bims-carter 2026-09-13 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2026–09–13
34 papers selected by
Luca Bolliger, lxBio

Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.
CRISPR-Engineered CAR-T Cell Therapy for Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: A Review of Emerging Therapeutic Prospects.
Chimeric antigen receptor T-cell therapy in systemic lupus erythematosus: From B cell depletion to immune reprogramming.
Safety profiles of CAR-T cell therapy in systematic autoimmune diseases: a systematic review and analysis.
Emerging frontiers in adoptive cell therapies: engineering innovations, current challenges, and manufacturing perspectives.
Chimeric antigen receptor (CAR)-T cell therapy for solid tumors in pediatric patients: current breakthroughs, dilemmas, and strategies.
[CAR-T cell therapy for systemic lupus erythematosus: immune reset or an expensive attempt?]
In vivo CAR-T for solid tumors: facing all the challenges of ex vivo CAR-T and more.
Short-chain fatty acids act as metabolic and epigenetic regulators in CAR T cell therapy.
[T-cell engagers: a transformative force or a redundant option in B-cell depletion therapy for rheumatic diseases?]
iPSC-derived CAR-NK extracellular vesicles for non-small cell lung cancer: evidence, engineering, and translational barriers.
Engineered cryo-shocked tumor cells recruit T cells for lung cancer immunotherapy.
Generalized myasthenia gravis: Clinical trials to watch.
A boost for CAR T cell therapy.
NK and CIK Cells in Hematologic Malignancies: Comparative Mechanisms, Clinical Evidence, and Translational Perspectives.
Targeting splicing-derived neoantigens for precision cancer immunotherapy.
From cellular therapy to biologics: Non-viral delivery strategies for in vivo CAR-T engineering.
Nanomedicine-Empowered CAR-T Therapy for Multiple Myeloma: Toward Programmable, Durable, and Precision Immunotherapy.
Multi-Omics-Enabled Precision Strategies for Overcoming CAR-T Therapy Limitations in Gastrointestinal Malignancies.
Ecosystem-matched reprogramming of the tumor-immune microenvironment to overcome cancer immunotherapy resistance.
Barriers to Patient Referral and Completion of CAR T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma.
Power to the Tregs in transplantation tolerance in LATAM: From the basics to the bedside.
Comprehensive microRNA profiling coupled with function-based feature selection reveals a biomarker panel for predicting CAR-T cell exhaustion.
From toxicity to immunity: Evaluating CAR-T and conventional therapies in multiple myeloma through quality-adjusted life year (QALY) outcomes.
Efficacy and Safety of CAR-T Cell Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia With Central Nervous System Involvement.
Bayesian optimization for identification of optimal biological dose combinations in personalized dose-finding trials.
A Bayesian model averaging method for dose ranging studies in oncology.
Cytokine release syndrome: Inflammatory signaling, panoptosis, and therapeutic perspectives.
CART-Cell Therapy in Pediatric Acute Lymphoblastic Leukemia: A Review for General Pediatricians.
Immunometabolic Reprogramming as a Therapeutic Platform: Integrating Systems Immunology with Precision Biopharmaceutical Engineering.
Integrating Heterogeneous Real-World Cancer Data for Semantic Interoperability in Oncology and Medical Imaging: Development and Validation of the Cancer Image Europe Hyperontology.
The Application of FDA Patient-Focused Drug Development Guidance in Rare Patient Populations: Innovation and Flexibility.
TCR-JANUS engager proteins enable bispecific targeting to overcome tumor heterogeneity in TCR-T cell therapy.
Donor lymphocyte infusion as immune modulation after pediatric allogeneic transplantation.

Stem Cell Res Ther. 2026 Sep 06. pii: 309. [Epub ahead of print]17(1):

Recent advances in molecular mechanisms to improve the efficacy of CAR-T cell therapy for viral diseases, cancer, and autoimmune diseases.

Hany E Marei, Giacomo Pozzoli, Sara Caratelli, Carlo Cenciarelli.

  Chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment of hematological malignancies, yet its broader application to solid tumors, chronic viral infections, and autoimmune diseases remains constrained by antigen heterogeneity, immunosuppressive tissue microenvironments, T-cell exhaustion, limited persistence, and treatment-associated toxicities. These challenges have shifted the field from optimizing individual receptor constructs toward engineering CAR-T cells as programmable immune systems capable of adapting to diverse disease contexts. This review synthesizes recent advances in molecular engineering strategies that enhance CAR-T cell function beyond conventional receptor design. We discuss how receptor engineering, genome editing, transcriptional and epigenetic regulation, metabolic reprogramming, synthetic gene circuits, and safety-control platforms collectively reshape CAR-T cell fate, persistence, and therapeutic efficacy. Rather than functioning independently, these engineering strategies are increasingly integrated to generate context-specific cellular therapies capable of adapting to diverse disease environments, including cancer, autoimmune diseases, and chronic viral infections. We also highlight the potential for translation into clinical practice or clinical translation and discuss the major challenges associated with clinical implementation. Next-generation CAR-T therapies will increasingly integrate molecular engineering strategies or will rely on molecular engineering strategies to integrate antigen recognition, cellular fitness, immune regulation, and longevity rather than simply maximizing cytotoxic activity. Recent advances in programmable cellular engineering coupled with rigorous clinical evaluation as well as scalable manufacturing technologies or scalable manufacturing platforms in the treatment of other diseases beyond oncology will facilitate the development of safer, more durable, and broadly applicable cellular therapies.

Keywords:  Allogeneic and; Chimeric Antigen Receptor (CAR) T cells; Gene editing and synthetic immunology; Immune tolerance–engineered CAR-T therapies; Next-generation CAR design and engineering; Tumor microenvironment resistance and cellular fitness; Universal

DOI:  https://doi.org/10.1186/s13287-026-05266-0
Rev Med Virol. 2026 Sep;36(5): e70199

CRISPR-Engineered CAR-T Cell Therapy for Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: A Review of Emerging Therapeutic Prospects.

Noor Allehyani, Mohammed Alissa, Abdullah Alghamdi, Mohammed A Alshehri, Ghadah S Abusalim, Alaa S Alhegaili, Tawfiq N Juraybi, Meshari A Alsuwat.

  Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) remains a clinically challenging malignancy, particularly in recurrent or metastatic disease where durable responses to chemoradiotherapy and immune checkpoint blockade are limited. The viral aetiology of NPC provides a strong biological rationale for immune-based treatment; however, translation of chimaeric antigen receptor (CAR) T-cell therapy into this solid tumour setting is constrained by poor tumour trafficking, antigen heterogeneity, limited surface accessibility of EBV latent antigens, T-cell exhaustion, and an immunosuppressive tumour microenvironment. This review critically evaluates the emerging therapeutic prospects of CRISPR-engineered CAR-T cell therapy for EBV-associated NPC. It synthesises evidence on EBV latency biology, NPC immune evasion, solid-tumour CAR-T limitations, and genome-engineering strategies including conventional CRISPR-Cas9, base editing, prime editing, and double-strand-break-sparing targeted integration. Particular attention is given to genotoxicity, chromosomal rearrangements, chromosome loss, bystander and off-target editing, manufacturing heterogeneity, and the regulatory and biological barriers that currently separate technical feasibility from NPC-specific clinical implementation. Available clinical evidence from checkpoint blockade, EBV-specific adoptive T-cell therapy, base-edited CAR-T cells in haematologic malignancy, and early CRISPR-edited T-cell trials supports the feasibility of immune and genetic redirection but does not establish efficacy of a clinically validated CRISPR-engineered CAR-T platform for NPC. Future development should prioritise surface-accessible antigen validation, fit-for-purpose selection of editing technology, genomic safety, scalable manufacturing, and biomarker-driven early-phase trials.

