bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–12–14
74 papers selected by
Luca Bolliger, lxBio
  1. Chimeric antigen receptor T cell therapy: Revolutionizing cancer treatment.
  2. Nonclinical regulatory considerations for investigational new drug applications for regulatory T cell therapies.
  3. Redefining Multiple Sclerosis with CAR-T Cell Therapy.
  4. Emerging role of lisocabtagene maraleucel chimeric antigen receptor-T cell in nodal and gastrointestinal follicular lymphoma.
  5. Fine-tuning affinity and spacer design enhances T cell potency in DLL3 and BCMA CAR T cells.
  6. Engineered cell therapies for autoimmune diseases: evaluating CAR-T and CAR-M progress and prospects.
  7. Strategies for the Development of NK Cell-Based Therapies for Cancer Treatment.
  8. Cancer-fighting cells made in body help patients.
  9. The Advanced Therapies model of Lund an integrated approach to accelerate access for many patients.
  10. Recurrent Limitations of CAR-T Therapy in Gliomas: Evidence from Preclinical and Phase I Clinical Studies.
  11. DR5 CAR-T cells target melanoma and suppress MDSCs with minimal toxicity.
  12. A Bidirectional EF1 Promoter System for Armoring CD19 CAR-T Cells with Secreted Anti-PD1 Antibodies.
  13. Chimeric antigen receptor (CAR) therapies for precise eradication of pathogenic cells in autoimmunity.
  14. Reaching maturity: Thymic γδ T cell differentiation in mice and humans.
  15. GMP-compliant manufacturing of allogeneic peripheral blood CAR-NK cells for the treatment of acute myeloid leukemia.
  16. ZAP327 signaling domain-driven chimeric antigen receptor generates robust and long-term antitumor immunity in mouse models.
  17. CAR Therapies: Ex Vivo and In Vivo Potential of Exosomes and Biomimetic Nanoparticles.
  18. Improving CAR T cell therapy against malignancies through gene knock-down/out strategies: a systematic review.
  19. The Potential of β-Synuclein-Specific Regulatory T Cell Therapy as a Treatment for Progressive Multiple Sclerosis.
  20. Tuning CAR-T cells by targeting cancer-associated glycan in pancreatic cancer.
  21. Tumor-localized immunomodulation: a critical advance in engineering CAR-t cells for solid malignancies.
  22. Advancing CAR T-Cell Therapy: Evidence-Based Trial Design for Chimeric Antigen Receptor T-Cell Therapy in Oncology.
  23. Progress in advanced cellular and gene therapies in South Africa and barriers to patient access: A National Consortium paper on behalf of the BloodSA Cell and Gene Therapy working party.
  24. Ex Vivo Gene and Cell Therapy in Hematopoietic Stem Cells.
  25. Addressing the limitations of the regulatory landscape in South Africa regarding advanced cell and gene therapies and related sectors involving human cells, tissues and organs.
  26. Characterization of Stimulated γδ T Cells: Phenotypic Analysis and Implications for Allogeneic Cellular Immunotherapy.
  27. Convergence of mRNA technology and chimeric antigen receptor therapy: targeted technology optimizing targeted therapy.
  28. A surprising link: TET2 clonal hematopoiesis boosts immune checkpoint therapy.
  29. CAR T-cell therapy induces remission in multiorgan IgG4-related disease with hepatobiliary involvement.
  30. Advances in the development of personalized neoantigen therapies.
  31. FcεRγI promotes canine CD8 chimeric antigen receptor T cell cytotoxicity through a Syk-NFκB axis.
  32. CAR T cells targeting C-C motif chemokine receptor 4 (CCR4) selectively deplete human Tregs ex vivo and in vivo.
  33. A universal boosting strategy for adoptive T cell therapy using a paired vaccine/chimeric antigen receptor.
  34. Guiding Antiviral Cell Therapy Approaches with an Online Resource of Clinically Scored Epitopes, T-Cell Receptors, and B-Cell Receptors.
  35. Digital Biomarkers of Cytokine Release Syndrome: Scoping Review and Ontology Development of the Role and Relevance of Digital Measures Using a Mixed Methods Approach.
  36. Bridging Technology and Healthcare: A Bibliometric Review of Assistive Technologies in Hospital Environments.
  37. CRISPR-engineered microbiome: living therapeutics revolutionize blood cancer immunotherapy.
  38. Machine learning-based predictive model for high- grade cytokine release syndrome in chimeric antigen receptor T-cell therapy.
  39. In-depth plasma proteomics reveals the dynamic changes and prognostic biomarkers for chimeric antigen receptor-glypican-3 T-cell therapy in patients with hepatocellular carcinoma.
  40. Sepsis and the diverse organ-gastrointestinal tract axis.
  41. Assisted Reproduction Therapy in Patients with Multiple Sclerosis: Narrative Review and Practical Recommendations.
  42. Optimizing Dosing Strategies in Cell Therapy With Machine Learning and Exposure-Response Integration.
  43. Autoimmune Neuromuscular Disorders at a Molecular Crossroad: Linking Pathogenesis to Targeted Immunotherapy.
  44. Siglecs in immunotherapy: current clinical landscape and prospects.
  45. Gene-corrected regulatory T cell therapy for IL2RA deficiency.
  46. Diagnosis and treatment of invasive fungal disease in children with hematological malignancies after chemotherapy: Challenges and strategies (Review).
  47. Preclinical development and selection of nanobody-based CAR-T cells targeting HER2-positive solid tumors.
  48. Therapy-induced mRNA, rRNA and tRNA methylation alterations confer tolerance phenotype in tumor cells: mechanism and implications.
  49. Restricted Supply, Rising Demand: Reimagining Prescription Stimulant Regulation Amid A National Shortage.
  50. Exploring the therapeutic potential of human umbilical cord mesenchymal stem cells derived extracellular vesicles in cancer immunotherapy.
  51. Musculoskeletal Digital Therapeutics and Digital Health Rehabilitation: A Global Paradigm Shift in Orthopedic Care.
  52. Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair.
  53. mRNA vaccine platforms and novel delivery systems: From mechanistic principles to clinical translation.
  54. Guide to Liquid Volume Measurements: A Review of Methods and Technologies.
  55. Next-Generation Probiotics in Allergy Therapy: Scientific Evidence and Clinical Applications.
  56. Introducing arginine residues into scFv in CAR-T cells shows promising antitumor effects.
  57. Funding Multi-indication Medicines: A Scoping Review of Health Technology Assessment and Reimbursement Frameworks.
  58. Principles and Key Technologies of Magnetic Particle Imaging System: A Comprehensive Review.
  59. Establishing an independent HTA agency in Ukraine: a conceptual framework for governance, operations, and long-term sustainability.
  60. Treating Pediatric Oncology Patients: The Emerging Role of Radioligand Therapy.
  61. Orthobiologics and Peptide Therapy for Central Nervous System Repair in Neurodegenerative Conditions.
  62. Bioinformatics and omics data management in genetic diagnosis.
  63. Advancements in the study of exosomes in disease diagnosis and treatment.
  64. Artificially Engineered Synthetic Biomarkers Revolutionizing Early Diagnosis of Diseases.
  65. Algorithm guided personalized T cell therapy: machine learning unlocks next generation TCR engineered immunotherapy.
  66. Innovative Interventions That Promote Access to Cancer Care Among People Experiencing Homelessness and Lessons Learned: A Systematic Review.
  67. The Early Experiences Of Health Technology Assessment Bodies In The Implementation Of The EU HTA Regulation (HTAR) For High-Risk Medical Devices: A Qualitative Study.
  68. Beyond sequence similarity: ML-powered identification of pHLA off-targets for TCR-mimic antibodies using high throughput binding kinetics.
  69. Is it still useful to publish case reports?
  70. Current state of machine learning implementation in pharmaceutical process modeling for oral solid dosage forms.
  71. The role of gut microbiota-derived metabolites in neuroinflammation.
  72. Digital Health Technologies: Learnings and Perspectives From a Patient Engagement Stakeholder Expectations Matrix Study.
  73. Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control.
  74. Recipient-derived vs. donor-derived CAR-T-cell therapy in relapsed B-cell acute lymphoblastic leukemia patients after transplantation: A multi-center retropective study.
  1. World J Clin Oncol. 2025 Nov 24. 16(11): 108667
    Chimeric antigen receptor T cell therapy: Revolutionizing cancer treatment.
    Samarah Arjumand, Asef Raj, Kazi Milenur Rahman Prattay, Humair Bin Md Omer, Faruque Azam.
      Chimeric antigen receptor T (CAR-T) cell therapy represents a major advance in cancer immunotherapy, offering targeted treatment options, particularly for hematologic malignancies. This review comprehensively explores the structural evolution, production processes, and cytotoxic mechanisms underlying CAR-T function. Therapy involves engineering autologous T cells with synthetic receptors that allow major histocompatibility complex-independent recognition of tumor-associated antigens. Key structural components such as antigen recognition domains, spacers, transmembrane, and intracellular domains are optimized to enhance specificity, persistence, and cytotoxicity. CAR-T therapy exerts antitumor effects via granzyme-perforin degranulation, Fas/Fas ligand signaling, and cytokine secretion. Over time, the development of second- to fifth-generation CARs has incorporated costimulatory molecules, transcriptional regulation, and logic-gated control to improve efficacy and safety. Additionally, novel engineering strategies such as dual CARs, tandem CARs, SynNotch systems, and universal or inhibitory CARs have expanded antigen targeting and reduced off-tumor toxicity. Emerging gene delivery technologies, including viral vectors, transposons, CRISPR/Cas9, and RNA-based electroporation, are improving CAR-T production. Despite notable clinical success, particularly in CD19- and B-cell maturation antigen-targeted therapies, CAR-T applications face challenges, including cell exhaustion, antigen escape, and therapy-induced toxicities, such as cytokine release syndrome and neurotoxicity. Ongoing efforts in engineering innovation, clinical trials, and regulatory support continue to shape CAR-T therapy into a safer, more precise tool for cancer treatment. This review highlights current advances while outlining the barriers and future prospects of CAR-T immunotherapy.
    Keywords:  Cancer immunotherapy; Chimeric antigen receptor; Chimeric antigen receptor T clinical trials; Chimeric antigen receptor structure; Immunotherapy challenges; T cell engineering
    DOI:  https://doi.org/10.5306/wjco.v16.i11.108667
  2. Front Med (Lausanne). 2025 ;12 1626067
    Nonclinical regulatory considerations for investigational new drug applications for regulatory T cell therapies.
    Phuong-Uyen Dinh, Lauren Mihalcik.
      Since FDA approval of the first chimeric antigen receptor (CAR) T cell therapy in 2017, the landscape of cell-based therapies has widely expanded. This expansion has encompassed both the types of cell therapies being developed as well as indications beyond oncology. As an example, the number of regulatory T cell (Treg) therapies in development have been steadily increasing, with targeted focus on treatment of autoimmune and inflammatory diseases. The nonclinical development pathway for Treg therapies has relied on leveraging existing regulatory guidance documents for cell and gene therapies, however the lack of Treg specific guidance coupled with often times limited appropriate preclinical models have created regulatory challenges for drug developers. In this review, preclinical considerations for the development of Treg therapies will be described. Specifically, topics will include the following: (1) Current health authority expectations for demonstrating pharmacodynamics, biodistribution, and safety of Treg therapies, including selection of relevant models, assay selection for bioanalytical endpoints, and strategic study planning to maximize study readouts while reducing animal use. (2) Approaches for conducting target liability assessments to supplement nonclinical development packages for indications with limited appropriate preclinical models. (3) Leveraging health authority interactions, such as the US Food and Drug Administration (FDA) Initial Targeted Engagement for Regulatory Advice on CBER/CDER Products (INTERACT) and Pre-Investigational New Drug (Pre-IND) meetings, to gain feedback and actionable directives to guide program development. (4) Guidance on generating high quality nonclinical regulatory documents, including study reports and submission documents, to support IND applications.
    Keywords:  CAR; FDA; Treg; drug development; guidelines; nonclinical; pharmacology; toxicology
    DOI:  https://doi.org/10.3389/fmed.2025.1626067
  3. Mol Ther. 2025 Dec 11. pii: S1525-0016(25)01045-7. [Epub ahead of print]
    Redefining Multiple Sclerosis with CAR-T Cell Therapy.
    Yan-Ruide Li, Yuning Chen, Lili Yang.
      Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system characterized by aberrant immune responses against myelin and neuronal antigens, resulting in demyelination, axonal injury, and progressive neurological impairment. Although current immunomodulatory therapies can reduce relapse frequency and slow disease progression, they rarely induce durable remission or reverse established pathology. Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy, initially developed for cancer treatment, has recently emerged as a promising strategy for autoimmune diseases. By engineering T cells to selectively eliminate autoreactive B cells or other pathogenic immune populations, CAR-T therapy holds the potential to achieve long-lasting disease control and even immune system reset. Preclinical studies and early-phase clinical trials targeting CD19+ B cells have shown encouraging efficacy in autoimmunity, including MS. Nonetheless, significant challenges remain, such as optimizing antigen targets, minimizing treatment-associated toxicities, sustaining therapeutic benefit, and advancing scalable, safe, and cost-effective clinical applications. In this review, we summarize recent advances in applying CAR-T cell therapy to MS, outline key lessons learned from oncology and other autoimmune diseases, and discuss future directions for establishing CAR-T cells as a transformative approach in neuroimmunology.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.022
  4. World J Gastroenterol. 2025 Dec 07. 31(45): 112336
    Emerging role of lisocabtagene maraleucel chimeric antigen receptor-T cell in nodal and gastrointestinal follicular lymphoma.
    Takuya Watanabe.
      Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative treatment option for relapsed or refractory follicular lymphoma (FL), particularly in patients in whom multiple lines of conventional therapy have failed. Among cluster of differentiation (CD) 19-targeted products, lisocabtagene maraleucel (liso-cel) offers distinct advantages owing to its defined CD4+/CD8+ composition and favorable safety profile. Compared with diffuse large B-cell lymphoma, FL patients consistently achieve higher overall response rates and exhibit lower rates of severe cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome, supporting the rationale for expanding CAR-T cell therapy in this subgroup. This editorial review the current CD19-directed CAR-T cell therapy landscape, focusing on the pivotal TRANSCEND FL trial, which demonstrated a 97% overall response rate and 94% complete response rate, with a minimal incidence of severe CRS or neurotoxicity. Comparative insights highlight the advantages of liso-cel over other CAR-T cell products, such as axicabtagene ciloleucel and tisagenlecleucel in terms of toxicity, logistics, and outpatient feasibility. The implications for gastrointestinal FL (GI-FL), a subtype often excluded from CAR-T cell studies, were also addressed, emphasizing the need to include advanced-stage GI-FL cases in future evaluations. With ongoing improvements in manufacturing, accessibility, and biomarker development, liso-cel is well-positioned to become a central component in the evolving treatment paradigm for FL. However, challenges remain regarding durability of response, cost, and access, which warrant careful discussion.
    Keywords:  Chimeric antigen receptor-T cell therapy; Follicular lymphoma; Gastrointestinal follicular lymphoma; Lisocabtagene maraleucel; Nodal follicular lymphoma
    DOI:  https://doi.org/10.3748/wjg.v31.i45.112336
  5. MAbs. 2026 Dec;18(1): 2602989
    Fine-tuning affinity and spacer design enhances T cell potency in DLL3 and BCMA CAR T cells.
    Nicholas Mazzanti, Ninkka Tamot, Andrea Francese, Jinquan Luo, M Jack Borrok, Julie Rossillo, Joseph Plummer, Gauri Anand Patwardhan, Chi Shing Sum, Michael Ports, Kara L Spiller, Madhusudhanan Sukumar.
