections after CAR T-cell therapy and bispecific antibodies (BsAbs), focusing on incidence, timing, pathogens, risk factors, and prevention. Following PRISMA guidelines, we searched PubMed through May 22, 2026, and included studies reporting infectious outcomes in RRMM patients treated with CAR-T cells or BsAbs. A total of 123 predominantly early-phase, non-comparative studies were analyzed. Across BCMA-directed CAR-T products and BsAbs, infections were frequent (any-grade incidence ~ 40-80%), with highest risk early after CAR-T infusion and during the first months of BsAb therapy. Grade ≥ 3 infections were common and exceeded 50% in several BsAb cohorts. Fatal infections were less frequent but occurred across both CAR-T and BsAb studies. In randomized CAR-T trials, grade 5 infections represented a substantial proportion of treatment-related deaths. Talquetamab showed lower infection rates (47-55%) but relevant mucocutaneous toxicity. Viral and bacterial pathogens predominated; CMV reactivation, invasive fungal infections, and Pneumocystis jirovecii pneumonia, particularly without prophylaxis, were also reported. Risk factors included neutropenia, corticosteroid/tocilizumab exposure, and hypogammaglobulinemia. Antiviral and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and, most notably, immunoglobulin replacement reduced infections, though residual risk persisted. Real-world data suggest higher infection-related healthcare use and mortality with BsAbs versus CAR-T therapy. Extended dosing intervals may reduce infections, particularly severe infections, while preserving efficacy. Infectious toxicity remains a key limitation. Risk is particularly high with BCMA-targeted therapies and continuous BsAb administration. Tailored prophylaxis, early immunoglobulin replacement, and response-adapted treatment strategies, including extended dosing intervals, may improve safety and outcomes.
    Keywords:  Bispecific antibodies; CAR-T cells; Immunosuppression; Infectious complications; Multiple myeloma
    DOI:  https://doi.org/10.1007/s00277-026-07140-8
  66. Front Immunol. 2026 ;17 1826283
    The impact of gut microbiota on cervical cancer and precancerous lesions: neglected status, mechanisms, challenges, and a call to action.
    Yanfang Li, Jingrui Zhang, Songxiao Wu, Zengbin Liu, Shan Qin.
      Cervical cancer (CC) remains a major global health threat closely associated with persistent high-risk human papillomavirus (HPV) infection. Although immune checkpoint inhibitors (ICIs) have emerged as a therapeutic option, their objective response rates remain unsatisfactory. Variations in the local vaginal microbiota alone cannot fully explain inter-individual differences in HPV clearance, suggesting that additional systemic immune determinants are involved. The gut microbiota, a central regulator of host systemic immunity, can profoundly influence HPV clearance and antitumor immune responses by shaping dendritic cell (DC) function, modulating the Th1/Th2 balance, regulating regulatory T cell (Treg) expansion, and affecting natural killer (NK) cell activity. Emerging evidence indicates that specific gut microbial taxa are causally associated with HPV infection, cervical intraepithelial neoplasia (CIN), and cervical cancer, and may reshape the vaginal microecological environment and enhance immunotherapy responses. However, this dimension has long received insufficient attention. This Perspective systematically addresses four core issues: the neglected status of gut microbiota research and the functional boundaries of vaginal microecology; key mechanisms through which gut microbiota regulate HPV clearance and cervical lesion progression; major challenges restricting progress; and potential strategies for promoting clinical translation. This work aims to establish a theoretical framework for gut microbiota-based interventions in cervical cancer prevention and treatment, providing directional guidance for this emerging interdisciplinary field.
    Keywords:  HPV clearance; cervical cancer; fecal microbiota transplantation; gut microbiota; immune regulation; short-chain fatty acids; vaginal microecology
    DOI:  https://doi.org/10.3389/fimmu.2026.1826283
  67. Rheumatology (Oxford). 2026 Jun 19. pii: keag317. [Epub ahead of print]
    JAK inhibitors in areas outside of inflammatory arthritis: focus on connective tissue diseases.
    Lorenza Bruno, Giacomo Cafaro, Roberto Dal Pozzolo, Valentina Valentini, Roberto Gerli, Elena Bartoloni, Carlo Perricone.
      Janus kinase (JAK) inhibitors have emerged as a transformative therapeutic class across autoimmune diseases by targeting multiple cytokine networks implicated in inflammation and fibrosis. Beyond inflammatory arthritis, increasing evidence supports their potential efficacy in connective tissue diseases such as idiopathic inflammatory myopathies, systemic sclerosis, primary Sjögren's disease, and systemic lupus erythematosus. Through modulation of type I/II interferon and interleukin signaling, JAK inhibition exerts broad anti-inflammatory and antifibrotic effects, translating into clinical improvements in cutaneous, articular, and pulmonary domains. Early clinical trials and real-world data confirm meaningful responses in refractory disease, though randomized evidence remains limited. Overall, JAK inhibitors represent a promising, mechanistically grounded option for systemic autoimmune diseases, with ongoing studies expected to refine selectivity, indications, and long-term safety profiles.
    Keywords:  Janus kinase inhibitors; Sjögren’s disease; autoimmunity; connective tissue diseases; dermatomyositis; interferon; polymyositis; systemic lupus erythematosus; systemic sclerosis
    DOI:  https://doi.org/10.1093/rheumatology/keag317
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