Keywords:  CAR‐T cell therapy; CRISPR‐Cas9; adoptive cellular therapy; epstein‐barr virus; nasopharyngeal carcinoma; tumour microenvironment

DOI:  https://doi.org/10.1002/rmv.70199
J Transl Autoimmun. 2026 Dec;13 100394

Chimeric antigen receptor T-cell therapy in systemic lupus erythematosus: From B cell depletion to immune reprogramming.

Wei Zhao, Man Chen, Jing Long, Peihua Lu, Jingyu Jin.

  Systemic lupus erythematosus (SLE) is a complex autoimmune disease in which current immunosuppressive and biologic therapies often fail to achieve durable remission in refractory patients. The emergence of chimeric antigen receptor T-cell (CAR-T) therapy has introduced a fundamentally new therapeutic concept, shifting therapeutic strategies from transient immune suppression toward the possibility of durable immune reprogramming. Recent studies suggest that the benefit of CAR-T therapy extends beyond depletion of autoreactive B cells. By depleting disease-associated immune cell populations and promoting immune reconstitution, CAR-T therapy may contribute to immune reprogramming, providing a potential biological basis for sustained treatment-free remission. In this review, we summarize the rapidly evolving landscape of CAR-based therapies for SLE, including conventional and next-generation strategies, and discuss their mechanisms, clinical efficacy, durability, and safety. We further highlight emerging approaches aimed at improving precision, accessibility, and long-term outcomes. Rather than serving solely as a B-cell-depleting therapy, CAR-T may represent a platform for immune reprogramming. Future advances in target selection, biomarker-guided patient stratification, and engineered cellular platforms may further improve the precision and durability of CAR-based therapies, with the long-term goal of achieving durable immune reprogramming and treatment-free remission.

Keywords:  B-cell depletion; Cellular immunotherapy; Immune reprogramming; Immune tolerance; Refractory systemic lupus erythematosus

DOI:  https://doi.org/10.1016/j.jtauto.2026.100394
Immunol Res. 2026 Sep 08. pii: 104. [Epub ahead of print]74(1):

Safety profiles of CAR-T cell therapy in systematic autoimmune diseases: a systematic review and analysis.

Yan Xie, Yang Liu, Xiaoyuan Chen, Qibing Xie.

   BACKGROUND: Chimeric antigen receptors (CARs)-T cell therapy is emerging as a potent approach for autoimmune diseases. However, its application in autoimmune conditions remains limited, and safety outcomes observed in malignancies can't reliably serve as a reference. Therefore, it's necessary to summarize the safety profiles in autoimmune diseases to provide evidence for future expanding trials.
METHODS: A systematic review was conducted to analyze the CAR-T therapy safety in rheumatic diseases via database searches up to December 2025. Studies reporting safety data were included, while abstracts, reviews, and cases with malignancies were excluded. Factors associated with cytokine release syndrome (CRS) were analyzed using Firth's penalized logistic regression.
RESULTS: This study included 38 studies, involving a total of 115 patients with autoimmune disease. Severe adverse events were rare. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 70.4% and 4.3% of patients, respectively. Most CRS were low-grade. Multivariate analysis identified BCMA-targeted therapy and allogeneic CAR-T products may as independent factors associated with a reduced risk of CRS. Transient hematologic toxicity and hypogammaglobulinemia were frequently reported, with infections occurring in nearly half of the patients. However, prolonged cytopenia and severe infection were infrequent.
CONCLUSION: Based on the current available evidence, CAR-T therapy appears to have a generally manageable safety profile in autoimmune diseases, supporting its potential as a promising treatment option for patients with relapsed or refractory autoimmune diseases. However, these findings remain preliminary, and further expanded studies are warranted in the future to provide higher-level evidence.

Keywords:  Autoimmune diseases; CAR-T therapy; Safety profiles; Systematic review

DOI:  https://doi.org/10.1007/s12026-026-09828-5
Mol Biol Rep. 2026 Sep 08. pii: 1554. [Epub ahead of print]53(1):

Emerging frontiers in adoptive cell therapies: engineering innovations, current challenges, and manufacturing perspectives.

Mahdieh Sadat Hosseini Nezhad, Sarvenaz Zeighami Gol, Pouya Gharavi, Hossein Javid.

  Immunotherapy through adoptive cell therapy (ACT) has become an effective cancer treatment method, using genetically modified immune cells or immune cells grown outside the body. The ACT methods use chimeric antigen receptor T (CAR-T) cells, with proven results for blood cancers, while tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells serve as effective methods to fight against solid tumors and intracellular antigens. The current medical field uses natural killer (NK) cell-based therapies because of their natural ability to destroy cells, their lower incidence of graft-versus-host disease, and their capability to generate readily available therapeutic products through allogeneic medical procedures. The clinical utilization of ACTs has been facing multiple obstacles, stemming from antigen diversity, immune system resistance, treatment-related adverse effects, and difficulties in production. The researchers are advancing multiple solutions to resolve current challenges through developing multi-targeted receptor designs and gene-editing technologies, enhanced cell persistence strategies, and scalable manufacturing platforms. The next-generation ACT platforms will achieve improved therapeutic results through a mix of combination therapies, biomarker-driven patient selection, and advanced manufacturing technologies. Emerging areas of biological research demonstrate how adoptive cell therapies can develop into key components of precision cancer immunotherapy. In this review, we discussed the principles, benefits, and challenges of ACT, with a focus on potential solutions to overcome these obstacles.

Keywords:  Adoptive cell therapy; CAR-T cells; Clinical studies; Emerging technologies; Translational research; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1007/s11033-026-12720-y
Exp Hematol Oncol. 2026 Sep 05. pii: 88. [Epub ahead of print]15(1):

Chimeric antigen receptor (CAR)-T cell therapy for solid tumors in pediatric patients: current breakthroughs, dilemmas, and strategies.

Yumiao Mai, Ziwen Wang, Juan Wang, Mengjia Song, Tong Xiang, Yuelin He, Alex H Chang, Yizhuo Zhang.

  Chimeric antigen receptor (CAR)-T cell therapy has demonstrated substantial clinical efficacy in pediatric hematologic malignancies; however, its application in pediatric solid tumors remains investigational and is constrained by substantial biological and clinical challenges. Key barriers comprise tumor heterogeneity, antigen escape, T-cell exhaustion, physical barriers and immunosuppressive tumor microenvironment, treatment-related toxicities, and pediatric-specific considerations, including optimal dosing and potential long-term developmental sequelae. Ongoing research focuses on identifying novel target antigens, optimizing CAR architectures, genetically engineering CAR-T cells, and improving delivery strategies to address these barriers. In this review, we summarize recent advances, persistent challenges, and emerging strategies for CAR-T cell therapy in pediatric solid tumors. We also discuss rational combination strategies involving CAR-T cell therapy with chemotherapy, radiotherapy, and immune checkpoint inhibitors aimed at improving therapeutic efficacy and safety. As the field continues to evolve, advances in CAR-T cell therapy may expand therapeutic options for pediatric solid tumors, although further clinical investigation is required to establish its long-term efficacy and safety.

Keywords:  CAR-T cell therapy; Combination therapy; Immunotherapy; Pediatric solid tumors; Tumor microenvironment

DOI:  https://doi.org/10.1186/s40164-026-00822-z
Zhonghua Yi Xue Za Zhi. 2026 Sep 08. 106(33): 3438-3443

[CAR-T cell therapy for systemic lupus erythematosus: immune reset or an expensive attempt?]

R H Li, Q Fu.