      Chimeric antigen receptor (CAR)-modified T cells have garnered substantial attention due to their clinical success, culminating in six Food and Drug Administration-approved therapies for hematological malignancies. Notably, CD19-specific CAR T cell therapies have achieved remarkable clinical efficacy in treating B-cell malignancies, but these profound and durable responses are not observed in CAR T therapies targeting other indications, particularly solid tumors. Key design elements of CAR constructs - namely, antigen binding affinity and spacer length - play critical roles in determining T cell effector function and overall therapeutic effectiveness. Refining CAR designs may enhance T cell functionality, extend clinical application, and potentially apply CAR T cell therapies across a wider array of malignancies. In this study, affinity variant and spacer variant CARs targeting BCMA and DLL3 tumor antigens were evaluated using in vitro measurements of antigen-binding properties and effector function. Each panel of CARs spanned 2-3 logs of antigen binding affinity (BCMA: 181 pM KD to 74 nM KD, DLL3: 417 pM to 407 nM). Additionally, CAR T cells were challenged with tumor spheroids composed of BCMA+ H929 and DLL3+ SHP77 tumor cells. We show that for both tumor models, higher affinity CARs (KD stronger than approximately 100 nM) paired with an intermediate length spacer (IgG1 Fc, CH2-CH3, 230AA) elicited the strongest levels of tumor killing, CAR+ T cell expansion, and proinflammatory cytokine production. These CARs displayed the strongest cellular affinity when measured in a conjugation assay, suggesting a relationship between cellular affinity and T cell functional performance. This study highlights the critical role of CAR design in enhancing T cell functionality, demonstrating that high-affinity CARs combined with intermediate-length spacers yield superior performance in targeting BCMA and DLL3 antigens. This study provides a framework for rational CAR design, informing strategies to broaden the clinical utility of CAR T-cell therapies beyond hematologic cancers.
    Keywords:  Affinity; CAR; CAR design; chimeric antigen receptor; spacer domain
    DOI:  https://doi.org/10.1080/19420862.2025.2602989
  6. Front Immunol. 2025 ;16 1658867
    Engineered cell therapies for autoimmune diseases: evaluating CAR-T and CAR-M progress and prospects.
    Mingxuan Zheng, Jiale Chen, Hong Yang.
      Autoimmune diseases (AID) comprise a diverse group of disorders driven by aberrant B-cell and T-cell reactivity against self-tissues. In recent years, cell-based therapies utilizing engineered T cells have emerged as a promising therapeutic strategy for AIDs. Notably, chimeric antigen receptor (CAR)-T cells have demonstrated the ability to selectively target and eliminate autoreactive immune populations, including pathogenic B cells and antibody-producing plasma cells. Beyond T-cell modulation, macrophages (MΦs) exhibit remarkable plasticity, differentiating into pro-inflammatory (M1) or anti-inflammatory (M2) phenotypes in response to microenvironmental cues. Advances in genetic engineering have enabled the development of CAR-MΦs (CAR-M), which hold potential for adoptive immunotherapy in certain diseases. However, CAR-M therapy remains experimental and requires further clinical validation. This review systematically evaluates the therapeutic potential of CAR-T and CAR-M in AIDs, comparing their respective advantages and limitations to provide a comprehensive foundation for future translational applications.
    Keywords:  CAR-M; CAR-T; RA; SLE; autoimmune diseases; macrophages
    DOI:  https://doi.org/10.3389/fimmu.2025.1658867
  7. Cells. 2025 Nov 25. pii: 1858. [Epub ahead of print]14(23):
    Strategies for the Development of NK Cell-Based Therapies for Cancer Treatment.
    Tatiana Budagova, Anna Efremova, Margarita Maiak, Dmitry Goldshtein.
      CAR-T cell therapy is a promising method of cancer treatment, but it has some disadvantages. These disadvantages have led scientists to explore the use of safer CAR-NK cells and new genetic modifications in order to improve the effectiveness of CAR cells. In this paper, we analyze existing approaches to modifying CAR-NK cells and discuss the results of clinical trials involving CAR-NK therapies. Conventionally, approaches to NK cell modification can be divided into three main groups: strategies to enhance antitumor cytotoxicity, strategies to improve the survival of CAR-NK cells and prolong their persistence in the body, and strategies to increase the safety of CAR-NK cells. The effects of CAR-NK cells on different tumor types are presented, and the number of clinical trials involving CAR-NK cells has been increasing every year, with positive results so far. As of September 2025, all the trials are in the early 1-2 stages of research, and it is expected that the first CAR-NK product will be approved in the near future.
    Keywords:  CAR-NK; IL-15/IL-15Rα; clinical trials; hnCD16; immune checkpoints; safety switches
    DOI:  https://doi.org/10.3390/cells14231858
  8. Science. 2025 Dec 11. 390(6778): 1084-1085
    Cancer-fighting cells made in body help patients.
    Mitch Leslie.
      Approach could be faster than making CAR-T cells in the lab-and early results are encouraging.
    DOI:  https://doi.org/10.1126/science.aee6253
  9. Mol Ther Methods Clin Dev. 2025 Dec 11. 33(4): 101637
    The Advanced Therapies model of Lund an integrated approach to accelerate access for many patients.
    Gisela Helenius, Stefan Jovinge, Anna Falk.
      Scientific breakthroughs in the field of cell and gene therapy lay the groundwork for therapeutic innovation, but their translation and integration into routine care is delayed by systemic inefficiencies and limited cross-sector alignment. The Advanced Therapies model of Lund is a proactive and integrated approach designed to accelerate the development of advanced therapies from discovery to reimbursement, facilitating close collaboration among three main entities: university, hospital, and the iActors (a coalition of the innovation system, incubators, investors, and industry). Unlocking the full potential of therapeutic innovation requires inclusive and proactive engagement from all entities to accelerate development timelines, optimize resource use across the ecosystem, and ultimately deliver curative, cost-effective advanced therapies to patients. This will ensure broad patient access and establishment of optimal conditions for developing the next generation of cell and gene therapies, while also facilitating innovation and economic growth. To operationalize this model, we developed the Cell and Gene Therapy Navigator, a visualization instrument designed to track and optimize the development of advanced therapies within the model framework. This tool leverages three-dimensional visualization to provide a dynamic and comprehensive overview of progress of the advanced therapy development across the three crucial entities: university, hospital, and iActors. We are confident that working according to the model will minimize translational gaps and result in seamless good manufacturing practices (GMP) transfer, fewer re-works, faster time to first-in-human, and the creation of more viable biotech companies.
    Keywords:  GMP; advanced therapies; cell therapy; gene therapy; patient access; regulatory science; tech transfer
    DOI:  https://doi.org/10.1016/j.omtm.2025.101637
  10. Int J Mol Sci. 2025 Nov 26. pii: 11435. [Epub ahead of print]26(23):
    Recurrent Limitations of CAR-T Therapy in Gliomas: Evidence from Preclinical and Phase I Clinical Studies.
    Jessica Bria, Andrea Filardo, Anna Di Vito, Attilio Della Torre, Angelo Lavano, Isabella Coscarella, Emanuela Chiarella, Emanuela Procopio, Maria Teresa Egiziano, Prospero Longo, Domenico La Torre.
      In recent years, the development of new immunotherapy strategies has been a significant breakthrough in cancer treatment. Among these, engineered T cell therapy with chimeric antigen receptors (CAR-T) has produced notable clinical results, especially in hematological malignancies. This success has sparked growing interest in extending the application of CAR-Ts to solid tumors, including gliomas. Gliomas-in particular, glioblastoma multiforme (GBM)-are among the most aggressive primary brain tumors, associated with a poor prognosis and a median survival of approximately one year after diagnosis. However, the translation of CAR-T therapy to gliomas presents significant challenges, related to factors such as tumor heterogeneity, presence of the blood-brain barrier (BBB), and a strongly immunosuppressive tumor environment. Despite this, in recent years, there has been an intensification of research efforts aimed at the identification of new antigenic targets and the development of preclinical models-both in vitro and in vivo-to evaluate the efficacy and safety of CAR-Ts in the treatment of gliomas. Despite promising results, currently available models still have essential limitations in faithfully reproducing the complexity of human gliomas. This review aims to offer an exhaustive overview of the most recent preclinical studies on CAR-T therapy in gliomas, with a focus on the identification of molecular targets, experimental strategies aimed at overcoming immunological barriers, and translational challenges that need to be addressed for future successful clinical implementation.
    Keywords:  CAR-T; CAR-T therapy; glioblastoma multiforme; glioma; molecular targets; organoids
    DOI:  https://doi.org/10.3390/ijms262311435
  11. Mol Ther. 2025 Dec 11. pii: S1525-0016(25)01048-2. [Epub ahead of print]
    DR5 CAR-T cells target melanoma and suppress MDSCs with minimal toxicity.
    Huaishan Wang, Shujing Liu, Prithvi Sinha, Fang Liu, Xiaogang Zhang, Yeye Guo, Beatriz Goncalves, Qiuxiang Zheng, Haiwei Mou, Jingbo Yang, Lili Huang, Fei Miao, Tingting Zeng, Giorgos Karakousis, Alexander C Huang, Tara Mitchell, Ravi Amaravadi, Lynn Schuchter, Michael Milone, Wei Guo, Carl June, Meenhard Herlyn, Yi Fan, Xiaowei Xu.
      Chimeric antigen receptor (CAR) T cell therapies have poor efficacy in solid tumors due to limited target specificity and an immunosuppressive tumor microenvironment. We investigated death receptor 5 (DR5) as a CAR target based on its high expression in both solid tumors and myeloid-derived suppressor cells (MDSCs). We engineered agonistic DR5-specific CAR constructs and evaluated their activity in multiple models, demonstrating DR5-expression-dependent tumor killing, confirmed by knockout and overexpression experiments. DR5-targeting single-chain variable fragments retained their pro-apoptotic activity when expressed on non-effector cells or extracellular vesicles. Among multiple CAR designs, we identified a construct with optimized binding affinity that maintained T cell viability while preserving strong tumor and MDSC-killing potency. To assess safety and efficacy in an immunocompetent setting, we also developed a murine DR5-targeted CAR. In multiple xenograft and syngeneic mouse models, DR5 CAR-T cells reduced tumor growth, prolonged survival, and did not cause detectable toxicity. In patient-derived organoids and tissue slices, DR5 CAR-T cells infiltrated tumor tissues, reduced MDSCs, boosted CD8+ T cell activity, and inhibited tumor growth. These findings support DR5-targeted CAR-T therapy as a promising strategy for treating solid tumors, combining direct tumor cytotoxicity with immune activation while minimizing off-target effects.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.025
  12. Int J Mol Sci. 2025 Nov 28. pii: 11566. [Epub ahead of print]26(23):
    A Bidirectional EF1 Promoter System for Armoring CD19 CAR-T Cells with Secreted Anti-PD1 Antibodies.
    Asmita Khaniya, Nattarika Khuisangeam, Supannikar Tawinwung, Koramit Suppipat, Nattiya Hirankarn.
      Chimeric antigen receptor (CAR) T cell therapy for B cell malignancies is often limited by T cell exhaustion, which is frequently driven by the PD-1/PD-L1 immune checkpoint axis. To overcome this, we developed an "armored" CAR-T cell strategy using a novel bidirectional promoter system. We engineered a single vector to co-express a CD19-specific CAR alongside a secreted anti-PD1 molecule, in either a full-length antibody or a single-chain variable fragment (scFv) format, using the Sleeping Beauty (SB) transposon system. The sequences for the anti-PD1 modules were derived from the clinical antibody nivolumab. Both armored constructs demonstrated robust CAR expression, comparable to or higher than conventional CAR-T cells, and proliferated significantly more than untransfected controls. The engineered cells successfully secreted their anti-PD1 payloads, with the full-length antibody showing more sustained secretion than the scFv. This autocrine blockade resulted in significantly reduced surface PD1 expression on the armored CAR-T cells. Functionally, the anti-PD1-secreting cells exhibited superior cytotoxicity against PD-L1-positive Raji target cells, particularly at low effector-to-target ratios. Critically, in a serial rechallenge assay designed to simulate chronic antigen exposure, both armored CAR-T cell groups showed markedly enhanced proliferation and persistence compared to conventional CAR-T cells, which failed to expand after repeated stimulation. Our findings validate the bidirectional EF1 promoter as an efficient system for generating multi-functional T cells and demonstrate that armoring CAR-T cells with secreted anti-PD1 antibodies is a potent strategy to enhance their persistence and anti-tumor efficacy.
    Keywords:  CAR-T cells; anti-PD1; bidirectional promoter
    DOI:  https://doi.org/10.3390/ijms262311566
  13. Arthritis Res Ther. 2025 Dec 06.
    Chimeric antigen receptor (CAR) therapies for precise eradication of pathogenic cells in autoimmunity.
    George D Kalliolias, Efthimia K Basdra, Athanasios G Papavassiliou.
      CAR-T cells (CAR-Ts) are genetically engineered T lymphocytes to express a receptor construct bearing an extracellular recognition domain that guides the killing specificity, a transmembrane domain, and an intracellular domain that elicits effector signaling. Upon encountering the target cell, CAR-Ts accomplish their cytolytic effector function directly via engagement of pro-apoptotic pathways and exocytosis of perforin and granzymes, or indirectly via secretion of cytokines that activate NK cells. Autologous CAR-Ts, bearing an extracellular recognition domain specific for the B-cell surface markers CD19 or BCMA, were initially approved for the treatment of late-stage hematologic malignancies. The last five years, mounting evidence from small studies in humans, employing autologous CAR-Ts targeting CD19 to selectively eliminate CD19 + cell subsets from the pool of the B-cell lineage, have revealed acceptable safety profile and encouraging efficacy in treatment-resistant systemic lupus erythematosus, systemic sclerosis, and idiopathic inflammatory myositis. Herein, we focus on a series of groundbreaking reports published within 2025 that enlighten the arising transformational potential and the emerging challenges of the CAR-based therapies regarding the management of life-threatening endotypes of autoimmune diseases.
    Keywords:  Allogeneic CAR-T cells; Autoimmune diseases; Autologous CAR-T cells; Chimeric antigen receptor t cell therapy; MRNA CAR-T cells
    DOI:  https://doi.org/10.1186/s13075-025-03711-8
  14. Sci Immunol. 2025 Dec 12. 10(114): eadn2093
    Reaching maturity: Thymic γδ T cell differentiation in mice and humans.
    Rúben G R Pinheiro, Bruno Silva-Santos.
      γδ T cells are promising players in immunotherapy because of pleiotropic functions, many of which can be preprogrammed in the thymus. Here, we review the cellular and molecular mechanisms that underlie γδ T cell development in the mouse and human thymi, focusing on their acquisition of diverse cytotoxic or cytokine-secreting functions and their dependence on interactions with the specialized thymic epithelium. We discuss the most recent findings and models that inform our understanding of γδ T cell differentiation and may affect the development of γδ T cell-based immunotherapies.
    DOI:  https://doi.org/10.1126/sciimmunol.adn2093
  15. Cytotherapy. 2025 Nov 16. pii: S1465-3249(25)00806-0. [Epub ahead of print]28(2): 101968
    GMP-compliant manufacturing of allogeneic peripheral blood CAR-NK cells for the treatment of acute myeloid leukemia.
    Laura Córdoba-Espejo, Laura Sánchez-Vega, Almudena García-Ortiz, Eva Castellano, Raquel Oliva, Alejandra Ortiz-Ruiz, Daniel Gil-Alós, Patricia Del Moral, Adrián Fernández, Diana Sanjurjo, Sandra López-García, Unai Perpiña, Josep M Canals, Dean A Lee, Daniel J Powell, Rafael Alonso, Paula Río, María Liz Paciello, Antonio Valeri, Alejandra Leivas, Joaquín Martínez-López.
       BACKGROUND AND AIM: Chimeric Antigen Receptor (CAR)-T cell therapy has shown promising results in hematological malignancies but faces limitations such as the need for autologous products or additional modifications of allogeneic T cell sources to prevent graft-versus-host disease (GvHD). In acute myeloid leukemia (AML), its application is particularly challenging due to antigen overlap between malignant cells and healthy hematopoietic stem cells, leading to severe and often fatal toxicities due to on-target, off-tumor effect. Natural killer (NK) cells offer a promising alternative for CAR therapy, as they are well tolerated and exert antitumor activity beyond CAR-mediated mechanisms. Peripheral blood (PB) is an accessible NK cell source with a relatively high proportion of mature NK cells; however, generating clinically relevant numbers of highly transduced PB-derived CAR-NK cells in closed systems remains challenging, and production protocols need optimization. Here, we evaluated different manufacturing strategies to generate NKG2D CAR-NK cells from PB in the CliniMACS Prodigy closed platform.