In the treatment of rheumatic and autoimmune diseases in China, patients often experience relapses after discontinuing traditional immunosuppressants, and those with refractory disease continue to face the challenge of progressive organ damage. In recent years, chimeric antigen receptor (CAR-T) cell therapy has achieved breakthroughs in autoimmune diseases such as systemic lupus erythematosus (SLE). Anti-cluster of differentiation 19 (CD19) CAR-T therapy can deeply eliminate B cells, enabling some patients to maintain long-term remission without the use of immunosuppressants. This has led to the concept of "immune reset", that is, the reconstruction of the immune system starting from hematopoietic progenitor cells and the restoration of self-tolerance. Taking SLE as an example, this article analyzes the success rates and limiting factors of different CAR-T strategies in achieving immune reset, using case data from 17 clinical studies. The results show that the dual-target strategy, targeting B-cell maturation antigen (BCMA) and CD19, has clear advantages in terms of the depth and durability of immune reset, enabling some patients with refractory SLE to achieve long-term drug-free remission. However, immune reset is not universally successful, and its achievement is constrained by multiple factors, including target coverage, pre-existing organ damage, and disease-driving mechanisms. In summary, CAR-T therapy offers an effective new option with the potential for immune reset in patients with refractory SLE, but clinical application requires individualized decision-making based on the patient's specific circumstances. As evidence accumulates and technology is optimized, this strategy may become a viable option for more patients with autoimmune diseases.

DOI: https://doi.org/10.3760/cma.j.cn112137-20260407-00944
Immunotherapy. 2026 Sep 08. 1-7

In vivo CAR-T for solid tumors: facing all the challenges of ex vivo CAR-T and more.

Yulong Xia, Jintian Song, Jiong Wu.

  The emergence of in vivo CAR-T technologies has generated considerable excitement as a means of simplifying cellular immunotherapy. However, whether current in vivo CAR-T platforms are truly positioned to succeed in solid tumors remains unclear. We argue that the major limitations of CAR-T therapy in solid tumors arise from a complex interplay between biological barriers and engineering constraints. Although in vivo CAR-T platforms may simplify manufacturing, the delivery strategy itself directly influences which T-cell populations are engineered, the level and duration of CAR expression, cellular phenotype, persistence, and safety. Therefore, in vivo CAR-T therapies do not eliminate the biological barriers that restrict ex vivo CAR-T therapy, including poor trafficking, stromal exclusion, antigen heterogeneity, T-cell dysfunction, and immunosuppressive tumor microenvironment (TME). Consequently, in vivo CAR-T therapies inherit nearly all of the challenges that have restricted ex vivo CAR-T therapy while simultaneously introducing additional limitations related to CAR-T generation, persistence, and controllability. The encouraging results observed in hematologic malignancies and autoimmune diseases may therefore not predict success in solid tumors. Future advances will likely depend less on improving gene delivery and more on establishing mechanisms that support CAR-T infiltration, expansion, and persistence within tumors.

Keywords:  CAR-T expansion; In vivo CAR-T therapy; TME; persistence; solid tumors

DOI:  https://doi.org/10.1080/1750743X.2026.2728543
Mol Ther Oncol. 2026 Sep 17. 34(3): 201322

Short-chain fatty acids act as metabolic and epigenetic regulators in CAR T cell therapy.

Ming-Yang Ma, Chen-Xin Zhou, Xin-Yu Shi, Jian-Min Zhu, Cai-Wen Duan.

  Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, but its efficacy in solid tumors remains constrained by poor infiltration, metabolic stress, and limited persistence. Short-chain fatty acids (SCFAs), particularly butyrate and pentanoate, offer a way to influence CAR T metabolism and chromatin state during manufacturing. Butyrate combines class I histone deacetylase inhibition with acetyl-CoA metabolism and AMP-activated protein kinase (AMPK)-associated restraint of mTORC1, whereas pentanoate can reinforce effector programs through mTOR signaling and a distinct TCA-ATP-citrate lyase carbon-routing pathway. Direct CAR T studies and clinical associations now support the biological relevance of both metabolites, although their effects depend on dose, exposure schedule, cell composition, and experimental context. Building on their complementary actions, we propose sequential butyrate-pentanoate conditioning, with early butyrate exposure used to support oxidative and progenitor-associated features and later pentanoate exposure used to reinforce effector function. This review develops the mechanistic basis for that strategy, defines the experiments needed to distinguish cooperation from antagonism, and considers its manufacturing and translational implications.

Keywords:  CAR T; HDAC inhibition; butyrate; epigenetic reprogramming; ex vivo conditioning; mitochondrial metabolism; pentanoate; short-chain fatty acids; solid tumors; tumor microenvironment

DOI:  https://doi.org/10.1016/j.omton.2026.201322
Zhonghua Yi Xue Za Zhi. 2026 Sep 08. 106(33): 3423-3430

[T-cell engagers: a transformative force or a redundant option in B-cell depletion therapy for rheumatic diseases?]

Q B Li, X Guan, C L Mei, Jason Xu.

The treatment of rheumatic diseases (RMD) is still challenged by long-term treatment dependence and refractory relapses. Therapeutic goals are therefore shifting from suppression of inflammation toward deep B-cell depletion and immune resetting. Conventional B-cell-depleting monoclonal antibodies have insufficient capacity for tissue B-cell depletion. Autologous chimeric antigen receptor T-cell (CAR-T) therapy has shown the potential for deep immune reconstitution, but its clinical use is constrained by individualized manufacturing, lymphodepleting conditioning, cost, and safety-management requirements. T-cell engagers (TCE) simultaneously bind cluster of differentiation (CD) 3 on T cells and target antigens on B cells or plasma cells. They redirect endogenous T cells to eliminate pathogenic target cells. TCE can offer the advantages of standardized manufacturing, no requirement for ex vivo cell preparation, and flexible adjustment of dose and treatment duration. Focusing on the latest advances in TCE therapy for rheumatic diseases, this review systematically summarizes studies targeting CD19, CD20, and B-cell maturation antigen (BCMA). Available evidence indicates that TCE can rapidly deplete B cells or plasma cells in systemic lupus erythematosus, systemic sclerosis, idiopathic inflammatory myopathies, and rheumatoid arthritis, and may reduce disease activity and promote remission. The main adverse events include cytokine release syndrome, infections, and hypogammaglobulinemia, most of which appear manageable. Accordingly, the clinical value of TCE in rheumatic diseases is becoming increasingly apparent. However, several key issues remain to be resolved, including the depth of tissue B-cell depletion, the quality of immune reconstitution, endogenous T-cell fitness, mechanisms of inadequate response, and long-term safety. TCE therapy is neither a costly duplication of existing B-cell-depleting therapies nor a definitive solution for immune resetting. Rather, it represents a more accessible and clinically manageable therapeutic approach that may offer a practical route toward immune resetting in RMD.

DOI: https://doi.org/10.3760/cma.j.cn112137-20260330-00853
Front Immunol. 2026 ;17 1934758

iPSC-derived CAR-NK extracellular vesicles for non-small cell lung cancer: evidence, engineering, and translational barriers.

Zhanhao Liang, Xutong Zhao, Mingru Jiang, Meizhu Zhou, Shibiao Liu, Yi Zhao.

  Non-small cell lung cancer (NSCLC) remains difficult to treat with adoptive cell therapies because of antigen heterogeneity, immunosuppressive tumor microenvironments, stromal barriers, and manufacturing variability. Direct evidence for iPSC-derived CAR-NK EV/sEV therapy in NSCLC is currently unavailable. Accordingly, this narrative review evaluates the platform as a translational hypothesis by integrating mechanistic evidence from CAR-engineered EV studies, biological-analog evidence from NK-cell EVs and other engineered EV systems, and clinical-analog evidence from living iPSC-NK or CAR-NK products. The proposed platform could combine a renewable producer-cell source, antigen-directed vesicle binding, and cytotoxic cargo delivery; however, each component, and particularly their integration into a single reproducible product, requires direct experimental validation. Compared with living cell products, CAR-NK sEVs may reduce selected risks related to cellular expansion, persistence, graft-versus-host disease, cytokine release syndrome, and neurotoxicity; however, they do not inherently eliminate antigen-dependent on-target/off-tumor toxicity. Their nanoscale size is hypothesized to improve access to selected stromal barriers in preclinical models, but human solid-tumor penetration remains unproven. Major unresolved issues include rapid systemic clearance and sequestration by hepatic and splenic components of the mononuclear phagocyte system, route-dependent pulmonary deposition, mucus and mucociliary clearance, pulmonary macrophage uptake, subtype- and lesion-specific antigen heterogeneity, EV identity and purity, CAR-positive vesicle quantification, potency-adjusted manufacturing yield, lot comparability, and the absence of potency assays validated across laboratories or linked to clinical outcomes. Thus, iPSC-CAR-NK sEVs should currently be viewed as an investigational translational concept rather than a clinically ready NSCLC therapy.

Keywords:  CAR-NK; NSCLC; extracellular vesicles; iPSC-derived NK cells; inhalation delivery; potency assay; small extracellular vesicles; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2026.1934758
J Control Release. 2026 Sep 11. pii: S0168-3659(26)00754-6. [Epub ahead of print] 115350

Engineered cryo-shocked tumor cells recruit T cells for lung cancer immunotherapy.

Huiheng Feng, Feng Liu, Zesheng Cheng, Huipeng Zhang, Wenyue Lv, Huanhuan Huang, Xuewen Yi, Kaixin He, Zhen Gu, Hongjun Li.

  Immune checkpoint blockade has transformed cancer therapy, yet its efficacy against solid tumors remains constrained by poor T cell infiltration and an immunosuppressive tumor microenvironment. Achieving localized and sustained chemokine signaling without systemic immune toxicity remains a central unmet challenge for cytokine-based immunotherapy. Here, we presented a cryo-engineered bio-depot platform derived from liquid‑nitrogen-treated (LNT) tumor cells for the site-restricted and controlled delivery of protein therapeutics. The cryo-shocked process preserves cellular integrity and protein bioactivity while abolishing pathogenicity of tumor cells, generating a versatile vehicle for therapeutic payloads. Applying this platform, we constructed LNT depots expressing C-X-C motif ligand 9 (CXCL9), which established a persistent chemokine gradient within the lung after intravenous injection, leading to robust T cell recruitment and augmented tumor growth inhibition. Furthermore, we demonstrated the platform adaptability by engineering LNT cells to secrete aPD-1, which significantly prolonged survival in a murine orthotopic lung cancer model. This cryo-engineered depot integrates the structural fidelity of biomaterials with the functional complexity of living systems, offering a generalizable route for personalized protein therapeutics in cancer immunotherapy.

Keywords:  Chemokine delivery; LNT cell; T cell recruitment; Targeted drug delivery; cancer immunotherapy

DOI:  https://doi.org/10.1016/j.jconrel.2026.115350
Med. 2026 Sep 11. pii: S2666-6340(26)00273-4. [Epub ahead of print]7(9): 101270

Generalized myasthenia gravis: Clinical trials to watch.

Sarah Hoffmann, Paolo Doksani, James F Howard.

Generalized myasthenia gravis is undergoing a highly dynamic phase of therapeutic development, with ongoing trials increasingly targeting upstream immune mechanisms. This Trial Watch highlights six studies evaluating B cell survival modulation, lymphocyte-directed immune reconstitution, BCMA- and CD19-directed CAR-T cell therapy, T cell engagement, and response-guided combination therapy, and considers their implications for future treatment strategies.

DOI: https://doi.org/10.1016/j.medj.2026.101270
Nat Mater. 2026 Sep 08.

A boost for CAR T cell therapy.

Emily Fitzgerald, Marshall S Padilla, Michael J Mitchell.

DOI: https://doi.org/10.1038/s41563-026-02725-0
Immunol Invest. 2026 Sep 10. 1-35

NK and CIK Cells in Hematologic Malignancies: Comparative Mechanisms, Clinical Evidence, and Translational Perspectives.

Shiva Mosadegh Manshadi, Ghazaleh Sankanian, Mohammadreza Moshari, Abbas Hajifathali, Elham Roshandel, Saeid Kaviani Jabali.

   BACKGROUND: Hematologic malignancies remain a major cause of morbidity and mortality despite advances in chemotherapy, targeted therapies, and hematopoietic stem cell transplantation. Adaptative cell therapy has emerged as a promising approach, in which natural killer (NK) and cytokine-induced killer (CIK) cells appear as potentially complementary effective platforms.
OBJECTIVE: This review critically compares NK and CIK cells as two adaptive cellular immunotherapy platforms for hematologic malignancies, focusing on their biological properties, antitumor mechanisms, production strategies, clinical evidence, safety profiles, and translational limitations.
METHODS: NK and CIK cells were comparatively evaluated with respect to their biological properties, antitumor mechanisms, production strategies, clinical evidence, safety profiles, and translational limitations.
RESULTS: NK cells, through the release of perforin-granzyme, death receptor pathways, and antibody-dependent cytotoxicity, perform rapid tumor clearance, allowing for immediate tumor volume reduction, but with limited persistence in vivo. In contrast, in vitro-expanded CIK cells (CD3+CD56+) show robust proliferation and sustained cytotoxicity, with an overall low, but not entirely zero, risk of graft-versus-host disease, supporting long-term immune surveillance. CAR engineering, cytokine-induced memory-like NK cells, and DC-CIK platforms may improve persistence, specificity, and metabolic fitness. Combination strategies with checkpoint inhibitors and standard therapies may enhance antitumor efficacy. However, most evidence is still preliminary and comes mainly from early-phase, single-arm, and heterogeneous studies.
CONCLUSIONS: NK and CIK cells may offer complementary benefits rather than direct competitive approaches. Their distinct functional properties provide the biological rationale for future combination or sequential strategies. However, prospective clinical studies are needed to define their efficacy, safety, durability, and optimal clinical application in hematological malignancies.

Keywords:  Adoptive cell therapy; combinatorial immunotherapy; cytokine-induced killer (CIK) cells; hematologic malignancies; investigational cellular therapy; natural killer (NK) cells

DOI:  https://doi.org/10.1080/08820139.2026.2713766
Front Immunol. 2026 ;17 1900283

Targeting splicing-derived neoantigens for precision cancer immunotherapy.

Mutian Tang, H Leighton Grimes, Nathan Salomonis.

  Aberrant pre-mRNA splicing in cancer generates protein sequences that are rare or absent in normal tissues, creating a rich source of tumor-specific neoantigens for immunotherapy. These splicing-derived neoantigens arise through diverse mechanisms, including recurrent somatic mutations in core spliceosome components (SF3B1, SRSF2, U2AF1, and ZRSR2), epigenetic derepression of transposable elements that give rise to chimeric exon-TE junctions, and coordinated dysregulation of splicing regulatory networks in cancers lacking spliceosome coding mutations. These processes produce two major classes of immunotherapeutic targets: 1) MHC class I-restricted neopeptides that can be recognized by T-cell-based therapies, and 2) extracellular neoepitopes (ExNeoEpitopes) within transmembrane proteins that are accessible to HLA-independent antibody-based modalities, including monoclonal antibodies (mAbs), bispecific engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T or CAR-NK cells. Despite their strong immunogenic potential, effective therapeutic exploitation requires overcoming key immunological barriers, including T-cell exhaustion, impaired antigen presentation through MHC-I downregulation, and suppression within the tumor microenvironment. Recent advances in computational neoantigen prediction, immunopeptidomics, surface proteomics, long-read and single-cell isoform sequencing, and AI-guided therapeutic design are enabling more systematic discovery and validation of splicing-derived targets. This review integrates current understanding of the biological origins, immunological barriers, target classes of splicing neoantigens, and the technologies that enable their advancement in cancer immunotherapy.

Keywords:  alternative splicing; cancer immunotherapy; immune tolerance; neoantigen; spliceosome

DOI:  https://doi.org/10.3389/fimmu.2026.1900283
Crit Rev Oncol Hematol. 2026 Sep 07. pii: S1040-8428(26)00474-9. [Epub ahead of print]227 105587

From cellular therapy to biologics: Non-viral delivery strategies for in vivo CAR-T engineering.

Shuyi Wu, Yiming Shen, Xuehui Tong, Sihui Nian, Peiwei Yang.