    RESULTS: We established an optimized protocol that achieved enhanced transduction efficiency, yielding high numbers of CAR+ cells. The final product met good manufacturing practice (GMP)-aligned safety and sterility requirements, displayed superior in vitro cytotoxicity against AML cell lines compared to the same product manufactured in the preclinical setting, and delayed tumor progression in an AML xenografted mouse model without cytokine support.
    CONCLUSIONS: This standardized, GMP-compliant protocol provides a robust platform for producing PB-derived CAR-NK cell therapies in a closed platform, advancing their clinical translation.
    Keywords:  CAR-NK; CliniMACS Prodigy; NKG2D CAR; acute myeloid leukemia; good manufacturing practice; immunotherapy
    DOI:  https://doi.org/10.1016/j.jcyt.2025.07.009
  16. Sci Transl Med. 2025 Dec 10. 17(828): eadz0529
    ZAP327 signaling domain-driven chimeric antigen receptor generates robust and long-term antitumor immunity in mouse models.
    Xin Liu, Jiayi Zhang, Junjun Chu, Yi-Jou Chen, Chen Qian, Helen Y Wang, Rong-Fu Wang.
      Chimeric antigen receptor (CAR) T cell therapy has shown impressive clinical responses in the treatment of blood cancers, but high percentages of disease relapse 1 year after T cell infusion and severe toxicities associated with CAR T cell therapy remain major issues. Here, we report the construction of CARs with a ZAP70-derived signaling domain (ZAP327) that enhances therapeutic antitumor activity with increasing in vivo T cell persistence. ZAP327-driven CAR T cells reduced cytokine release and expression of T cell exhaustion markers but maintained similar or better cytolytic activity against tumor cells compared with conventional CAR T cells. The costimulatory domains, such as CD28 and 4-1BB, in the ZAP327 CAR constructs are required for providing a spacer between the transmembrane domain and ZAP327 kinase domain for optimal kinase structure folding and function, as well as costimulatory signaling. Furthermore, ZAP327-driven CAR T cells outperform conventional and several recently improved CAR T cells in therapeutic antitumor immunity, particularly in an antigen-low expression tumor model, which is clinically relevant and important for immune escape and disease relapse. Mechanistically, we show that the ZAP327 domain tuned down TCR signaling, increased the pools of stem-like memory T cells, and exhibited metabolic features associated with memory T cells by using the oxidative phosphorylation pathway. These results highlight the therapeutic potential of ZAP327-driven CAR T cells to overcome the limitations of the current CAR T cell therapies and enhance the potency and persistence of antitumor T cell responses in solid tumors as well.
    DOI:  https://doi.org/10.1126/scitranslmed.adz0529
  17. Cancers (Basel). 2025 Nov 25. pii: 3766. [Epub ahead of print]17(23):
    CAR Therapies: Ex Vivo and In Vivo Potential of Exosomes and Biomimetic Nanoparticles.
    Ekaterina Tkachenko, Natalia Ponomareva, Konstantin Evmenov, Artyom Kachanov, Sergey Brezgin, Anastasiya Kostyusheva, Vladimir Chulanov, Elena Volchkova, Alexander Lukashev, Dmitry Kostyushev, Peter Timashev.
      Chimeric antigen receptor (CAR) therapy represents a promising modality for treating cancer and autoimmune diseases, employing genetically engineered immune cells. Despite remarkable clinical outcomes, its broad implementation is constrained by significant challenges, including toxicity, limited specificity, and complexities associated with genetic material delivery. Biological nanoparticles, such as exosomes, virus-like particles, and biomimetic nanostructures, possess unique properties that can address these limitations. These nanoplatforms enable targeted delivery of genetic constructs, mitigate the risk of cytokine release syndrome, modulate CAR cell activity, and can function as biosensors. Furthermore, they facilitate non-viral, in vivo CAR cell engineering, streamlining the process compared to conventional ex vivo methods. The advancement of in vivo strategies underscores the critical need to overcome toxicity hurdles inherent to current CAR-T platforms. In this context, exosomes and biomimetic nanoparticles offer considerable potential due to their innate biocompatibility, programmability, and versatile cargo capacity for payloads like mRNA and circular RNA. This review comprehensively outlines contemporary genetic platforms for CAR expression and examines the opportunities presented by biological delivery vehicles. It focuses on recent achievements and revisits fundamental CAR principles through the lens of emerging technologies aimed at confronting persistent challenges in the field.
    Keywords:  CAR-T therapy; T cells; biological nanoparticles; gene therapy; targeted delivery
    DOI:  https://doi.org/10.3390/cancers17233766
  18. Cancer Cell Int. 2025 Dec 07.
    Improving CAR T cell therapy against malignancies through gene knock-down/out strategies: a systematic review.
    Amirali Karimi, Sayedeh-Zahra Kazemi-Harikandei, Sanam Alilou, Dorsa Salabat, Seyed Morteza Pourfaraji, Fatemeh Ojaghi Shirmard, Niloofar Seighali, Saba Maleki, Behnia Akbari, Farshid Noorbakhsh, Jamshid Hadjati, Hamid Reza Mirzaei.
       BACKGROUND: CAR T cells still face numerous obstacles in treating hematologic and solid malignancies. Although gene editing technologies have improved CAR T cell therapy, there are currently no systematic reviews to broadly address preclinical and clinical outcomes of gene-edited CAR T cells. Therefore, we aimed to systematically review the preclinical and clinical studies that evaluate the outcomes of knocked-out/knocked-down (KO/KD) CAR T cells.
    METHODS: This study was submitted to international Prospective Register of Systematic Reviews (PROSPERO) with the ID CRD42022320541 and follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines. We searched Five databases (PubMed, EMBASE, Cochrane Library, Web of Science, and Clinicaltrials.gov) up to March 19th, 2022 for the keywords of "CAR T cell" and "knock-out/knock-down". The retrieved records then underwent a two-step screening process based on the inclusion criteria, first title/abstract and then full-text screenings, and their data were used for qualitative synthesis.
    RESULTS: Our search results yielded 3780 records. Finally, a total of 241 records, including 193 animal and 52 human studies (four concurrent in both groups) that reported KO/KD genes for 105 proteins were included. The positive effects of these 105 KO/KD were categorized into five groups: (1) enabling allogeneic CAR production while limiting GVHD, (2) increasing the efficacy of CAR T cells, (3) Decreasing their side effects, (4) limiting CAR T cell fratricide, and (5) enabling the use of concurrent therapies. In the human section, solid tumors had fewer studies with less favorable outcomes compared to hematologic malignancies.
    CONCLUSIONS: This systematic review emphasized the various mechanisms by which CAR T cell effects could be boosted. Future researchers can choose their desired genes out of the 105 mentioned candidates. We also encourage the researchers to increase their efforts on solid tumors to compensate for the lack of increased efficacy in this group.
    Keywords:  CAR T cell; Cancer immunology; Gene editing; Knock-down; Knock-out
    DOI:  https://doi.org/10.1186/s12935-025-04090-5
  19. Int J Mol Sci. 2025 Nov 28. pii: 11534. [Epub ahead of print]26(23):
    The Potential of β-Synuclein-Specific Regulatory T Cell Therapy as a Treatment for Progressive Multiple Sclerosis.
    Grace E Osmond, Nevin A John, Yi Tian Ting, Joshua D Ooi.
      Disease progression in multiple sclerosis (MS) is now known to affect many patients, even those not diagnosed with progressive subtypes. Progressive and neurodegenerative aspects of MS are poorly treated by currently available therapies. Research on new therapeutic options is needed to improve health outcomes in people with MS. This review highlights the potential for treatment using an engineered T cell receptor-regulatory T cell (TCR-Treg) therapy targeting the presynaptic protein beta-synuclein. Tregs respond to self-antigens presented on human leukocyte antigen (HLA) class II with anti-inflammatory and pro-neural healing effects, but this response is impaired in MS patients. Since the HLA-DRB1*15:01 allele is known to contribute to MS pathogenesis, a TCR specific to a known antigen presented on DRB1*15:01 can be transduced into Tregs to direct them to activate within the inflamed brain tissue. Beta-synuclein is released from neurons at a high level after neural damage, may be presented on HLA, enables homing of specific T cells to the grey matter, and is immunogenic in progressive MS patients. This review presents beta-synuclein as a disease-relevant antigen to target for therapeutic development.
    Keywords:  Treg therapy; autoantigens; autoimmune disease; autoimmunity; beta-synuclein; cell-based therapy; multiple sclerosis; regulatory T cells; translational immunology
    DOI:  https://doi.org/10.3390/ijms262311534
  20. Nat Commun. 2025 Dec 10.
    Tuning CAR-T cells by targeting cancer-associated glycan in pancreatic cancer.
    Sangwoo Park, Cassidy E Ho, Eli P Darnell, Alexandra N Wolff, Hana Takei, Filippo Birocchi, Amanda A Bouffard, Diego Salas-Benito, Giulia Escobar, Mark B Leick, Adele Mucci, Trisha R Berger, Marcela V Maus.
      Chimeric antigen receptor (CAR) T cell therapy has transformed cancer treatment but its efficacy remains limited in solid tumors due to antigen heterogeneity, an immunosuppressive microenvironment, and the glycocalyx barrier. The glycocalyx, composed of dense glycoproteins such as MUC1, is markedly expanded in cancers, where it impedes immune cell access and antigen engagement, thereby reducing efficacy. In most adenocarcinomas, Tn antigen, comprising N-acetylgalactosamine linked to serine or threonine, is overexpressed. Tn-MUC1, a truncated form of MUC1 decorated with Tn antigen, is frequently overexpressed in pancreatic cancer. Here, we incorporate a non-signaling glyco-bridge binder recognizing Tn-MUC1 into mesothelin-directed CAR-T cells. This bridge enhances tumor recognition and cytotoxicity by increasing avidity and facilitating CAR activation in a density- and affinity-dependent manner. To broaden its applicability, we design a tandem Helix pomatia agglutinin (HPA) lectin-based bridge that recognizes Tn antigens across cancer types. CAR-T cells with the HPA-bridge exhibit superior cytotoxicity in pancreatic cancer models.
    DOI:  https://doi.org/10.1038/s41467-025-66102-2
  21. Ann Med Surg (Lond). 2025 Dec;87(12): 9193-9194
    Tumor-localized immunomodulation: a critical advance in engineering CAR-t cells for solid malignancies.
    Maryam Abid, Ursula Abu Nahla, Muhammad Nabeel Saddique.
      Chimeric antigen receptor (CAR)-T cell therapy, despite revolutionizing hematological malignancies, remains limited in solid tumors due to immunosuppressive microenvironments and systemic toxicities from combination immunotherapies. Recent engineering innovations demonstrate that physically linking anti-PD-L1 antibodies to interleukin-12 within CAR-T cells creates tumor-localized immunomodulation, concentrating therapeutic activity at PD-L1-positive sites while minimizing systemic exposure. In preclinical models, PD-L1-binding IL-12 fusion proteins achieved superior antitumor responses (100 vs. 50% complete responses) compared to non-binding controls, with significantly reduced inflammatory toxicity. Spatial proteomic analysis revealed comprehensive tumor microenvironment remodeling including enhanced CD8+ T cell infiltration and reduced immunosuppressive myeloid populations. Validation in human CAR-T cells targeting TAG72-positive ovarian cancer confirmed appropriate PD-L1 binding and enhanced cytotoxicity. This rational engineering strategy addresses multiple barriers simultaneously through molecular sequestration, offering a promising platform applicable to alternative checkpoint-cytokine combinations and other cellular therapeutics. Clinical translation represents a critical next step for extending CAR-T efficacy to solid malignancies.
    Keywords:  CAR-T cells; checkpoint inhibitors; immunotherapy; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.1097/MS9.0000000000004256
  22. JAMA. 2025 Dec 08.
    Advancing CAR T-Cell Therapy: Evidence-Based Trial Design for Chimeric Antigen Receptor T-Cell Therapy in Oncology.
    Upendra Mahat, Asha Das, Vijay Kumar, Vinay Prasad.
      
    DOI:  https://doi.org/10.1001/jama.2025.21721
  23. S Afr Med J. 2025 Jun 03. 115(5): e3070
    Progress in advanced cellular and gene therapies in South Africa and barriers to patient access: A National Consortium paper on behalf of the BloodSA Cell and Gene Therapy working party.
    C Hendricks, I Viljoen, M Botes, D Brittain, J Mahlangu, E Verburgh, T Gerdener, C Herd, M Logan, A L Marais, T N Glatt, R Cockeran, C Poole, J Du Toit, M S Pepper.
      The fields of molecular and cellular medicine have, in recent years, witnessed a great deal of progress globally, particularly in understanding disease pathogenesis and through the development of advanced cellular therapy products and gene therapies. Despite the transformative potential of these new therapies, low- and middle-income countries face significant barriers to their access. Advanced cellular therapy legislation in South Africa (SA) has not kept up with this fast-advancing field, and requires a fast-tracked renewal. Furthermore, the prohibitive cost of commercial therapies, including chimeric antigen receptor (CAR) T-cell products, and the lack of infrastructure, manufacturing and research capacity, must be addressed to make equitable patient access an achievable goal in our setting. To this end, a national cell and gene therapy consortium, comprising clinicians, clinician-scientists, scientists, legal experts, postgraduate students and representatives from industry, the national blood service and the pharmaceutical industry, was initiated. The mandate of this group is to aid the progression of advanced cellular therapies in SA, and the purpose of this article is to outline the progress that has been made. We will highlight the gaps in each core field of practice within this space, and provide a proposal for making these therapies more accessible in SA.
    DOI:  https://doi.org/10.7196/SAMJ.2025.v115i5.3070
  24. Int J Mol Sci. 2025 Nov 26. pii: 11466. [Epub ahead of print]26(23):
    Ex Vivo Gene and Cell Therapy in Hematopoietic Stem Cells.
    Irina O Petrova, Svetlana A Smirnikhina.
      Ex vivo cell and gene therapy is a prospective approach to treatment of genetic diseases. To date, one of the most prevalent examples of genetically engineered cell therapies is hematopoietic stem/progenitor cells (HSPCs). This mini review is focused on HSPC therapy methods that have been approved for medical use. Most gene therapy methods rely on the lentiviral integration of the gene into the target cell genome, as lentiviruses are extremely effective, particularly in transduction of non-dividing cells. In this constantly evolving field, it is important to find the balance between safety concerns and efficiency. Analyzing cases of several diseases, for which ex vivo gene therapy was developed, we strive to understand which factors are crucial to success and what the potential drawbacks are. Although in general, viral gene integration demonstrates a considerable therapeutic effect, it has oncogenic potential. Development of self-inactivating vectors was a breakthrough in regard to safety, but the possibility of oncogenesis remains, and strict analysis of integration sites is required.
    Keywords:  CRISPR/Cas; gene therapy; hematoietic stem/progenitor cells; viral vectors
    DOI:  https://doi.org/10.3390/ijms262311466
  25. S Afr Med J. 2025 Feb 18. 115(1): e2629
    Addressing the limitations of the regulatory landscape in South Africa regarding advanced cell and gene therapies and related sectors involving human cells, tissues and organs.
    I M Viljoen, M S Pepper.
      Advanced cell-based and gene therapy products emerged during the 1990s as new health product categories for treating and curing previously untreatable or incurable conditions. These products are complex, diverse and therapeutically specific, requiring specialised regulatory frameworks. During the last three decades, several jurisdictions have constructed specific regulatory frameworks to ensure these products' safety, clinical efficacy and quality. As these are new and disruptive products, these frameworks are continuously evolving. However, South Africa (SA)'s regulatory frameworks for medicines, human biological materials and genetically modified organisms have not kept pace with scientific and technological developments, leaving regulatory gaps. We briefly describe these novel products and their regulatory frameworks, and propose a way forward in SA.