  Although CAR-T cell therapy has achieved breakthrough progress in the treatment of hematological malignancies, its current reliance on ex vivo manufacturing presents significant limitations in terms of efficiency, cost, and potential impact on cellular functionality. In vivo CAR-T strategies are increasingly recognized as a pivotal pathway toward the scalable and widely applicable deployment of CAR-T technologies. Among these, non-viral delivery systems have emerged as one of the principal enabling approaches. This review provides an overview of the key physiological barriers encountered in in vivo CAR-T cell engineering, alongside the corresponding principles of engineered design. It further outlines the evolving trends in the chemical composition of delivery materials and discusses the functional roles of various genetic payloads within in vivo CAR-T therapy. The objective of this comprehensive survey is to provide a forward-looking perspective to guide the rational design and clinical translation of non-viral-mediated in vivo CAR-T technologies.

Keywords:  Biomaterials; CAR-T cells; Immunotherapy; Vectors

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105587
Int J Nanomedicine. 2026 ;21 628321

Nanomedicine-Empowered CAR-T Therapy for Multiple Myeloma: Toward Programmable, Durable, and Precision Immunotherapy.

Can Huang, Xuyan Zhang, Yuanyin Teng, Zhongsong Zhang, Bing Wang, Panpan Gu, Xiang Deng, Dianwen Wang, Hongli Xiao, Lingli Zou, Meng Zhao, Caifeng Zheng, Gaochun Zeng, Jianyun Li, Zoufang Huang.

  Multiple myeloma (MM) remains a difficult-to-cure hematologic malignancy. Although B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor T-cell (CAR-T) therapy has substantially deepened clinical responses in patients with relapsed/refractory MM, its broader clinical application remains constrained by post-treatment relapse, insufficient response durability, prolonged manufacturing timelines, and limited accessibility. Increasing evidence indicates that relapse after CAR-T therapy in MM arises not from a single mechanism but from the convergence of tumor antigen remodeling, CAR-T cell exhaustion, impaired metabolic fitness, and bone marrow microenvironment-mediated immunosuppression. Nanomedicine provides modular engineering strategies to address these interconnected barriers to therapeutic efficacy. For example, lipid nanoparticles, polymeric carriers, biomimetic nanoplatforms, and targeted delivery systems may optimize ex vivo CAR-T manufacturing, enable in vivo CAR-T cell generation, regulate BCMA antigen density, remodel the bone marrow niche, and facilitate dynamic monitoring of relapse risk. This review systematically examines the major biological mechanisms underlying relapse after CAR-T therapy in MM, with particular emphasis on both the therapeutic potential of nanotechnology and the translational challenges associated with CAR-T manufacturing optimization, in vivo immune programming, bone marrow microenvironment remodeling, and relapse control in the post-BCMA era. By integrating advances in tumor immunology, materials science, and hematologic oncology, this review proposes a conceptual framework and future research priorities for developing faster, more controllable, durable, and accessible CAR-T therapeutic strategies for MM.

Keywords:  BCMA; CAR-T cell therapy; bone marrow microenvironment; multiple myeloma; nanomedicine

DOI:  https://doi.org/10.2147/IJN.S628321
Biofactors. 2026 Sep-Oct;52(5):52(5): e70150

Multi-Omics-Enabled Precision Strategies for Overcoming CAR-T Therapy Limitations in Gastrointestinal Malignancies.

Ke Su, Zunyuan Tan, Han Li, Kai You, Susu Xiao, Haiqing Chen, Danyang Li, Xin Liu, Xinrui Du, Jiaxin Hu, Kun He, Yantian Xu, Jian Chen, Yunwei Han.

  Gastrointestinal malignancies, including gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic ductal adenocarcinoma, remain major causes of cancer-related morbidity and mortality worldwide. Although chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of hematologic malignancies, its efficacy in gastrointestinal solid tumors remains limited by antigen heterogeneity, insufficient trafficking and infiltration, immunosuppressive tumor microenvironments, on-target off-tumor toxicity, and adaptive resistance. In this review, we summarize the current landscape of CAR-T therapy in gastric cancer, colorectal cancer, hepatocellular carcinoma, and pancreatic cancer, with a focus on representative target antigens and emerging biomarker strategies. We further discuss two major categories of biomarkers: target antigen-related biomarkers and conventional dynamic biomarkers, including serum tumor markers, cytokine changes, CAR-T expansion kinetics, and antigen-loss monitoring. In addition, we highlight how single-cell ribonucleic acid sequencing and spatial transcriptomics provide complementary insights into cellular states, immune exhaustion, stromal barriers, and spatially restricted immune exclusion. By integrating these multi-omics approaches with biomarker-guided patient stratification and next-generation CAR-T engineering, gastrointestinal solid tumor CAR-T therapy may evolve from empirical optimization toward mechanism-driven and precision-guided clinical translation.

Keywords:  biomarker; chimeric antigen receptor T‐cell therapy; gastrointestinal malignancies; precision oncology; single‐cell ribonucleic acid sequencing; spatial transcriptomics

DOI:  https://doi.org/10.1002/biof.70150
Mol Cancer. 2026 Jul 31. pii: 211. [Epub ahead of print]25(1):

Ecosystem-matched reprogramming of the tumor-immune microenvironment to overcome cancer immunotherapy resistance.

Xiaodong Wang, Qianqian Wang, Wei Gao, Songjiang He, Di Xiong, Yiping Huang, Bingwen Zou.

  Immune checkpoint blockade has redefined cancer therapy, yet durable responses remain constrained by resistance states that arise from coordinated tumor-cell, immune, stromal, vascular, lymphatic, and metabolic programs rather than from a single defective pathway. This review develops a translational framework in which tumor-intrinsic immune invisibility, myeloid and regulatory lymphocyte suppression, defective dendritic-cell priming, stromal and vascular exclusion, lymphatic control of antigen drainage, metabolic stress, and ILC2/type 2 immune plasticity are interpreted as interdependent ecosystem states. We discuss therapeutic strategies that reprogram these states, including myeloid and Treg modulation, stromal and vascular remodeling, preservation or restoration of productive lymphatic communication, cytokine and metabolic interventions, alternative checkpoint blockade, oncolytic viruses, vaccines, engineered cell therapies, and nanomedicine-enabled local delivery. Emphasis is placed on the lessons of failed or modestly effective trials, which show that biologically plausible interventions often fail when the dominant resistance bottleneck is not defined, tissue target engagement is not verified, or treatment sequence is not matched to the immune architecture of the tumor. We propose that future progress will depend on ecosystem-matched combinations guided by spatial biomarkers, on-treatment pharmacodynamics, and adaptive trial designs capable of linking mechanism to clinical decision-making.

Keywords:  Immunotherapy resistance; Lymphatic vessels; Translational immuno-oncology; Tumor–immune ecosystem; Type 2 immunity

DOI:  https://doi.org/10.1186/s12943-026-02748-w
Transplant Cell Ther. 2026 Sep 09. pii: S2666-6367(26)00713-X. [Epub ahead of print]

Barriers to Patient Referral and Completion of CAR T-Cell Therapy for Relapsed/Refractory Large B-Cell Lymphoma.

Mazyar Shadman, Jenny Ahlstrom, Meghan Gutierrez, Loretta Nastoupil, David Porter, Ashley Schmitt, Laura Zitella, Tara Graff.

  Chimeric antigen receptor (CAR) T-cell therapy has improved outcomes for patients with hematologic malignancies such as relapsed or refractory large B-cell lymphoma. However, research indicates that a substantial proportion of medically eligible patients with relapsed or refractory large B-cell lymphoma in the United States do not receive CAR T-cell therapy. Multiple barriers across the treatment pathway contribute to the significant gap between patient eligibility and receiving treatment. To further examine these barriers, a multistakeholder panel was convened on October 8, 2025. Key barriers identified included limited patient awareness of CAR T-cell therapy, inadequate knowledge and application of eligibility criteria, logistical and financial burdens, and delays resulting from health system processes. The panel members identified potential ways to improve treatment access and completion, including expanding treatment sites capable of delivering CAR T-cell therapy in community settings and shifting supportive resources (financial counselors, social workers, patient navigators) from treatment centers to community oncology practices.

Keywords:  CAR T-cell therapy; axicabtagene ciloleucel; large B-cell lymphoma; lisocabtagene maraleucel; patient access; tisagenlecleucel; treatment barriers

DOI:  https://doi.org/10.1016/j.jtct.2026.09.010
Semin Immunol. 2026 Sep 11. pii: S1044-5323(26)00053-9. [Epub ahead of print]84 102066

Power to the Tregs in transplantation tolerance in LATAM: From the basics to the bedside.

Karina Pino-Lagos, Gloria Soldevila.

  T regulatory cells (Tregs) come in different flavors, but they all share suppressive function and the role in the generation and maintenance of immune tolerance. Due to this essential activity, Tregs are targets for immunotherapy: Tregs promotion is wanted in pathological conditions such as autoimmunity, allergies and transplantation, whereas their elimination is the main goal in the context of cancer. Transplantation is the only treatment available when organ failure is detected but unfortunately transplant rejection has not been fully achieved regardless of all efforts made, such as the identification and use of new immunosuppressant drugs and biological therapies. During the last two decades, Tregs have become a cellular source for therapy to control primarily Graft-versus-Host Disease (GvHD) -in the case of cellular transplantation- and rejection of solid allografts as in liver and kidney transplants. Like in other biomedical disciplines, many advances applying immunological technologies only reach the patients if developed in the north hemisphere, and transplantation is not an exception. Here, we present the contribution of Latin America (LATAM), regarding solid organ transplantation from basic and clinical immunology research, focusing on Tregs as the main topic of study.

Keywords:  Cell Therapy; Immune regulation; T regulatory cells; Transplantation tolerance

DOI:  https://doi.org/10.1016/j.smim.2026.102066
Biochem Biophys Res Commun. 2026 Sep 08. pii: S0006-291X(26)01333-1. [Epub ahead of print]836 154569

Comprehensive microRNA profiling coupled with function-based feature selection reveals a biomarker panel for predicting CAR-T cell exhaustion.

Noriko Nakamura, Hyemin Seo, Risa Hamada, Hiromasa Kaneko, Yuki Kagoya, Seiichi Ohta.

  Chimeric antigen receptor (CAR)-T cell exhaustion limits durable therapeutic efficacy, particularly under persistent antigen stimulation. While transcriptomic and epigenomic analyses have advanced the understanding of CAR-T cell exhaustion, the contribution of microRNAs (miRNAs) remains poorly characterized. Here, we present the first comprehensive landscape of miRNA expression in exhausted CAR-T cells generated using an in vitro repeated antigen stimulation model. Bulk miRNA sequencing identified 39 differentially expressed miRNAs between exhausted and control CAR-T cells. Subsequent reverse transcription-quantitative polymerase reaction validation reduced the candidate list to 18 miRNAs, which retained enrichment in pathways associated with cellular proliferation. To select an optimal biomarker panel for predicting exhaustion, we further applied functional analysis-based feature selection to minimize pathway redundancy, resulting in a six-miRNA panel. Machine learning models using these miRNAs achieved superior predictive performance (area under the curve = 0.958) compared with larger panels. Our findings identify miRNAs as key molecular hallmarks of CAR-T cell exhaustion and establish a rational framework for biomarker panel selection, with potential applications in CAR-T cell quality control, therapeutic response prediction, and manufacturing optimization.

Keywords:  Biomarker panel; CAR-T cell exhaustion; Functional analysis; RT-qPCR; miRNA; miRNA sequencing

DOI:  https://doi.org/10.1016/j.bbrc.2026.154569
Ther Adv Hematol. 2026 ;17 20406207261484713

From toxicity to immunity: Evaluating CAR-T and conventional therapies in multiple myeloma through quality-adjusted life year (QALY) outcomes.

Guluzar Gulnur Itez, Asuman Sunguroğlu.

  Multiple myeloma (MM) remains characterized by recurrent relapse and cumulative treatment burden despite major therapeutic advances. This study compared conventional stepwise regimens with CAR-T cell therapy in terms of QoL, toxicity, cost, and ethical considerations within a model-based comparative framework. This comparative pharmacoeconomic modeling analysis was based on published clinical trial data. Kaplan-Meier survival curves were digitized to estimate mean overall survival (OS) and progression-free survival (PFS) using area-under-the-curve integration. Treatment costs were calculated based on published pricing and trial-derived treatment durations. A simple and transparent ECOG-based utility model was developed to enable clinicians, researchers, and health policy authorities to estimate quality-adjusted life years (QALY) and incremental cost-effectiveness ratios (ICER) across regimens spanning heterogeneous treatment lines. The present analysis synthesizes outcome data from 19 pivotal trials and real-world cohorts (N = 7,793 patients). Among heavily pretreated patients, CAR-T therapy approximately doubled OS and PFS compared with other late-line regimens and yielded higher QALY estimates with lower cumulative treatment burden. Daratumumab-based combinations improved outcomes but reached very high costs (∼USD 1 million/patient), while carfilzomib-based regimens remained costly but clinically important for high-risk disease. VMP represented a practical lower-cost option for transplant-ineligible or resource-limited patients. In treatment-line-stratified analysis, later-line/RRMM regimens had higher median ICER-equivalent values than early-line/induction regimens (USD 739,050/QALY vs USD 218,687/QALY; 3.4-fold higher), whereas CAR-T regimens showed a median ICER-equivalent estimate of USD 299,723/QALY, approximately 2.5-fold lower than later-line/RRMM conventional regimens. Within this model-based comparative framework, CAR-T provided substantial survival and quality-adjusted outcome gains after three or more prior therapy lines, with promising potential for earlier use. Despite its upfront single-payment structure, CAR-T did not show a disproportionate ICER-equivalent burden compared with later-line conventional regimens. However, limited global availability raises ethical concerns regarding access, infrastructure, reimbursement, and equity. Further studies incorporating longer follow-up and patient-level QoL data are needed to refine its role in multiple myeloma care.

Keywords:  CAR-T cell therapy; Eastern Cooperative oncology group (ECOG) performance status; cost-effectiveness; drug toxicity; multiple myeloma; quality-adjusted life years (QALY); value-based medicine

DOI:  https://doi.org/10.1177/20406207261484713
Cancer Med. 2026 Sep;15(9): e72262

Efficacy and Safety of CAR-T Cell Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia With Central Nervous System Involvement.

Yanghong Yu, Hui Xu, Lei Xue, Xingbing Wang.

  Central nervous system (CNS) involvement in B-cell acute lymphoblastic leukemia (B-ALL) is associated with relapse, treatment refractoriness, and poor prognosis. Although chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable efficacy in relapsed/refractory (R/R) B-ALL, its efficacy and safety in CNS leukemia (CNSL) remain unclear. We retrospectively analyzed 113 R/R B-ALL patients who received CAR-T cell therapy, stratifying them into CNS-positive (n = 22) and CNS-negative (n = 91) groups based on the presence of CNSL prior to infusion. At Day 28 after CAR-T infusion, the overall complete remission (CR) rate was 81.8%, with no significant difference between groups. The incidence of cytokine release syndrome (CRS) and neurotoxicity was comparable. The 3-year cumulative incidence of relapse (CIR), event-free survival (EFS), and overall survival (OS) were similar between groups. However, CNSL patients exhibit a higher cumulative relapse rate following CAR-T-induced remission, with an increased risk of CNS relapse compared to patients without CNS involvement. Multivariate analysis identified allo-HSCT as consolidation post-CAR-T as an independent protective factor for improved EFS and OS in CNSL patients. In conclusion, CAR-T therapy offers similar efficacy and safety in R/R B-ALL patients regardless of CNS involvement. Furthermore, CAR-T cell therapy was not sufficient to maintain sustained remission, and consolidative allo-HSCT may improve long-term survival in this high-risk group.