    DOI:  https://doi.org/10.7196/SAMJ.2025.v115i1.2629
  26. Cells. 2025 Dec 02. pii: 1917. [Epub ahead of print]14(23):
    Characterization of Stimulated γδ T Cells: Phenotypic Analysis and Implications for Allogeneic Cellular Immunotherapy.
    Anna Bold, Heike Gross, Marco Bardenbacher, Elisabeth Holzmann, Stefan Knop, Martin Wilhelm.
      Due to their anti-tumor activity and non-major histocompatibility complex (MHC) binding T cell receptor, γδ T cells are suitable candidates for allogeneic cellular immunotherapy in cancer. Recently, we developed a new protocol called Ko-Op for stimulation of γδ T cells (specifically Vy9Vδ2 T cells) that generates a cell product consisting mainly of γδ T cells with preserved anti-tumor activity targeted for clinical-grade application. In this study, we investigated the phenotype of stimulated γδ T cells and correlated this with results of functional assays to obtain a deeper understanding of the characteristics of stimulated γδ T cells. Additionally, an intensive analysis of surface molecules of unstimulated and stimulated γδ T cells is presented. Since heterogeneous results regarding the response to therapy with γδ T cells observed in earlier clinical trials could be a consequence of various extents of γδ T cell adhesion and migration ability, we addressed surface molecules associated with cellular activity and adhesion and migration functions as well. By investigating correlations between the phenotype of unstimulated γδ T cells and cellular cytotoxicity, as well as the degranulation ability of stimulated γδ T cells, we could draw conclusions about optimal donors for further allogeneic cellular therapies. Finally, we demonstrated that the phenotype varies over the time of culture and is clearly modifiable by changing the stimulation protocol.
    Keywords:  Vy9Vδ2 T cells; activation; cellular immunotherapy; interleukin 2; phenotype; surface molecules; zoledronate; γδ T cells
    DOI:  https://doi.org/10.3390/cells14231917
  27. J Transl Med. 2025 Dec 09. 23(1): 1393
    Convergence of mRNA technology and chimeric antigen receptor therapy: targeted technology optimizing targeted therapy.
    Huajing Chen, Jiayi Zhang, Jiansong Huang, Zichen Wu, Lirui Tang, Yuxin Tian, Shan Gao, Shihan Huang, Jiaying Cao, Jiali Chen, Yuhua Li.
      
    Keywords:  CAR mRNA; CAR therapy; CAR-T cells; Delivery system; Future prospects; Safety; Therapeutic efficacy; mRNA technology
    DOI:  https://doi.org/10.1186/s12967-025-07470-7
  28. Immunity. 2025 Dec 09. pii: S1074-7613(25)00514-X. [Epub ahead of print]58(12): 2931-2933
    A surprising link: TET2 clonal hematopoiesis boosts immune checkpoint therapy.
    Qiang Dong, Chengcheng Jin.
      TET2 mutations can drive clonal hematopoiesis (CH), but their impact on tumor immunity remains unresolved. Recently in Cancer Cell, Herbrich et al. reported that TET2-mutant CH reprograms tumor-associated macrophages to enhance antigen presentation and immune-checkpoint therapy efficacy in solid tumors.
    DOI:  https://doi.org/10.1016/j.immuni.2025.11.012
  29. J Hepatol. 2025 Dec 08. pii: S0168-8278(25)02711-4. [Epub ahead of print]
    CAR T-cell therapy induces remission in multiorgan IgG4-related disease with hepatobiliary involvement.
    Verena Keitel, Michael C Kreissl, Tobias Goetze, Carola Dröge, Christina Katharina Kuhn, Nhu-Nguyen Pham, Dennis Löffler, Dominique Borie, Jens Schreiber, Martin Boettcher, Katrin Hippe, Maciej Pech, Martin Mikusko, Ulrike Köhl, Denise Walther, Kristin Reiche, Dimitrios Mougiakakos.
      IgG4-related disease (IgG4-RD) is a fibroinflammatory disorder in which IgG4+ B cells and T cells interact to drive chronic organ inflammation. Patients with multiorgan involvement may become refractory to standard therapy, resulting in progressive organ damage and risk of organ failure. Here, we report a patient with treatment-refractory multiorgan IgG4-RD treated with CD19-directed CAR T cells and describe the clinical and immunologic effects over more than 12 months of follow-up. A 60-year-old man with IgG4-RD involving the pancreas, hepatobiliary tract, and lungs refractory to long-term immunosuppression received autologous CD19-directed CAR T cells. Disease course was monitored longitudinally, and peripheral blood underwent multimodal immune profiling. CAR T cell therapy was well tolerated, with only grade 1 cytokine release syndrome, no neurotoxicity, and transient cytopenias without infections. Treatment induced B cell aplasia lasting six months, and serum IgG4 normalized by month 8 and remained within the reference range. FAPI PET/CT demonstrated regression of fibroinflammatory activity, accompanied by improved lung function and quality of life. Immunosuppressive therapy was completely discontinued without disease flares for more than 12 months. B cell reconstitution consisted predominantly of naïve and transitional subsets. This was paralleled by a decline in T follicular helper cells and CD4+ cytotoxic T cells and attenuation of fibro-inflammatory and B cell-mediated signaling networks on interactome analyses. In this treatment-refractory case of multiorgan IgG4-RD, CD19-directed CAR T cell therapy induced durable, treatment-free remission with normalization of serum IgG4 and improvement across multiple clinical endpoints. Multimodal immune profiling indicates that CAR T cells can reset the B cell compartment and dampen pathogenic T cell and stromal interactions, supporting prospective evaluation of CAR T cell therapy in IgG4-RD.
    Keywords:  B cell depletion; CAR T cells; IgG4-related disease; autoimmune diseases; cholangitis; immune reset
    DOI:  https://doi.org/10.1016/j.jhep.2025.11.027
  30. J Exp Med. 2026 Feb 02. pii: e20241234. [Epub ahead of print]223(2):
    Advances in the development of personalized neoantigen therapies.
    Spencer E Mirabile-Brightman, Lisa H Butterfield.
      The ability to specifically engage tumor-reactive T cells for therapeutic benefit is the ultimate goal of cancer immunotherapy. Whereas currently approved immunotherapies leverage and modulate existing endogenous T cells in an antigen non-specific manner, cancer vaccines and neoantigen therapeutics promise the ability to selectively amplify T cells specific for targeted antigens. Advances in the identification of tumor-specific antigens coupled with a greater understanding of T cell biology and immunization platforms have culminated in recent trials where signs of clinical efficacy have been observed, particularly in randomized adjuvant clinical settings. In this review, we discuss the identification of tumor-specific antigens for cancer therapy, the benefits of including antigens recognized by CD4+ T cells, clinical data investigating novel immunization platforms, and emerging clinical settings where promotion of tumor-specific immunity may be optimal.
    DOI:  https://doi.org/10.1084/jem.20241234
  31. Mol Ther. 2025 Dec 10. pii: S1525-0016(25)01033-0. [Epub ahead of print]
    FcεRγI promotes canine CD8 chimeric antigen receptor T cell cytotoxicity through a Syk-NFκB axis.
    Emma E Goodman, Abdulla Berjis, Neil C Sheppard, Nicola J Mason, Roddy S O'Connor, Aimee S Payne.
      Comparative oncology has advanced cancer immunotherapy, although cellular mechanisms governing chimeric antigen receptor T cell (CART) therapy in canines are poorly understood. In a first-in-canine trial, anti-CD20 CART with canine 4-1BB-CD3ζ (cBBζ) domains induced CD20-negative lymphoma outgrowth but did not persist or deplete B-cells. Here we show that canine CARTs incorporating human (h)BBζ demonstrate superior therapeutic function, mediated by FcεRγI. HBBζ-CART showed greater cytolysis and CD8 T cell outgrowth than cBBζ-CART in repetitive killing assays and a canine B-cell leukemia xenograft model. Transcriptional profiling revealed upregulation of FCER1G and innate-like genes in CD8 hBBζ- versus cBBζ-CARTs. CRISPR-mediated FCER1G deletion and pharmacologic Syk/NFκB inhibition indicated that Syk-NFκB signaling regulates FcεRγI-mediated enhancement of hBBζ-CART cytotoxicity, associated with increased granzyme B and IFNγ/TNFα production. Syk-NFκB signaling promotes FcεRγI expression in hBBζ CARTs, and CAR-TCR interactions potentiate NFκB signaling to upregulate FcεRγI and enhance CART function. These studies identify a potent therapeutic subset of innate-like canine CARTs induced by hBBζ signaling, which holds potential to improve both canine and human CART therapy.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.010
  32. Blood Adv. 2025 Dec 10. pii: bloodadvances.2025017573. [Epub ahead of print]
    CAR T cells targeting C-C motif chemokine receptor 4 (CCR4) selectively deplete human Tregs ex vivo and in vivo.
    Caitlin M Tilsed, Karen P Fong, Xinyi Shi, Tatiana Akimova, Liqing Wang, Estela Noguera-Ortega, Ryan Krouse, Andres Bermudez, Sunil Singhal, Regina M Young, Evgeniy Eruslanov, Keisuke Watanabe, Wayne W Hancock, Carl H June, Steven Albelda.
      Regulatory T cells (Tregs) are essential for maintaining immune tolerance but also contribute to immune suppression within the tumor microenvironment (TME), dampening anti-tumor immunity in hematologic and solid tumors. As such, strategies aimed at depleting Tregs or reducing their suppressive activity are of great clinical interest. C-C Chemokine receptor 4 (CCR4) is highly expressed on intratumoral Tregs and mediates Treg migration into the TME. Although current therapies targeting CCR4 using monoclonal antibodies have shown some Treg depletion in clinical trials, their clinical efficacy has been limited. We therefore tested whether chimeric antigen receptor (CAR) T cell therapy could be used to deplete Tregs. We evaluated human-specific CCR4-directed CAR T cells (CCR4-CARTs) previously developed for T cell malignancies and determined whether these CARTs could deplete human Tregs ex vivo and in vivo. In patient-derived malignant pleural effusions and lung cancer tumor digests, CCR4 CARTs almost completely depleted Tregs, plus a small population of CCR4+ CD4+ non-Tregs, while sparing CD8+ T cells. When tested in vivo in humanized mice, a single dose of CCR4 CART led to nearly complete Treg depletion. These findings support the potential of CCR4 CARTs as a selective and effective approach to Treg modulation and warrant further clinical investigation.
    DOI:  https://doi.org/10.1182/bloodadvances.2025017573
  33. Cancer Immunol Res. 2025 Dec 08.
    A universal boosting strategy for adoptive T cell therapy using a paired vaccine/chimeric antigen receptor.
    Rebecca Burchett, Claire G Morris, Mira Ishak, Nickolas J Serniuck, Derek T Cummings, Christopher L Baker, Ricardo Marius, Natasha Kazdhan, Christopher M Silvestri, John Bell, Brian D Lichty, Scott R Walsh, Yonghong Wan, Joanne A Hammill, Jonathan L Bramson.
      Vaccines that encode tumour-associated antigens are potent boosting agents for adoptively transferred tumour-specific T cells. Employing vaccines to boost adoptively transferred tumour-reactive T cells relies on a priori knowledge of tumour epitopes, isolation of matched epitope-specific T cells, and personalized vaccines, all of which limit clinical feasibility. Here, we investigated a universal strategy for boosting transferred tumour-specific T cells where boosting is provided through a chimeric antigen receptor (CAR) that is paired with a vaccine encoding the CAR target antigen. To this end, we developed and employed a model wherein murine T cells expressing a TCR specific for antigen on syngeneic tumours were engineered with boosting CARs against a distinct surrogate boosting antigen for studies in immunocompetent hosts. Boosting CAR-engineered tumour-specific T cells with paired vesicular stomatitis virus (VSV) vaccines was associated with robust T cell expansion and delayed tumour progression in the absence of prior lymphodepletion. CAR-T cell expansion and antitumour function was further enhanced by blocking IFNAR1. However, vaccine-boosted CAR-T cells rapidly contracted and antigen-positive tumours re-emerged. In contrast, when the same T cells were boosted with a vaccine encoding antigen that stimulates through the TCR, the adoptively transferred T cells displayed improved persistence, tumour-specific endogenous cells expanded in parallel, and tumour cells carrying the antigen target were completely eradicated. Our findings underscore the need for further research into CAR-mediated vaccine boosting, how this differs mechanistically from TCR-mediated boosting, and the importance of engaging endogenous tumour-reactive T cells during vaccination to achieve long-term tumour control.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-0070
  34. Transfus Med Hemother. 2025 Dec;52(6): 350-359
    Guiding Antiviral Cell Therapy Approaches with an Online Resource of Clinically Scored Epitopes, T-Cell Receptors, and B-Cell Receptors.
    Theresa Kaeuferle, Britta Eiz-Vesper, Andreas Moosmann, Uta Behrends, Michel Decker, Lilli Gutjahr, Josef Mautner, Florian Klein, Christoph Kreer, Mira Reger, Dirk H Busch, Elvira D'Ippolito, Florian Kohlmayer, Amrei Menzel, Semjon Willier, Britta Maecker-Kolhoff, Tobias Feuchtinger.
       Introduction: The clinical application of cell-based immunotherapies is a rapidly emerging field, and recent advances in gene therapy have opened up a new era of innovative treatment approaches. Introducing a specific T-cell receptor (TCR) against viral epitopes or chimeric antigen receptor (CAR) into T cells and effector cells allows reprogramming of their specificity and utilization for advanced therapeutic applications in infectious diseases and virus-induced malignancies. Many technologies have been developed to genetically engineer T cells, and existing databases in silico predict or describe identified viral epitopes, TCRs, or B-cell receptors (BCRs). However, their therapeutic application is still hampered by limited knowledge on their clinical impact.
    Methods: An open-access online resource was developed, integrating a data-mining algorithm scoring the epitopes, TCRs, and BCRs (ETB database) according to clinical evidence.
    Results: We hereby present a new level of clinical evidence-based knowledge transfer for selecting individual protective TCRs or BCRs for therapeutic application. The database is publicly available at https://app.bitcare.de/epitopeFrontend/.
    Conclusion: Redirecting T-cell specificity by genetic engineering using clinically protective TCR or CAR sequences will not only bring significant progress to the field of adoptive T-cell therapies but also lay the groundwork for broader applications such as off-the-shelf approaches.
    Keywords:  Adoptive T-cell transfer; Antibodies; Antigens; B-cell receptor; Epitope; Immune response; Infections; MHC; T cells; T-cell receptor
    DOI:  https://doi.org/10.1159/000548312
  35. J Med Internet Res. 2025 Dec 11. 27 e71956
    Digital Biomarkers of Cytokine Release Syndrome: Scoping Review and Ontology Development of the Role and Relevance of Digital Measures Using a Mixed Methods Approach.
    Christopher J Medberry, Charlotte Zoe Angel, Ashita S Batavia, Sarah Bradley, Nunzio Camerlingo, Melinda Chen, Mohamed Datoo, Premal Kamdar, Erik Koenig, Lieke Kusters, Celine Marquez, Ujwani Nukala, Michael Pettinati, Ruth Phillips, Daniel P Sanchez, Nazila Shafagati, Jenifer Siegelman, Mark Stewart, Cindy Varga, Benjamin Vandendriessche, Matt Wilkes, Dana L Wolff-Hughes, David Zahavi, Sylvain Zorman, Samantha J McClenahan.