Keywords:  central nervous system leukemia; chimeric antigen receptor; hematopoietic stem cell transplantation; relapsed/refractory B‐cell acute lymphoblastic leukemia

DOI:  https://doi.org/10.1002/cam4.72262
Biometrics. 2026 Jul 01. pii: ujag152. [Epub ahead of print]82(3):

Bayesian optimization for identification of optimal biological dose combinations in personalized dose-finding trials.

James Willard, Shirin Golchi, Erica E M Moodie.

  Early-phase, personalized dose-finding trials for combination therapies seek to identify patient-specific optimal biological dose (OBD) combinations, which are defined as safe dose combinations that maximize therapeutic benefit for a specific covariate pattern. Given the small sample sizes that are typical of these trials, it is challenging for traditional parametric approaches to identify OBD combinations across multiple dosing agents and covariate patterns. To address these challenges, we propose a Bayesian optimization approach to dose-finding that incorporates efficacy and toxicity information into the sequential search strategy. Independent Gaussian processes are used to model the efficacy and toxicity surfaces, and an acquisition function is utilized to define the dose-finding strategy. Furthermore, we define an adaptive stopping rule using the posterior entropy for the location of the OBD. This work is motivated by a personalized dose-finding trial which considers a dual-agent therapy for obstructive sleep apnea (OSA), where OBD combinations are tailored to OSA severity. Via a simulation study, the approach is first investigated across varying degrees of response heterogeneity for both efficacy and toxicity, and then a collection of final designs for the OSA trial are compared. We demonstrate that the proposed approach toward personalized dose-finding yields good performance under the considered scenarios.

Keywords:  Bayesian adaptive clinical trial; Gaussian process; constrained dose optimization; dose-escalation; efficacy; toxicity

DOI:  https://doi.org/10.1093/biomtc/ujag152
Biometrics. 2026 Jul 01. pii: ujag156. [Epub ahead of print]82(3):

A Bayesian model averaging method for dose ranging studies in oncology.

Adetayo Kasim, Nathan W Bean, Elena Parkhomenko, Amelia Cottle, Andre Acusta, Helen Zhou, Tai-Tsang Chen, Antony Sabin, Matthew A Psioda.

  Dose finding and optimization studies are important in oncology drug development for making new drugs available to patients at pace and for reducing the risk of toxicity. The requirement by Project Optimus to conduct a randomized dose optimization study necessitates a change in the oncology drug development paradigm, and standard dose-response modeling approaches (e.g., Multiple Comparisons Procedure-Modeling, MCP-Mod) are not always applicable due to small sample sizes and a small number of doses that are typical of dose optimization studies. An innovative Bayesian model averaging method for dose ranging studies (BAMADOS) is proposed for the design and analysis of oncology trials with binary endpoints. The method assumes a monotonic relationship between response and doses of an investigational drug. It does not require pre-specification of candidate models but instead evaluates all possible models in a constrained model space. To minimize the potential impact of the Occam's razor property, non-conjugate moderately informative priors from the family of generalized normal priors are implemented. We show via simulation studies that BAMADOS correctly identifies the optimal biological dose in a dose optimization setting. It further estimates response rates with little bias, even in the presence of discordance between the priors and observed data. Compared to MCP-Mod, BAMADOS exhibited higher power for small sample sizes (30 or fewer participants per dose) and comparable power for larger sample sizes in several scenarios considered.

Keywords:  Bayesian model averaging; MCP-Mod; dose optimization; dose response; generalized normal distribution; oncology

DOI:  https://doi.org/10.1093/biomtc/ujag156
Cytokine Growth Factor Rev. 2026 Sep 06. pii: S1359-6101(26)00072-9. [Epub ahead of print]92 101527

Cytokine release syndrome: Inflammatory signaling, panoptosis, and therapeutic perspectives.

Wenxi Xie, Xiaoling Su, Zhijie Huang, Kun Zhou, Shan Yu, Guofeng Chen, Yu Huang, Jieying Lei, Youjun Chen, Ping Luo, Ji Zhang.

  Cytokine release syndrome (CRS) is a major limitation of current immunotherapy. Inflammatory complications are prone to occur after chimeric antigen receptor T-cell therapy and other immune-binding strategies. Cytokine overproduction is a well-defined feature of CRS. Yet the progression of CRS involves a complex interplay between immune activation, inflammatory cell death, endothelial dysfunction, and tissue damage. PANoptosis is a form of cell death that integrates pyroptosis, apoptosis, and necroptosis mechanisms. This review discusses the role of PANoptosis in the pathogenesis of CRS and highlights the reciprocal regulation between inflammatory signaling and cell death programs. Cytokine-mediated cellular reprogramming and innate immune activation promote PANoptotic responses. The inflammatory mediators and injury-related signals released by dying cells further aggravate immune activation and tissue damage. These processes lead to the persistence and amplification of CRS. Current and emerging therapeutic approaches targeting cytokine signaling, inflammatory pathways, and PANoptotic modulation are also discussed. Understanding the interplay of cytokine signaling and inflammatory cell death in CRS may provide a more complete perspective for studying disease progression and developing mechanism-directed interventions.

Keywords:  CAR-T therapy; Cytokine release syndrome; Cytokine storm; Inflammatory cell death; PANoptosis

DOI:  https://doi.org/10.1016/j.cytogfr.2026.101527
Pediatrics. 2026 Sep 10. pii: e2026076924. [Epub ahead of print]

CART-Cell Therapy in Pediatric Acute Lymphoblastic Leukemia: A Review for General Pediatricians.

Antonio Grasso, Avijeet K Mishra, Juliana Silva, Persis J Amrolia.

Chimeric antigen receptor (CAR) T cell therapy has transformed outcomes for children and young adults with relapsed/refractory CD19+ B-cell acute lymphoblastic leukemia (B-ALL), enabling deep remissions even in patients who are refractory to chemotherapy or have relapsed after hematopoietic stem cell transplantation (HSCT). Use of adoptive cellular immunotherapy requires a strict clinical pathway and is delivered at designated CART-cell centers. Initial complete remission rates are high and often MRD (minimal residual disease)-negative, but relapse remains frequent through loss of persistence or antigen escape. Key acute toxicities are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), whereas longer-term issues include prolonged cytopenias, infection risk, B-cell aplasia, and hypogammaglobulinemia requiring immunoglobulin replacement. This narrative review for general pediatricians reviews the current state-of-the-art of CART-cell therapy for ALL and summarizes key principles about CART-cell indications, production, outcomes, complications, and relevant issues for shared-care centers on follow-up in the short and long term.

DOI: https://doi.org/10.1542/peds.2026-076924
Immunol Invest. 2026 Sep 11. 1-20

Immunometabolic Reprogramming as a Therapeutic Platform: Integrating Systems Immunology with Precision Biopharmaceutical Engineering.

Hosein Yousefi, Cobra Moradian.

   INTRODUCTION: Immunometabolism integrates energy demands, biosynthesis, redox homeostasis, and immune-cell function, yet metabolic phenotypes remain context dependent. This review conceptualizes immunometabolic reprogramming as a multiscale regulatory network connecting microenvironmental pressures, nutrient sensing, metabolic flux, metabolite-mediated regulation, immune-cell states, systems-level biomarkers, and precision therapeutic engineering.
METHODS: A structured narrative review synthesized literature published from January 2022 onward across five domains: microenvironmental metabolic control; metabolic signaling and pathway interactions; systems immunology and biomarker discovery; engineered therapeutic platforms; and translational evidence, safety, and patient stratification. Quantitative findings were retained only when their experimental context supported interpretation.
RESULTS: Oxygen, nutrient, pH, cytokine, and metabolite availability can reshape AMPK, mTOR, HIF-1α, and related signaling, thereby altering glycolytic, mitochondrial, lipid, amino-acid, and redox metabolism. These changes interact with transcriptional and epigenetic mechanisms to regulate immune-cell states. Systems-level profiling enables biomarker development, while engineered biologics, targeted delivery systems, extracellular-vesicle platforms, and metabolically conditioned immune cells offer emerging therapeutic opportunities. However, translational maturity varies substantially across interventions.
CONCLUSION: Immunometabolic reprogramming should be interpreted as a context-dependent network rather than a collection of isolated pathways. Clinical translation requires evidence-graded interventions, tissue- and dose-aware strategies, validated biomarkers, and patient stratification to distinguish established benefit from promising but unproven engineering approaches.