       Background: Advancements in cancer-targeted immunotherapies have transformed care, yet these therapies present a high likelihood of cytokine release syndrome (CRS), a potentially severe immune-related adverse event. The ability to identify CRS earlier could improve care by mitigating risks, widening patient access, and reducing the burden on patients, caregivers, and health care providers. Digital health technologies (DHTs) are promising for early CRS detection by enabling continuous measurement of vital signs before symptoms are detected through standard intermittent clinical assessments. While the number of studies is increasing, inconsistencies in the symptoms and measures strongly associated with CRS highlight the need for a comprehensive review to identify the most reliable and commonly reported indicators. Despite this growing body of research, reliable predictive and diagnostic measures for early warning for CRS following the administration of immunotherapy have yet to be established.
    Objective: This scoping review aims to address this gap by developing an ontology of early warning signs for CRS-a structured model defining measurement concepts, properties, and interrelationships-for advancing early warning models for CRS.
    Methods: We conducted a mixed methods study including a scoping literature review, surveys, and interviews. The literature review searched PubMed and Embase (last searched March 19, 2024) for articles reporting measures collected between therapy administration and CRS onset and linked to CRS onset. Studies were limited to publications between January 2014 and March 2024, excluding those that did not assess an immunotherapy-based treatment, were not conducted in humans, did not compare collected measures to CRS diagnosed using standard of care, or were not available in English. Identified measures were further assessed through surveys and interviews with subject matter experts (SMEs; n=22) and key opinion leaders (KOLs; n=8) and analyzed using qualitative and quantitative methods.
    Results: Thirty studies met eligibility criteria and used a variety of grading scales and thresholds for severe CRS. A comprehensive ontology of early warning signs for CRS that includes physiological signs, clinical symptoms, and laboratory markers was developed. Within the full ontology, a common set of early warning signs for CRS-temperature, heart rate, blood pressure, and oxygen saturation-was identified as the minimally necessary data to evaluate for their predictive value for CRS. Three of these 4 signs align with the American Society for Transplantation and Cellular Therapy (ASTCT) criteria for CRS grading and other clinical grading scales for CRS.
    Conclusions: Standardization and adoption of the ontology of early warning signs for CRS will streamline data collection to support the creation of robust, fit-for-purpose datasets. This approach ensures practical and informative data collection, ultimately enhancing the ability to predict and manage CRS effectively. Developing predictive models based on these early warning signs can enhance CRS risk assessment, support decentralized trials, and improve access to cancer-targeted immunotherapies.
    Keywords:  PRISMA; Preferred Reporting Items for Systematic Reviews and Meta-Analyses; cytokine release syndrome; digital biomarkers; digital health; immunotherapy; scoping review
    DOI:  https://doi.org/10.2196/71956
  36. Healthcare (Basel). 2025 Nov 21. pii: 3009. [Epub ahead of print]13(23):
    Bridging Technology and Healthcare: A Bibliometric Review of Assistive Technologies in Hospital Environments.
    Debopriyo Roy, Eleni Gkiolnta, George F Fragulis.
      Today, healthcare systems face many challenges due to the increasing number of elderly people and the complex needs of patients with multiple diseases. Previous research has shown that assistive technologies (ATs), like wearable devices, mobile health (mHealth) apps, and smart monitoring systems, can help improve patient care and make healthcare services more efficient. However, many of these studies do not focus so much on hospitals and do not clearly show the effects on clinical outcomes. In this study, the authors conducted a bibliometric analysis using the Scopus database to determine how much research has been carried out on assistive technologies in hospitals, especially for patient profiling and treatment. The authors chose articles from the last 20 years using specific inclusion and exclusion criteria, and VOSviewer software (version 1.6.20) was used to study keywords, co-authorship, and citation networks to find research trends and missing areas. The results show that even if assistive technologies are growing fast, there are not many studies that focus on hospitals or on important outcomes like quality of care and treatment results. Most of the research is in computer science and engineering, and many keywords for hospital use are not common. This study discusses how assistive technologies can help change healthcare and also shows the current problems, like system integration, data privacy, cost, and whether users accept the technologies. The authors suggest that future research must look at personal solutions, international standards, and better cooperation between doctors, engineers, and policymakers.
    Keywords:  assistive technologies (ATs); bibliometric analysis; healthcare systems; hospital applications; patient profiling
    DOI:  https://doi.org/10.3390/healthcare13233009
  37. NPJ Biofilms Microbiomes. 2025 Dec 13.
    CRISPR-engineered microbiome: living therapeutics revolutionize blood cancer immunotherapy.
    Fang Cheng, Hamed Soleimani Samarkhazan, Yeganeh Khazaei.
      Blood cancers such as leukemia, lymphoma, and myeloma remain refractory in many patients due to immune escape, antigen heterogeneity, and therapy‑related toxicities. To address these challenges, we review recent strategies that harness CRISPR‑engineered gut commensals as precision "living therapeutics" to modulate host immunity and directly target malignant clones. We frame this review around three principal themes: (1) mechanistic strategies whereby CRISPR-engineered commensals modulate host immunity and directly antagonize malignant clones; (2) the enabling technologies and delivery/containment platforms, CRISPR variants, phage/LNP delivery, genetic circuits and biocontainment, that make living therapeutics feasible; and (3) translational progress, outstanding technical and safety barriers, and ethical/regulatory challenges that must be addressed for clinical deployment. To illustrate these themes, we discuss three concrete therapeutic modalities: engineered microbial secretion of immunomodulators, targeted delivery of tumor-lytic payloads, and engineered production of anticancer metabolites, and how these are enabled by contemporary CRISPR and synthetic-biology toolkits. Selected preclinical models report substantial antitumor effects, often >60% tumor reduction in rodent studies, and restoration of CAR-T cell function in controlled settings; however, effect sizes vary across models, and human translation remains unproven. We also analyze key technical barriers, strain stability, biocontainment, off‑target effects, and propose solutions, including auxotrophic kill-switches and AI‑guided strain optimization. Finally, we outline future directions, from in situ phage delivery to multi‑omics-driven patient stratification. CRISPR‑microbiome editing represents a paradigm shift in hematologic oncology, offering localized, sustained therapy with reduced systemic toxicity.
    DOI:  https://doi.org/10.1038/s41522-025-00882-9
  38. Front Immunol. 2025 ;16 1692892
    Machine learning-based predictive model for high- grade cytokine release syndrome in chimeric antigen receptor T-cell therapy.
    Xiaofeng Yu, Qingqing Wang, Tangnuran Halimulati, Jiling Lv, Kai Zhou, Guilai Chen, Li Yin, Yulin Liu, Jingwang Bi, Zhuo Xiang, Qiang Wang.
       Introduction: The development of robust predictive models for high-grade cytokine release syndrome (CRS) in CAR-T recipients remains limited by sparse clinical trial data.
    Methods: We analyzed of 496 COVID-19 patients revealed that CRS plays a pivotal role in disease progression and serves as a valuable data source for understanding CRS progression. Building on this insight, we evaluated and compared the predictive performance of three machine learning models, with the ultimate goal of developing a predictive model for high-grade CRS in patients receiving CAR-T therapy.
    Results: Among evaluated algorithms (XGBoost, Random Forest, Logistic Regression), XGBoost demonstrated superior performance in high-grade CRS prediction. Feature importance analysis identified SpO2, D-dimer, diastolic blood pressure, and INR as key predictors, enabling development of a validated riskassessment algorithm. In an independent CAR-T cohort (n=45), the algorithm achieved impressive predictive performance for high-grade CRS prediction.
    Discussion: Using machine learning, we identified key clinical biomarkers strongly associated with high-grade CRS. This tool efficiently predicts progression to high-grade CRS post-onset and shows significant potential for clinical deployment in CAR-T therapy.
    Keywords:  CAR-T therapy; COVID-19; XGBoost model; cytokine release syndrome; machine learning technique
    DOI:  https://doi.org/10.3389/fimmu.2025.1692892
  39. Gastroenterol Rep (Oxf). 2025 ;13 goaf100
    In-depth plasma proteomics reveals the dynamic changes and prognostic biomarkers for chimeric antigen receptor-glypican-3 T-cell therapy in patients with hepatocellular carcinoma.
    Xudong Zhu, Ziliang Yang, Bin Li, Zhou Tong, Junyi Yan, Lei Song, Xuanwen Bao, Libin Hong, Yuzhi Jin, Lina Meng, Lulu Liu, Xiaomeng Dai, Tianyi Zhao, Shiting Wen, Haokang Qin, Sujie Jin, Peng Zhao, Yi Zheng, Weijia Fang, Zonghai Li, Xuqi Sun, Tingbo Liang.
       Background: Chimeric antigen receptor (CAR) T-cell therapy has shown notable advancements in the treatment of solid tumors. Nevertheless, its effectiveness is limited to a small group of patients, highlighting the need for predictive biomarkers. This study aimed to investigate biomarkers associated with the efficacy of CAR-T therapy in hepatocellular carcinoma (HCC).
    Methods: We prospectively collected plasma samples from 17 patients with HCC before and after they underwent CAR-glypican-3 (GPC3) T-cell therapy as part of three clinical trials. Plasma proteomic profiling was conducted by using liquid chromatography-mass spectrometry. We examined sequential plasma samples to evaluate the impact of CAR T-cell therapy on the systemic plasma proteome. Additionally, we compared the pretreatment plasma protein profiles between groups with and without clinical benefit (CB) to identify proteins linked to treatment efficacy. The Cox proportional hazard model was used to evaluate the relationship between plasma protein levels and survival outcomes.
    Results: Among 5337 plasma proteins, 225 exhibited significant changes following CAR-GPC3 T-cell therapy. The CB group showed an increased expression in proteins related to the type I interferon signaling pathway, T-cell proliferation and activation, tumor necrosis factor production, and antigen processing and presentation. In addition, plasma proteins were significantly associated with survival outcomes, whereas no significant association was observed between clinical variables and prognosis.
    Conclusions: Plasma proteomics not only captured CAR-GPC3-driven plasma microenvironment remodeling but also identified baseline proteins predictive of CB and survival, which were superior to clinical variables, thus constituting a candidate biomarker panel for HCC patient selection and response monitoring.
    Keywords:  CAR T-cell therapy; hepatocellular carcinoma; prognostic; proteomics
    DOI:  https://doi.org/10.1093/gastro/goaf100
  40. World J Crit Care Med. 2025 Dec 09. 14(4): 105547
    Sepsis and the diverse organ-gastrointestinal tract axis.
    Jia Dong James Wang, Enhui Suan, Sean Siwei Li, Vishal G Shelat.
      Sepsis remains a leading cause of morbidity and mortality worldwide, driven by a dysregulated host immune response to infection that culminates in multi-organ dysfunction. Recent advances highlight the gut microbiota's pivotal role in modulating immune responses and influencing the pathophysiology of sepsis through the organ-gastrointestinal tract axis. This review synthesizes current evidence on the bidirectional interplay between gut dysbiosis and the dysfunction of major organ systems-liver, lungs, kidneys, brain, and heart-during sepsis. We explore how gut-derived factors such as microbial translocation, endotoxins, and altered metabolite production exacerbate systemic inflammation and organ injury. In particular, we emphasize the roles of short-chain fatty acids, uremic toxins, bile acids, and trimethylamine-N-oxide in mediating immune dysfunction across the gut-organ axes. Therapeutic strategies targeting the gut microbiota- including prebiotics, probiotics, synbiotics, and fecal microbiota transplantation- show promise in preclinical and early clinical settings. However, challenges related to patient heterogeneity, safety, and the lack of precise biomarkers persist. This review consolidates disparate findings to underscore the gut as a central modulator in sepsis and advocates for microbiota-based interventions as adjunctive therapies in sepsis management.
    Keywords:  Critical care; Gut microbiota dysbiosis; Multi-organ dysfunction; Organ-gut axis; Sepsis
    DOI:  https://doi.org/10.5492/wjccm.v14.i4.105547
  41. Healthcare (Basel). 2025 Dec 03. pii: 3155. [Epub ahead of print]13(23):
    Assisted Reproduction Therapy in Patients with Multiple Sclerosis: Narrative Review and Practical Recommendations.
    Lenka Mekiňová, Iva Šrotová, Petra Hanáková, Pavlína Danhofer, Robert Hudeček, Michal Ješeta.
      Objective: The objective of this study is to present contemporary findings regarding the relationship between the application of assisted reproduction methods and their impact on the incidence of multiple sclerosis. Design: This study adopts a narrative review design. Text: Assisted reproductive technology (ART) is increasingly used to treat human infertility. Due to the massive use of these techniques, it is increasingly important to record not only the course of fertilization and embryonic and fetal development of the individual but also the overall health status of the children born and their mothers. The incidence of autoimmune diseases continues to rise for reasons that remain unclear. One of the factors considered in connection with autoimmune disorders is ART. Opinions on the safety and reliability of ART methods are not consistent. Recently, extensive studies focusing on this issue have been presented and have not found a connection between infertility treatment with assisted reproductive techniques and the development of multiple sclerosis (MS). Conclusions: Current evidence suggests that, in adherence to the principles of evidence-based medicine and modern approaches to multiple sclerosis therapy, assisted reproduction in women with this disease is effective and does not pose a serious health risk. Therefore, it is necessary to always individualize therapy with regard to future pregnancy. Interdisciplinary cooperation on the timing of IVF therapy and minimizing the risk of MS exacerbation is also important.
    Keywords:  IVF; agonist protocol; antagonist protocol; autoimmune disease; multiple sclerosis; ovarian stimulation
    DOI:  https://doi.org/10.3390/healthcare13233155
  42. Pharm Stat. 2026 Jan-Feb;25(1):25(1): e70048
    Optimizing Dosing Strategies in Cell Therapy With Machine Learning and Exposure-Response Integration.
    Shuqi Wang, Yunqi Zhao, Jia Li, Rachael Liu, Ganesh Mugundu.
      In cell therapy product development, cell expansion is highly correlated with response and safety. Significant heterogeneity in patient and product characteristics contributes to variability in cell expansion, persistence and response. Integrating exposure assessments enables us to use comprehensive information to make informed dose selection decisions, aligning with the expectations outlined in FDA's Project OPTIMUS. We propose a seamless phase I/II design that integrates data from toxicity, efficacy, cellular kinetics (CK), and baseline patient/product characteristics for optimal dose selection. Utilizing random forest (RF) with all available data, we guide dose escalation and subsequently narrow down the dose options. Additional patients are then randomly assigned to promising doses for further investigation. Throughout this process, interim analyses based on RF estimations are conducted to discontinue doses that are deemed futile or toxic. The optimal dose (OD) is ultimately chosen based on its safety profile and highest efficacy rate. The proposed RF-based seamless phase I/II design, incorporating exposure data, is entirely data-driven for dose determination. Simulation studies show that the proposed design has desirable operating characteristics, including high accuracy in selecting the optimal dose and effectively allocating patients to potentially therapeutic doses while minimizing exposure to toxic doses. On average, the RF-based algorithm selects 0-3 doses for further exploration.
    Keywords:  cell therapy; cellular kinetics; dose optimization; phase I/II clinical trial; random forest
    DOI:  https://doi.org/10.1002/pst.70048
  43. Int J Mol Sci. 2025 Dec 04. pii: 11736. [Epub ahead of print]26(23):
    Autoimmune Neuromuscular Disorders at a Molecular Crossroad: Linking Pathogenesis to Targeted Immunotherapy.
    Anca-Maria Florea, Dimela-Gabriela Luca, Eugenia Irene Davidescu, Bogdan-Ovidiu Popescu.
      Myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, and idiopathic inflammatory myopathies are among the most widely recognized autoimmune neuromuscular disorders. Although they differ in clinical presentation, shared immunopathogenic mechanisms place them at a molecular crossroads. Evidence of overlapping pathways has led to the development of targeted strategies including complement inhibition, FcRn antagonism, B-cell depletion, and the CAR-T cell approach. In this review, we analyze current knowledge regarding pathogenic mechanisms and their link to immunotherapy, extensively outlining both similarities and distinctions. We further discuss existing challenges, including diagnostic limitations and refractory disease variants, how technological advances have already addressed some of these issues, and where further progress is still needed.
    Keywords:  B-cell depletion therapy; FcRn antagonists; autoantibodies; chronic inflammatory demyelinating polyneuropathy; complement inhibition; idiopathic inflammatory myopathies; myasthenia gravis; targeted immunotherapy
    DOI:  https://doi.org/10.3390/ijms262311736
  44. Trends Pharmacol Sci. 2025 Dec 08. pii: S0165-6147(25)00258-5. [Epub ahead of print]
    Siglecs in immunotherapy: current clinical landscape and prospects.
    Abhinav Purohit, Ishaan Joshi, Pratik S Bhojnagarwala, Jean D Boyer, J Joseph Kim, David B Weiner, Devivasha Bordoloi.
      Siglecs are a family of sialic acid-binding immunoglobulin-like lectins that regulate immune signaling and maintain homeostasis through glycan recognition. Despite their central role in immune modulation, their therapeutic potential remains underexplored. Advances in antibody engineering, glycan biology, and molecular design have greatly expanded our understanding of Siglec-ligand interactions, revealing their promise in regulating immunosuppression in cancer and autoimmunity. The current clinical landscape shows trials targeting mainly Siglec-2 and -3, with a predominant focus on hematological cancers. This review evaluates preclinical and recent clinical progress in Siglec-targeted immunotherapies, emphasizing mechanisms, safety, and efficacy, and proposes a translational framework to accelerate therapy development and broader immunotherapy advancements.
    Keywords:  Siglecs; autoimmune diseases; cancer; immune checkpoint; immunotherapy; sialic acid
    DOI:  https://doi.org/10.1016/j.tips.2025.11.004
  45. Mol Ther. 2025 Dec 09. pii: S1525-0016(25)01027-5. [Epub ahead of print]
    Gene-corrected regulatory T cell therapy for IL2RA deficiency.
    Alvin S Ha, Nechama Kalter, Michael Rosenberg, Luis A Acevedo, Brianna Liang, Weihong Liu, Sreenivasan Paruthiyil, Meenal Sinha, Alexander Vu, Vinh Nyguen, Zhongxia Qi, Netravathi Krishnappa, Jinna Shu, Jingwei Yu, Jason Catanzaro, Jeffrey A Bluestone, Qizhi Tang, Fyodor D Urnov, Alexander Marson, Ayal Hendel, Kevan C Herold, Brian R Shy, Jonathan H Esensten.
      Biallelic germline deficiency of IL2RA causes a rare autoimmune disease with impaired regulatory T cell (Treg) function and IL-2 signaling. Definitive treatment is currently limited to allogeneic hematopoietic stem cell transplantation, which carries significant morbidity and mortality risks. We previously identified a family with three siblings affected by compound heterozygous mutations in IL2RA, resulting in dysfunctional Tregs. Here, we introduce a novel therapeutic approach involving ex-vivo generation of gene-corrected autologous regulatory T cells (gcTregs). One of the two disease-causing mutations in patient-derived Tregs was corrected with CRISPR-Cas9-mediated homology-directed repair, restoring IL2RA expression. The resulting gcTregs demonstrated robust suppressive activity in vitro. Clinical-scale manufacturing from a patient with IL2RA deficiency showed efficient gene correction, restored IL2RA expression, and functional equivalence to healthy donor Tregs. This work establishes a Good Manufacturing Practice (GMP)-compatible manufacturing process for personalized gcTreg therapies, potentially providing a safer treatment option for patients with IL2RA deficiency as well as a framework for treating other inborn errors of immunity.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.004
  46. Exp Ther Med. 2026 Jan;31(1): 21
    Diagnosis and treatment of invasive fungal disease in children with hematological malignancies after chemotherapy: Challenges and strategies (Review).
    Mingxin He, Feng Chen, Xiaomin Xian, Zhi Guo.
      Invasive fungal disease (IFD) has a high incidence rate in pediatric patients with hematological malignancies and hematopoietic stem cell transplantation, markedly elevating mortality rates. Major pathogens include Aspergillus, Candida and emerging non-Aspergillus molds. Clinical manifestations such as persistent fever and dyspnea are frequently non-specific, complicating early diagnosis. Invasive candidiasis typically manifests as candidemia or hepatosplenic infection, whereas invasive aspergillosis predominantly involves the lower respiratory tract. Prophylactic antifungal therapy reduces IFD risk but may lead to breakthrough IFD, particularly during prolonged neutropenia (>14 days). Treatment strategies require individualized selection between monotherapy and combination regimens, incorporating patient status, local epidemiology, prior antifungal exposure, drug metabolism and socioeconomic factors; however, treatment strategies can be hindered by diagnostic challenges including age-specific biomarker thresholds. Emerging techniques such as metagenomic next-generation sequencing show promise for rapid pathogen identification. Central nervous system involvement occurs in a certain proportion of pediatric cases and requires multimodal intervention. Early diagnosis through optimized imaging and timely initiation of targeted therapy are key to overcome clinical challenges and improving prognosis in this vulnerable population. The present review aimed to systematically review the epidemiological characteristics, diagnostic challenges and therapeutic strategies of IFD in pediatric hematological malignancies post-chemotherapy. By collating current clinical evidence, the present review provides an evidence-based framework for optimizing management in this high-risk population.
    Keywords:  children; diagnosis; hematological malignancies; invasive fungal disease; treatment
    DOI:  https://doi.org/10.3892/etm.2025.13016
  47. Mol Ther Oncol. 2025 Dec 18. 33(4): 201088
    Preclinical development and selection of nanobody-based CAR-T cells targeting HER2-positive solid tumors.
    Fien Meeus, Arne Van der Vreken, Dorien Autaers, Timo W M De Groof, Arthur Esprit, Lorenzo Franceschini, Philippe Parone, Cleo Goyvaerts, Yannick De Vlaeminck, Nick Devoogdt, Karine Breckpot.
      Chimeric antigen receptor (CAR)-T cell therapy revolutionized treatment of hematological malignancies, but translation to solid tumors remains difficult. Therefore, different avenues are explored to develop novel CAR-T cell products. Nanobodies have advantageous features for CAR design, such as ease of engineering and low immunogenicity, but predictive values on nanobody characteristics for optimal CAR-T cell function remain unclear. We performed a side-by-side evaluation of 12 nanobody-based (nano)CARs against human epidermal growth factor receptor 2 (HER2). All nanoCARs showed the ability to activate a reporter T cell line upon recognition of HER2pos cells. When evaluated in primary T cells, 6/12 nanoCARs showed the strongest reactivity and cytotoxicity against HER2pos glioblastoma and breast cancer cells. Moreover, only 1/12 was able to confer potent cytotoxicity against HER2pos melanoma cells. These data add to the current view that nanobody selection for CAR design remains subject to extensive side-by-side screening. Still, superior cytotoxicity across multiple solid tumor cell lines-determined using in vitro assays evaluating activation, cytokine secretion, and target cell-specific killing-led to selection and further characterization of a lead nanoCAR 1R59b, showing tumor control in an in vivo xenograft model, providing a promising HER2 nanoCAR for further (pre)clinical investigation.
    Keywords:  CAR-T; Chimeric antigen receptors; HER2; MT: Regular Issue; breast cancer; glioblastoma; immunotherapy; melanoma; nanobody; solid tumors
    DOI:  https://doi.org/10.1016/j.omton.2025.201088
  48. Int J Biol Sci. 2026 ;22(1): 86-110
    Therapy-induced mRNA, rRNA and tRNA methylation alterations confer tolerance phenotype in tumor cells: mechanism and implications.
    Anfeng Jiang, Shujie Liu, Zhiyuan Li, Xiongzhou Zhang, Minghao Duan, Bin Li.
      Drug tolerant persister cells (DTPs) refer to a transient drug-tolerance sub-population of cancer cells characteristics of phenotype plasticity and heterogeneity. This adaptive cell state is a critical transitional phase, standing on the crossroad that cancer cells reacquire drug sensitivity or enter into the permanent drug resistance. Emerging evidences indicate the epitranscriptomic regulations, particularly RNA methylations are the important mechanism underline post-transcriptional regulations of genes expression across all RNA species. RNA is integral to gene expression as messenger RNA (mRNA), transfer RNA (tRNA) and ribosomal RNA (rRNA), which play roles in transmitting information from DNA to the synthesis of functional proteins. Methylation modifications on these RNAs are prevalent and represent a well-recognized non-genetic mechanism, exerting multifaceted regulatory effects on nucleic acid metabolism, such as nucleotide precursor availability, RNA processing dynamics, sub-cellular localization, transcript stability and translational fidelity/ efficiency. This review systematically sorts out the relevant references, demonstrating recent advances on the knowledge of the patterns of methylation modifications on mRNA, tRNA and rRNA, and how these modifications drive the generation and development of DTPs, which hallmarks of epithelial-mesenchymal transition, metabolism shift and immune escape. And then clinical strategies are delineated, leveraging pharmacological modulators of RNA-modifying enzymes alongside non-pharmaceutical lifestyle advice, for the development of therapy strategies preventing DTPs-rooted tumor relapse in this anti-tumor armamentarium with cytotoxic reagents, targeted therapies and immunotherapies.
    Keywords:  RNA; clinical strategies; drug tolerant tumor cells; methylation
    DOI:  https://doi.org/10.7150/ijbs.120764
  49. J Law Med Ethics. 2025 Dec 12. 1-7
    Restricted Supply, Rising Demand: Reimagining Prescription Stimulant Regulation Amid A National Shortage.
    Neha V Dantuluri.
      This paper examines the prescription stimulant shortage in the United States, a crisis that has intensified since the FDA's 2022 announcement of an Adderall shortage. The regulatory, systemic, and societal factors driving the shortage are analyzed - including the surge in attention-deficit/hyperactivity disorder (ADHD) diagnoses, expanded use of telehealth services, and disproportionate impact of the shortage on marginalized communities. It's argued that existing health inequities are exacerbated by barriers to medication access as current regulatory frameworks are ill-equipped to address the growing demand for prescription stimulants, causing substantial harm to patients. A series of reforms are proposed - including modernizing the DEA's quota system, strengthening interagency collaboration between the DEA, FDA, and HHS, and diversifying pharmaceutical supply chains to enhance resilience. These reforms aim to balance the dual imperatives of preventing misuse and ensuring equitable access to medications for patients with legitimate medical needs. By offering a comprehensive analysis of the prescription stimulant shortage and actionable policy recommendations, this paper seeks to inform regulatory reform, foster a more adaptive, patient-centered approach to ADHD care, and provide a roadmap for addressing one of the most pressing healthcare challenges of our time.
    Keywords:  Controlled Substances Act; Drug Enforcement Administration; Health Equity; Prescription Stimulant Shortage; Regulatory Reform
    DOI:  https://doi.org/10.1017/jme.2025.10204
  50. Discov Oncol. 2025 Dec 06.
    Exploring the therapeutic potential of human umbilical cord mesenchymal stem cells derived extracellular vesicles in cancer immunotherapy.
    Faeze Dehghani, Mona Daghaighei, Alireza Azani, Mohammad Amin Mahdizadeh, Mohammadreza Moradi Takhtizadeh, Zahra Mehrdad, Saba Pourali, Malihe Sharafi, Danial Akhondi, Hamid Rastegar Movahed, Arshia Javadizadeh, Yasaman Naghibzadeh, Danial Amiri Manjili, Sepide Javankiani, Mahshaad Norouzi, Pegah Kavousinia.
      The therapeutic potential of human umbilical cord mesenchymal stem cells derived extracellular vesicles (hUCMSC-EVs) in cancer immunotherapy is an emerging area of research that offers promising avenues for enhancing treatment efficacy. This review explores the distinct characteristics of hUCMSC-EVs, highlighting their unique composition and functional properties that differentiate them from extracellular vesicles derived from other sources. We compared the immunomodulatory effects of MSCs derived from the umbilical cord with those of MSCs derived from alternative sources, highlighting their superior therapeutic potential in cancer therapy. Furthermore, we examined the impact of hUCMSC-EVs on cancer cells and the tumor microenvironment, elucidating the mechanisms of signaling pathways involved in their effects. Recent advances in the application of hUCMSC-EVs have yielded encouraging therapeutic outcomes, highlighting several advantages over conventional cancer immunotherapies. However, challenges remain in the translational application of these therapies, including variability in EV production, pharmacokinetics, and standardization of protocols, necessitating further research to overcome barriers and optimize their clinical implementation. This review uniquely focuses on the therapeutic implications of hUCMSC-EVs in cancer immunotherapy, highlighting their distinct advantages over EVs from other MSC sources and providing an updated synthesis of mechanistic insights and clinical perspectives not covered in previous reviews.
    Keywords:  Cancer immunotherapy; Mesenchymal stem cells; Umbilical cord-derived extracellular vesicles
    DOI:  https://doi.org/10.1007/s12672-025-04156-w
  51. J Clin Med. 2025 Nov 28. pii: 8467. [Epub ahead of print]14(23):
    Musculoskeletal Digital Therapeutics and Digital Health Rehabilitation: A Global Paradigm Shift in Orthopedic Care.
    Youn Kyu Lee, Eun-Ji Yoon, Tae Hyung Kim, Jong-Ick Kim, Jong-Ho Kim.
      Musculoskeletal disorders (MSDs) affect over 1.7 billion people globally and represent the leading cause of disability worldwide. Conventional rehabilitation strategies face challenges including limited accessibility, suboptimal adherence, and lack of personalization. Digital therapeutics (DTx)-evidence-based, software-driven interventions regulated as medical devices-have emerged as transformative solutions in chronic disease management. This review provides a narrative synthesis of representative studies in the field, drawing on a broad survey of literature from medical and engineering sources to capture current trends and clinically relevant developments. Seventy-five publications were examined, including clinical trials and validation studies, many of which reported outcomes comparable or superior to traditional rehabilitation approaches, with adherence gains of 15-40% and cost reductions of approximately 30-40%. We summarize the major technological foundations of musculoskeletal DTx and digital rehabilitation across orthopedic subspecialties, describing core-enabling technologies including artificial intelligence-driven motion analysis, wearable sensors, tele-rehabilitation platforms, and cloud-based ecosystems. Clinical applications spanning spine, upper and lower extremities, sports injuries, and trauma were analyzed alongside global regulatory frameworks, economic considerations, and implementation challenges. Early clinical evidence demonstrates improvements in functional outcomes, adherence, and cost-effectiveness. Future directions include digital twin-based precision rehabilitation, predictive analytics, and scalable integration into value-based orthopedic care. By establishing a comprehensive framework for musculoskeletal DTx implementation, this review highlights their potential to improve outcomes, reduce healthcare costs, and address global rehabilitation access gaps. However, evidence on long-term effectiveness, sustained cost benefits, and large-scale clinical integration remains limited and warrants further investigation.
    Keywords:  artificial intelligence; digital therapeutics; musculoskeletal rehabilitation; orthopedic surgery; precision orthopedics; tele-rehabilitation; wearable sensors
    DOI:  https://doi.org/10.3390/jcm14238467
  52. Cells. 2025 Nov 26. pii: 1872. [Epub ahead of print]14(23):
    Psychedelics in Multiple Sclerosis: Mechanisms, Challenges, and Prospects for Neuroimmune Modulation and Repair.
    Ivan Anchesi, Maria Francesca Astorino, Ivana Raffaele, Deborah Stefania Donato, Serena Silvestro, Aurelio Minuti, Marco Calabrò, Michele Scuruchi, Giovanni Luca Cipriano.
      Multiple Sclerosis (MS) therapies effectively modulate peripheral immune responses but largely fail to promote neural repair within the central nervous system. This review evaluates whether psychedelic compounds (PSYs), via 5-HT2A activation, can fill a critical therapeutic gap: the need for agents that simultaneously suppress neuroinflammation and promote regeneration. We dissect the evidence suggesting PSYs can reprogram the neuroimmune milieu by downregulating key pro-inflammatory cytokines (e.g., TNF-α, IL-6) in glial cells while concurrently upregulating crucial neurotrophic factors (e.g., BDNF) that promote synaptic plasticity and oligodendrocyte support. However, we argue that the current evidence, largely derived from non-specific inflammation models, is insufficient to predict clinical efficacy in an autoimmune disease like MS. We critically analyze the significant translational barriers-from cardiovascular and psychiatric risks to profound legal and ethical challenges-that temper the immediate clinical promise. Finally, we propose a forward-looking perspective, suggesting that the true value of PSYs may lie not in their direct clinical use, but in uncovering novel therapeutic pathways. The emergence of non-hallucinogenic, functionally selective 5-HT2A agonists, inspired by psychedelic pharmacology, represents a more viable strategy to harness these mechanisms for MS therapy, demanding rigorous preclinical validation in disease-relevant models.