Keywords:  Biomarkers; immunometabolism; immunotherapy; metabolic reprogramming; patient stratification; precision biopharmaceutical engineering; systems immunology; tumor microenvironment

DOI:  https://doi.org/10.1080/08820139.2026.2731116
J Med Internet Res. 2026 Sep 08. 28 e85607

Integrating Heterogeneous Real-World Cancer Data for Semantic Interoperability in Oncology and Medical Imaging: Development and Validation of the Cancer Image Europe Hyperontology.

Mirna El Ghosh, Varvara Kalokyri, Maciej Bobowicz, Melanie Sambres, Morgan Vaterkowski, Olga Giraldo, Jean Charlet, Laure Fournier, Catherine Duclos, Xavier Tannier, Gianna Tsakou, Manolis Tsiknakis, Ferdinand Dhombres, Christel Daniel.

   Background: Semantic interoperability in health care, essential for seamless integration of information systems, is partially achieved through the use of terminologies and common data standards that define the semantic structure of data. Various complexities arise when using real-world health care data, including different interpretations of terms and concepts and gaps in domain coverage in standard terminologies. However, ensuring compatibility becomes increasingly challenging when big data are distributed across diverse repositories that use heterogeneous health care standards and overlapping terminologies. Ontologies are key solutions to bridge these gaps, enabling consistent semantic interoperability and data harmonization.
Objective: We aim to develop and validate a hyperontology within the EUCAIM (Cancer Image Europe) project to semantically integrate and harmonize clinical, biological, and imaging metadata, along with associated data from heterogeneous, disparate cancer image data models, to achieve semantic interoperability in oncology and medical imaging. The hyperontology will be used to support several EUCAIM components, including the extract, transform, and load process; federated query; image annotation and segmentation; and ultimately, AI-federated processing.
Methods: The ontology development process combines real-world data from a network of European projects on cancer imaging (AI for Health Imaging) with their semantic mappings, as well as conceptual unpacking and modeling of the Minimal Common Oncology Data Elements (mCODE) specifications. The mCODE is a core set of structured data elements for oncology electronic health records. The building process is supported by ontology grounding, layering, and modularization. We adopted this hybrid approach to simplify ontology design, semantically reflect oncology's essential entities and their interactions, and enhance the extensibility and reusability of the hyperontology. We initiated ontology development with a set of competency questions derived from the provided knowledge, which helped clarify the ontology's scope and requirements and identify inconsistencies or incomplete information. We also assessed whether the requirements were fulfilled by formalizing the competency questions using SPARQL.
Results: We developed a FAIR hyperontology that semantically integrates and harmonizes clinical, biological, and imaging metadata and data spread across disparate sources. The ontology also captures and accurately represents oncology and medical imaging. The hyperontology, which covers various cancer types, is rich in axiomatizations and patterns, supporting the semantic understanding and harmonization of heterogeneous data. Additionally, semantic mappings are established across data models and standards, ensuring the efficient and meaningful sharing and integration of health care data. Finally, we evaluated the ontology model and demonstrated its applicability using real-world prostate and breast cancer use cases.
Conclusions: EUCAIM's hyperontology is a valuable effort that provides a unifying framework for the essentials of oncology and medical imaging, facilitating communication among disparate and heterogeneous cancer image data models. The ontology model is evaluated and validated using multiple methods, demonstrating compliance with the specified ontological requirements. Challenges include ensuring that the ontology is scalable, extensible, and applicable, given the complexity and dynamic nature of the application domain.

Keywords:  Findable, Accessible, Interoperable, Reusable; artificial Intelligence; cancer imaging; data heterogeneity; health care data standards; hyperontology; medical imaging; oncology; ontology-driven conceptual modeling; semantic interoperability

DOI:  https://doi.org/10.2196/85607
Value Health. 2026 Sep 07. pii: S1098-3015(26)02637-9. [Epub ahead of print]

The Application of FDA Patient-Focused Drug Development Guidance in Rare Patient Populations: Innovation and Flexibility.

Stacie Hudgens.

DOI: https://doi.org/10.1016/j.jval.2026.09.001
Sci Adv. 2026 Sep 11. 12(37): eaed9825

TCR-JANUS engager proteins enable bispecific targeting to overcome tumor heterogeneity in TCR-T cell therapy.

Chenxi Cheng, Ting Liang, Pengju Yao, Wenling Wang, Huxuan Chen, Xiaowen Li, Ying Tian, Jie Wang, Ni Yan, Danli Xie, Fuming Qiu, Shuguang Tan.

T cell receptor (TCR)-based immunotherapy is limited by tumor antigen heterogeneity, which frequently leads to relapse. We developed a bispecific TCR-JANUS engager that functions synergistically with TCR engineered T cells (TCR-T). In contrast to conventional T cell engagers targeting CD3, TCR-JANUS engages both the variable region of a transgenic TCR (TRBV) and a tumor surface antigen. Using a model system targeting a humanized KRAS-G12V-specific TCR and trophoblast cell surface antigen 2 (Trop2), we show that TCR-JANUS effectively redirects TCR-T cells to lyse Trop2-expressing tumor cells while preserving intrinsic specificity toward the cognate pHLA target, thereby enabling simultaneous dual-antigen recognition. In heterogeneous tumor models, the combination of TCR-JANUS with TCR-T cells, an integrated system termed T Cell Dual Arsenal Recon, potently suppressed tumor growth by clearing antigenically divergent populations. Moreover, TCR-JANUS maintained enhanced T cell functionality with reduced exhaustion compared to anti-CD3-based engagers upon chronic stimulation. Together, this approach offers a targeted and durable strategy to overcome antigenic heterogeneity, expanding the clinical prospects of TCR-T cell therapy for solid tumors.

DOI: https://doi.org/10.1126/sciadv.aed9825
Blood Immunol Cell Ther. 2026 Jun;2(2): 100055

Donor lymphocyte infusion as immune modulation after pediatric allogeneic transplantation.

Dimitrios Filioglou, Richard J Simpson, Emmanuel Katsanis.

Relapse remains a leading cause of failure after allogeneic hematopoietic cell transplantation for pediatric hematologic malignancies. Donor lymphocyte infusion (DLI) offers a uniquely accessible and scalable form of nonengineered adoptive cellular therapy. Although historically viewed as salvage therapy, emerging data support a paradigm shift toward using DLI as strategic immune modulation rather than rescue. This review synthesizes the biological rationale and clinical evidence for DLI in children, integrating the adult data when necessary to define translatable principles. Across platforms, outcomes rely on timing, disease burden, and the immune context. We highlight the superiority of prophylactic and preemptive DLI over therapeutic use and review contemporary structured approaches relying on treatment initiation at low and safe doses and escalation based on strict tolerance and monitoring criteria. Special consideration is given to haploidentical transplantation and mechanisms of immune escape such as HLA loss that limit T-cell-based interventions. Furthermore, we examine emerging combinations, including DLI with blinatumomab in B-cell acute lymphoblastic leukemia and hypomethylating agents in myeloid malignancies. Finally, we discuss T-cell subset manipulation to mitigate graft-versus-host disease while preserving the graft-versus-leukemia effects. All these data support a modern framework for pediatric DLI that prioritizes early, biology-informed interventions and rational combinations, underscoring the urgent need for pediatric-specific prospective studies.

DOI: https://doi.org/10.1016/j.bict.2026.100055