    Keywords:  BDNF; HTR2A receptors; glial cells; multiple sclerosis; neuroinflammation; neuroplasticity; psychedelic compounds; therapeutic strategies
    DOI:  https://doi.org/10.3390/cells14231872
  53. Hum Vaccin Immunother. 2025 Dec;21(1): 2597629
    mRNA vaccine platforms and novel delivery systems: From mechanistic principles to clinical translation.
    Yunchang Yang, Yunqin Sun, Xinyao Kang, Yaofeng Wang.
      Messenger RNA (mRNA) vaccines have revolutionized the field of vaccinology, offering rapid design flexibility, scalable manufacturing, and strong immunogenicity. The unprecedented success of COVID-19 mRNA vaccines has accelerated research into novel delivery platforms and expanded therapeutic applications beyond infectious diseases to cancer immunotherapy and immune-mediated disorders. This review provides a comprehensive overview of the mechanistic principles underlying mRNA vaccine design, including mRNA engineering strategies, delivery innovations such as lipid nanoparticles (LNPs), polymeric nanoparticles (PNPs), and virus-like particles (VLPs), as well as emerging needle-free administration technologies. We further highlight recent advances in therapeutic areas spanning infectious diseases (e.g. HIV, tuberculosis, respiratory syncytial virus), oncology, and non-traditional indications such as autoimmune disorders. Despite remarkable progress, critical challenges persist in vaccine stability, delivery efficiency, large-scale manufacturing, and global accessibility. Finally, we discuss future research directions integrating artificial intelligence, nanotechnology, and systems immunology to accelerate next-generation mRNA vaccine development and clinical translation.
    Keywords:  artificial intelligence; cancer immunotherapy; global health; infectious diseases; lipid nanoparticles (LNPs); mRNA vaccines; needle-free delivery; polymeric nanoparticles (PNPs); vaccine stability; virus-like particles (VLPs)
    DOI:  https://doi.org/10.1080/21645515.2025.2597629
  54. SLAS Technol. 2025 Dec 05. pii: S2472-6303(25)00141-4. [Epub ahead of print] 100382
    Guide to Liquid Volume Measurements: A Review of Methods and Technologies.
    Nathaniel G Hentz, John Thomas Bradshaw.
      The need to measure volume is an important component of any liquid-based assay, because the final result is often based upon the concentration of some analyte within the assay. Volume measurements can be used to determine the actual amount of sample throughout an assay. They can also be used to calibrate, routinely verify performance of, or optimize liquid classes for liquid handling platforms or other automated or manual pipetting devices. This review surveys current liquid volume measurement methods and technologies available for use in life science laboratories. Volumes considered in this review range from picoliters to a few milliliters, which are typical for life science assays. While the need for volume measurement extends across many different industries, the focus here is on applications in biopharmaceutical and clinical life science laboratories. This review evaluates key measurable attributes, including the addressable volume range, as well as the attainable precision and accuracy of the method or technology. Several important features are also considered such as the ability to measure actual samples, commercial availability, regulatory compliance, sample type, workflow integration, suitability for in-line use, and relative ease of use.
    Keywords:  Volume measurement; assay validation; liquid class optimization; liquid handler calibration; liquid handler performance; liquid handler volume measurement; liquid handler volume verification; liquid handling variability; performance verification; sample validation; sample volume measurement; volume assessment; volume measurement methods; volume measurement technologies
    DOI:  https://doi.org/10.1016/j.slast.2025.100382
  55. Antiinflamm Antiallergy Agents Med Chem. 2025 Dec 04.
    Next-Generation Probiotics in Allergy Therapy: Scientific Evidence and Clinical Applications.
    Vatan Chaudhary, Atul Pratap Singh, Himanchal Sharma, Dhananjay Taumar.
      The global increase in allergic diseases, such as atopic dermatitis, allergic rhinitis, asthma, and food allergies, has become a major public health issue. These diseases typically involve immune dysregulation, including a Th1/Th2 imbalance, increased IgE levels, regulatory T cell (Treg) dysfunction, and epithelial barrier dysfunction. New research has recognised an important role for the gut and mucosal microbiome in regulating immune responses and has prompted interest in the therapeutic utility of probiotics. Probiotics are live microbes that, when given in adequate amounts, confer health benefits, generally such as immunomodulation or restoration of gut barrier function. Traditional probiotics (i.e., Lactobacillus and Bifidobacterium species) reduce allergic inflammation through promotion of Treg differentiation, increases in antiinflammatory cytokines (e.g., IL-10), suppression of Th2 cytokines (e.g., IL-4), and modification of IFNγ. Traditional probiotics also support mucosal barrier function and restore microbial composition by producing short-chain fatty acids (SCFAs), like butyrate, which act directly on Gprotein- coupled receptors and histone deacetylases to suppress inflammation. Next-generation probiotics (NGPs), such as Akkermansia muciniphila, Faecalibacterium prausnitzii, Bacteroides fragilis, and some clusters of Clostridia, can provide more targeted effects. These NGPs can secrete anti-inflammatory metabolite compounds, such as polysaccharide A (PSA), which modulate dendritic cells and increase Treg activity, and can promote mucin production to improve gut barrier function. Overall, there are key issues with strain specificity, dose, safety in immunocompromised individuals, and possible regulatory classification issues. Future opportunities may include precision microbiome profiling, synthetic biology, and artificial intelligence-driven strain discovery to develop personalised approaches to allergy immunotherapy.
    Keywords:  Allergic diseases; allergy therapy.; gut microbiome; immune modulation; microbiome sequencing; next-generation probiotics; personalized medicine; regulatory T cells
    DOI:  https://doi.org/10.2174/0118715230407403251105101126
  56. Mol Ther. 2025 Dec 09. pii: S1525-0016(25)01029-9. [Epub ahead of print]
    Introducing arginine residues into scFv in CAR-T cells shows promising antitumor effects.
    Shingo Maeta, Atsushi Fukunaga, Yuriko Egashira, Yasushi Akahori, Linan Wang, Naohiro Seo, Yusuke Atarashi, Daisuke Ejima, Hiroshi Fujiwara, Hiroshi Shiku.
      Current research investigating chimeric antigen receptor (CAR)-T cell therapeutics indicates that CAR properties other than intracellular signaling systems, such as high association rate constants and enhanced self-interaction of the antigen-binding domain (ABD), elicit enhanced therapeutic efficacy and are key factors for CAR-T candidates. However, rational strategies to achieve these features are to be established. To develop novel CAR-T cells with these characteristics, ABD was engineered by introducing several arginine residues into the light-chain framework region-3 of the single-chain fragment variable. The mutant CAR-T cells exhibited a higher cell-killing efficacy than that of wild-type cells and superior antitumor effects in mice, prolonged persistence in vivo, and decreased interferon-γ secretion. RNA sequencing revealed differential gene expression profiles between the mutant and wild-type CAR-T cells before and after antigen stimulation. In conclusion, we proposed a design strategy to generate CAR-T cells with high therapeutic efficacy by modulating CAR properties using an arginine cluster.
    DOI:  https://doi.org/10.1016/j.ymthe.2025.12.006
  57. Appl Health Econ Health Policy. 2025 Dec 09.
    Funding Multi-indication Medicines: A Scoping Review of Health Technology Assessment and Reimbursement Frameworks.
    Isaiah Luc, Mah Laka, Drew Carter, Tracy Merlin.
       BACKGROUND: Medicines with multiple indications pose efficiency problems for health technology assessment (HTA). Evaluating indications separately may result in years of duplicative evaluation work and ultimately delay patient access. The price of these medicines is also difficult to determine because the value may vary between the different indications.
    OBJECTIVES: A scoping review was conducted to identify HTA and reimbursement frameworks for evaluating and pricing multi-indication medicines for reimbursement decisions and to explore whether there are elements in these frameworks that would have utility if implemented in jurisdictions with well-established HTA systems.
    METHODS: PubMed, Embase and Scopus were systematically searched and a targeted search of HTA agency websites was conducted in September 2025. Documents were included in the review if they discussed HTA and reimbursement frameworks concerning multi-indication medicines in high-income countries.
    RESULTS: Sixteen frameworks were identified, describing four main approaches: policy (3), pricing (6), HTA evaluation methods (4) and decision-making (3). Policy approaches included implementing conditional listing processes and streamlining the evaluation of multi-indication medicines. Pricing frameworks including indication-based pricing frameworks and volume-based agreements were reported most frequently.
    CONCLUSIONS: While pricing frameworks are commonly used in high-income countries, they do not help reduce duplication of effort in the evaluation and appraisal of these medicines. Policy change allowing for the streamlined incremental evaluation of each new indication may be helpful, although the methodological characteristics of a streamlined HTA have yet to be defined. Subscription-based approaches to purchasing medicines represent another option. Stakeholder engagement is needed to determine the merit and feasibility of different approaches.
    DOI:  https://doi.org/10.1007/s40258-025-01020-4
  58. J Magn Reson Imaging. 2025 Dec 12.
    Principles and Key Technologies of Magnetic Particle Imaging System: A Comprehensive Review.
    Jiayi Zhang, Yinong Cui, Yuanhao Cai, Lin Yin, Lizhi Zhang, Jintao Li, Xiaowei He, Hongbo Guo.
      Magnetic particle imaging (MPI) is an emerging noninvasive, ionization-free three-dimensional tracer imaging technology that achieves imaging by leveraging the nonlinear magnetization response of superparamagnetic nanoparticles. This study conducts a systematic review of the principles and key technologies of the MPI system through literature searches in databases including PubMed, Web of Science, and Google Scholar. First, this review introduces MPI's imaging principles, image reconstruction processes, and the technical characteristics of different types of MPI devices, aiming to deepen the understanding of device applications. Second, it presents the development history of three categories of MPI systems: closed-bore, open-bore, and single-sided. Finally, this review conducts a comparative analysis of the advantages and limitations of each category and discusses the future development trends and challenges of the MPI system. This review aims to provide researchers in the field with a systematic theoretical understanding of the MPI system, promote knowledge sharing, and further encourage more scientific efforts to engage in this highly promising area of molecular imaging. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 1.
    Keywords:  closed‐bore system; magnetic particle imaging; open‐bore system; physical principles; single‐sided system
    DOI:  https://doi.org/10.1002/jmri.70186
  59. Int J Technol Assess Health Care. 2025 Dec 11. 41(1): e85
    Establishing an independent HTA agency in Ukraine: a conceptual framework for governance, operations, and long-term sustainability.
    Rabia Sucu, Daniel Erku, Olena Filiniuk, Rebecca Kohler.
       OBJECTIVES: Health technology assessment (HTA) has become an integral part of Ukraine's health system since its formal introduction into national legislation in 2017. By 2020, HTA was mandated for evaluating publicly funded medicines, laying the groundwork for more evidence-based healthcare decisions. Although the creation of an independent HTA agency was initially planned for 2022, implementation was delayed due to the COVID-19 pandemic and Russia's ongoing invasion. The relevant Cabinet Resolution calls for the establishment of an autonomous agency by January 2026. This commentary outlines a strategic, evidence-informed framework to guide the agency's formation.
    METHODS: Drawing on the 2018 State Strategy for Access to Medicines, the 2022 Law on Medicinal Products, and international best practices, we proposed to the Government of Ukraine a two-tier structure encompassing core business functions (HTA and appraisal, guideline development, pricing, and listing) and support business functions (data and analytics, finance and strategy, IT, human resources, legal, and communications). Each department is tasked with clear mandates and supported by performance indicators to promote transparency, accountability, and operational efficiency.
    RESULTS: A phased roadmap for 2025-2027 details the legal, institutional, and financial steps required for successful implementation. Key opportunities - including international partnerships and system-wide reform - are weighed alongside risks such as funding uncertainty, workforce limitations, and geopolitical instability.
    CONCLUSION: By embedding HTA into national policy processes and ensuring institutional independence, Ukraine can enhance the value of healthcare investments and build long-term resilience into its health system.
    Keywords:  Ukraine; governance; health policy; health technology assessment; priority setting in health
    DOI:  https://doi.org/10.1017/S0266462325103255
  60. Cancers (Basel). 2025 Nov 28. pii: 3821. [Epub ahead of print]17(23):
    Treating Pediatric Oncology Patients: The Emerging Role of Radioligand Therapy.
    Theodore W Laetsch, Lisa J States, Margot A Lazow, Aman Chauhan.
      Pediatric neuroendocrine tumors (NETs) and neuroblastomas are rare malignancies with poor outcomes when metastatic. Limited treatment options are currently available for pediatric NETs. Recently, radioligand therapy (RLT) consisting of a radionuclide attached to a ligand, such as [177Lu]Lu-DOTA-TATE, has been approved for the treatment of NETs in adolescents aged ≥12 years. Although long-term safety of RLT in adolescents and other pediatric patients needs to be further investigated, data from large adult studies and early pediatric studies suggest feasibility and low toxicity. Future research is needed to assess potential combinations of RLTs with conventional chemotherapy and radiation sensitizers in order to optimize the treatment for pediatric patients with NETs. This review highlights the current status and future directions for RLTs as theranostics for pediatric patients with NETs and neuroblastomas.
    Keywords:  NETs; pediatric; radioligand therapy
    DOI:  https://doi.org/10.3390/cancers17233821
  61. Cells. 2025 Nov 25. pii: 1853. [Epub ahead of print]14(23):
    Orthobiologics and Peptide Therapy for Central Nervous System Repair in Neurodegenerative Conditions.
    Cézar Augusto Alves de Oliveira, Bernardo Scaldini Oliveira, Amanda Scaldini Oliveira, Rafael Duarte de Souza Loduca, Carlos Roberto Massella Junior, Gabriel Silva Santos.
      Alzheimer's disease and Parkinson's disease remain the most prevalent neurodegenerative disorders associated with aging and continue to lack curative treatments. Their pathophysiology is often multifaceted, encompassing protein aggregation, mitochondrial dysfunction, chronic neuroinflammation, synaptic degeneration, and vascular compromise. This complex landscape reduces the effectiveness of single-target pharmacological agents and underscores the need for therapies capable of acting across multiple axes. Orthobiologics and peptide-based strategies exemplify this approach. Autologous cellular alternatives such as platelet-rich plasma, bone marrow aspirates, mesenchymal stromal cell derivatives, and extracellular vesicles deliver paracrine signals that can reprogram glia, preserve mitochondrial function, and promote synaptic and vascular repair. Peptide therapeutics, including glucagon-like peptide-1 receptor agonists and novel sequences targeting protein aggregation or mitochondrial pathways, provide complementary precision by engaging defined receptors and intracellular cascades. Together, these modalities converge on mechanisms central to circuit preservation rather than symptomatic relief alone. Preclinical studies across Alzheimer's and Parkinson's disease demonstrate consistent neuroprotective and functional benefits, and early human trials support feasibility and safety. The translational path forward requires standardized preparation, biomarker integration, optimized delivery routes such as intranasal administration, and regulatory frameworks adapted to biologic therapies. This review synthesizes current evidence on orthobiologics and peptides in neurodegeneration, outlines safety and translational considerations, and highlights future directions, including rational combinations and biomarker-driven trials. By uniting the broad signaling capacity of orthobiologics with the precision of peptides, neurology can move beyond symptomatic care toward regenerative strategies that aim to preserve neural circuits and improve long-term outcomes in Alzheimer's disease and Parkinson's disease.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; exosomes; orthobiologics; peptides; regenerative neurology
    DOI:  https://doi.org/10.3390/cells14231853
  62. An Pediatr (Engl Ed). 2025 Dec 05. pii: S2341-2879(25)00420-X. [Epub ahead of print] 504013
    Bioinformatics and omics data management in genetic diagnosis.
    Angela Del Pozo.
      Next Generation Sequencing (NGS) encompasses a range of technologies that have transformed genomic research since the 2000s. By allowing the sequencing of large DNA fragments at a significantly lower cost than Sanger sequencing, NGS has become an indispensable tool in molecular laboratories, particularly in the field of molecular genetics. Its high efficiency and speed make it a first-line technique in genetic analysis. A crucial step in achieving a diagnosis is bioinformatics analysis. Short-read sequencing technology generates raw data that must be processed to extract meaningful and interpretable information. This process enables the identification of causal links between genetic findings and phenotypic traits. Clinical bioinformatics specialists carry out this analysis using specialized tools and pipelines, which take into account the specific characteristics of the sequencing platforms, protocols and the particular diseases under study. The quality review is an essential complement to the pipeline analysis. Its primary objective is to assess which samples are suitable for diagnosis and, in cases where results are negative, to identify the reasons, whether they are related to the incidence or other factors. Additionally, the quality review offers insight into the overall effectiveness of the experimental procedures. Despite its many advantages, NGS still faces several challenges, including the need for more efficient technologies, enhanced regulatory frameworks and improved training of medical staff.
    Keywords:  Análisis de datos; Bioinformática clínica; Clinical bioinformatics; Data analysis; Enfermedades raras; Genomics; Genética molecular; Genómica; Molecular genetics; NGS; Omics; Rare diseases; Secuenciación; Sequencing; Ómicas
    DOI:  https://doi.org/10.1016/j.anpede.2025.504013
  63. Int J Pharm. 2025 Dec 09. pii: S0378-5173(25)01308-0. [Epub ahead of print] 126471
    Advancements in the study of exosomes in disease diagnosis and treatment.
    Tingting He, Yanni Wang, Xiaolong Li, Caiyue Xiang, Shuang Tan, Rou Fan, Jian Tian, Linwei Pan, Wenli Wu, Daxiu Li, Jing Xie.
      Exosomes are small, membrane-enclosed vesicles that can originate from a variety of sources and contain a wealth of material. They are involved in physiological processes such as cell-cell communication, cell migration, and anti-tumor immunity, and are linked to the emergence and progression of various diseases, including neurological disorders and cancer. Exosomes have great potential in the area of precise control and targeted treatment of medical conditions. By serving as a unique biomarker of the disease, they can be utilized to observe the disease's evolution and the response to treatment. Besides, exosomes hold the potential to be utilized as drug carriers in clinical treatment, owing to their capability to break through the blood-brain barrier and pass through the cell plasma membrane. In recent years, exosomes have become an emerging hot research topic.The intersection with artificial intelligence technology has notably influenced the diagnosis of exosome-related diseases. The purpose of this review is to present the latest advancements in the use of exosomes for drug delivery and disease treatment. It elucidates the connection between exosomal biomarkers and various diseases, discusses the role of exosomes in early diagnosis and cancer treatment, and offers a systematic and comprehensive overview of the application of exosomes in disease diagnosis and therapy. The challenges in the process of clinical transformation are pointed out, the basic research and clinical transformation of exosomes are promoted, and the future prospects of exosomes are discussed.
    Keywords:  Biomarkers; Detection technology; Diagnosis; Drug delivery; Exosomes
    DOI:  https://doi.org/10.1016/j.ijpharm.2025.126471
  64. Molecules. 2025 Nov 24. pii: 4532. [Epub ahead of print]30(23):
    Artificially Engineered Synthetic Biomarkers Revolutionizing Early Diagnosis of Diseases.
    Anyun Wang, Min Wei, Keying Yu, Siying Heng, Xinyue Zhao, Wenxi Jian, Jinsong Zhao, Yanfeng Gao, Yanping Wang.
      Early detection of disease, particularly cancer, is pivotal for improving patient outcomes. However, diagnostic approaches relying on traditional endogenous biomarkers often face significant limitations, primarily due to the low abundance and lack of specificity of these markers, which can lead to delayed or inaccurate diagnosis. Synthetic biomarkers, artificially engineered exogenous agents that are designed to interact with specific biological targets to generate detectable signals, represent a revolutionary approach in diagnostic medicine. By allowing for the conversion and amplification of specific disease-related signals, synthetic biomarkers enable accurate diagnosis, prognosis, and therapy monitoring, holding immense promise for the early detection of diverse disease states to facilitate prompt treatment initiation and to improve clinical outcomes. This review provides a comprehensive overview of the evolution, classification, working mechanisms, and diagnostic applications of synthetic biomarkers, along with a discussion of their future potential in advancing precision medicine and effective disease management.
    Keywords:  artificially engineered biomarkers; cancer; disease diagnosis; exogenous biomarkers; point-of-care testing; precision medicine; synthetic biology
    DOI:  https://doi.org/10.3390/molecules30234532
  65. Pharmacol Rep. 2025 Dec 10.
    Algorithm guided personalized T cell therapy: machine learning unlocks next generation TCR engineered immunotherapy.
    Zahid Rafiq, Tanzeel Bashir, Weiqin Lu, Nahum Puebla Osorio.
      
    Keywords:  AI; Immunotherapy; ML; T-cell therapy; TCR
    DOI:  https://doi.org/10.1007/s43440-025-00812-8
  66. J Health Care Poor Underserved. 2025 ;36(4): 1105-1137
    Innovative Interventions That Promote Access to Cancer Care Among People Experiencing Homelessness and Lessons Learned: A Systematic Review.
    Sunil R Dommaraju, Regina M Koch, Adrian Mayo, Amye Tevaarwerk.
      Early detection of cancer and prompt linkage to medical care in people experiencing homelessness (PEH) are crucial to improve the disparity in cancer incidence and mortality between PEH and their housed counterparts. A systematic review was conducted across 3 academic databases in April 2024 to identify interventions that aim to improve adherence to cancer care among PEH. Data from 16 eligible studies were extracted and organized around intervention type, and thematic analysis was conducted to extract key lessons learned. All studied cancer screening, taking part in mostly urban settings in the United States. The most common interventions were increasing cancer screening accessibility (n=7) and patient navigation (n=6). In one randomized trial, patient navigation was associated with 8.51 higher odds of lung cancer screening completion. Combining multiple interventions had the greatest impact on screening rates, but future interventions should also link PEH to diagnostic procedures, cancer treatment, and survivorship.
    DOI:  https://doi.org/10.1353/hpu.2025.a975576
  67. Value Health. 2025 Dec 06. pii: S1098-3015(25)06151-0. [Epub ahead of print]
    The Early Experiences Of Health Technology Assessment Bodies In The Implementation Of The EU HTA Regulation (HTAR) For High-Risk Medical Devices: A Qualitative Study.
    Rasha A Alshaikh, Kieran A Walsh, Susan Spillane, Patricia Harrington, Michelle O'Neill, Conor Teljeur, Máirín Ryan, Caitriona M O'Driscoll.
       OBJECTIVES: The EU Health Technology Assessment Regulation (HTAR) introduces Joint Clinical Assessments (JCAs) to harmonise clinical evidence evaluation across Member States. JCAs are commencing in 2026 for high-risk medical devices (MD) and in vitro diagnostics (IVD), but little is known about how national health technology assessment (HTA) bodies are preparing for implementation. This study aims to explore how selected EU/EEA HTA bodies are planning for JCAs integration and HTAR implementation for high-risk MD/IVD.
    METHODS: Semi-structured interviews were conducted with 15 participants from 11 different HTA bodies across 11 EU/EEA Member States. Interviews were recorded and transcribed verbatim before being anonymised and coded using NVivo Software. Data were analysed using thematic analysis.
    RESULTS: All participants recognised JCAs as a potential tool for improving evidence quality for high-risk devices and highlighted their willingness to use JCA-generated evidence in their clinical assessment. Some HTA bodies have initiated procedural or legislative adaptations; however, many remain in an observational position, waiting for further implementation documents. Key opportunities identified included work-sharing, improved evidence standards, and capacity-building, particularly in smaller HTA systems that might not have access to high-quality assessments without JCAs. However, substantial challenges were reported, including regulatory uncertainty, timing misalignments, and limited manufacturer preparedness for JCA evidence demands.
    CONCLUSIONS: HTAR is viewed as an opportunity to strengthen HTA practices for high-risk MD/IVD. However, realising its goals will require further collaboration, alignment of procedural timelines, and investment in national capacity. Further studies are needed after full HTAR implementation for high-risk MD/IVD to capture ongoing experiences.
    Keywords:  Evidence Generation; Health Technology Assessment Regulation; Joint Clinical Assessment; Medical Devices; Reimbursement
    DOI:  https://doi.org/10.1016/j.jval.2025.11.013
  68. MAbs. 2026 Dec;18(1): 2601360
    Beyond sequence similarity: ML-powered identification of pHLA off-targets for TCR-mimic antibodies using high throughput binding kinetics.
    Alexander Sinclair, Stefan Krämer, Christoph Reinhart, Jennifer Stehle, Simon Schuster, Tobias Herz, Hoor Al Hasani, Pranav Hamde, Oliver Selinger, Joerg Birkenfeld.
      T-cell receptor mimic (TCRm) antibodies are an emerging class of tumor-targeting agents used in advanced immunotherapies such as bispecific T-cell engagers and CAR-T cells. Unlike conventional antibodies, TCRms are designed to recognize peptide - human leukocyte antigen (pHLA) complexes that present intracellular tumor-derived peptides on the cell surface. Due to the typically low surface abundance and high sequence similarity of pHLAs, TCRms require high affinity and exceptional specificity to avoid off-target toxicity. Conventional methods for off-target identification such as sequence similarity searches, motif-based screening, and structural modeling focus on the peptide and are limited in detecting cross-reactive peptides with little or no sequence homology to the target. To address this gap, we developed EpiPredict, a TCRm-specific machine learning framework trained on high-throughput kinetic off-target screening data. EpiPredict learns an antibody-specific mapping from peptide sequence to binding strength, enabling prediction of interactions with unmeasured pHLA sequences, including sequence-dissimilar peptides. We applied EpiPredict to two distinct TCRms targeting the cancer-testis antigen MAGE-A4. The model successfully predicted multiple off-targets with minimal sequence similarity to the intended epitope, many of which were experimentally validated via T2 cell binding assays. These findings establish EpiPredict as a valuable tool for lead optimization of TCRms, enabling the identification of antibody-specific off-targets beyond the scope of traditional peptide-centric methods and supporting the preclinical de-risking of TCRm-based therapies.
    Keywords:  BLI; Binding kinetics; HLA; MAGE-A4; MHC; SCORE; T2-binding; TCR-like antibody; X-scan; machine learning; off-target toxicity; pHLA; pMHC; peptide-MHC complex; preclinical de-risking
    DOI:  https://doi.org/10.1080/19420862.2025.2601360
  69. Swiss Med Wkly. 2025 Dec 09. 155 5203
    Is it still useful to publish case reports?
    Gérard Waeber, Stefano Bassetti, Stefan Weiler.
      Although the medical literature is flooded with case descriptions, it is difficult to dismiss the significant impact that a clinical observation limited to one or two patients can have. Case reports can also play a critical role in other areas such as drug safety by serving as early warning signals for adverse drug reactions. Unlike the aggregated data and statistical abstractions of clinical trials or meta-analyses, case reports reflect the real-world context of medical practice, where decisions are made patient by patient. This alignment with everyday clinical experience makes case reports particularly relatable and valuable to practicing clinicians, offering insights that resonate far beyond the confines of population-based evidence. The "Swiss Medical Weekly" wishes to participate in the dissemination of high-quality case reports. A new section entitled "Clinical reasoning" will provide a dedicated platform for well-structured case reports while upholding the journal's high and very strict editorial standard and its Diamond Open Access model.
    DOI:  https://doi.org/10.57187/s.5203
  70. Int J Pharm. 2025 Dec 08. pii: S0378-5173(25)01316-X. [Epub ahead of print] 126479
    Current state of machine learning implementation in pharmaceutical process modeling for oral solid dosage forms.
    Maryam Rezaeizadeh, Sonia M Razavi, Fernando J Muzzio.
      Driven by the Food and Drug Administration's Quality-by-Design initiative and the advancements of Industry 4.0, the pharmaceutical industry is transitioning from traditional batch manufacturing to advanced manufacturing. This transition requires reshaping manufacturing by enabling predictive adaptive modeling, real-time process optimization, and real-time quality control. Artificial intelligence (AI) and machine learning (ML) are central to this data-driven paradigm and enable technologies to meet these requirements. In this review, we provide a perspective on the applications of ML in the manufacturing of oral solid dosage forms focusing on unit operations and process analytical technology (PAT). Applications span a variety of areas, including the prediction of critical quality attributes such as granules size distribution and moisture content in wet granulation, the optimization of key process parameters such as temperature and screw speed to achieve target product qualities in extrusion processes, and the development of adaptive, real-time PAT frameworks. While ML demonstrates promise in enabling requirements of advanced manufacturing, challenges remain in data availability, model interpretability, extrapolation, uncertainty quantification, and integration with existing manufacturing workflows. Future directions include integrating ML with digital twins, addressing model scalability to work across different scales, and incorporating uncertainty quantification to increase reliability and decision-making in dynamic variable process environments.
    Keywords:  Artificial intelligence; Ascorbic acid (PubChem CID: 5785).; Calcium carbonate (PubChem CID: 10112); Celecoxib (PubChem CID: 2662); Data-driven; Ethenzamide (PubChem CID: 3282); Ethylene-vinyl acetate copolymer (PubChem CID: 32742); Lactose (PubChem CID: 6134); Machine learning; Paracetamol (PubChem CID: 1983); Pharmaceutical manufacturing; Process modeling; Sucrose (PubChem CID: 5988)
    DOI:  https://doi.org/10.1016/j.ijpharm.2025.126479
  71. Neuroprotection. 2025 Jun;3(2): 131-144
    The role of gut microbiota-derived metabolites in neuroinflammation.
    Lingjie Mu, Yijie Wang.
      Neuroinflammation, a key defense mechanism of the nervous system, is associated with changes in inflammatory markers and stimulation of neuroimmune cells such as microglia and astrocytes. Growing evidence indicates that the gut microbiota and its metabolites directly or indirectly regulate host health. According to recent studies, bacterial dysbiosis in the gut is closely linked to several central nervous system disorders that cause neuroinflammation, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, sepsis-associated encephalopathy, and ischemic stroke. Recent findings indicate a bidirectional communication network between the gut microbiota and central nervous system that influences neuroinflammation and cognitive function. Dysregulation of this system can affect the generation of cytotoxic metabolites, promote neuroinflammation, and impair cognition. This review explores the lesser-studied microbiota-derived metabolites involved in neuroinflammation-bile acids, trimethylamine-N-oxide, and indole derivatives-as targets for creating new treatment tools for neuroinflammatory illnesses, as well as possible biomarkers for early diagnosis and prognosis.
    Keywords:  TMAO; bile acids; indoles; microbiota‐gut–brain axis; neuroinflammation
    DOI:  https://doi.org/10.1002/nep3.70001
  72. J Med Internet Res. 2025 Dec 09. 27 e81463
    Digital Health Technologies: Learnings and Perspectives From a Patient Engagement Stakeholder Expectations Matrix Study.
    Leanne West, Derick Mitchell, Stuart D Faulkner, Birgit Bauer, Nicholas Brooke, Elizabeth Priest.
      As digital health technologies become increasingly integrated into health care systems worldwide, there is growing recognition that their full potential can be realized only when development is rooted in patient engagement (PE). Despite its proven value in clinical research and health care delivery, PE remains insufficiently embedded in digital health design and implementation. This perspective paper explores the current state of PE in digital health through findings from the Stakeholder Expectations Matrix program developed by Patient Focused Medicines Development. Drawing from 37 in-depth interviews across 6 key stakeholder groups, complemented by insights gathered during a multisession cocreation track at the Patient Engagement Open Forum, this paper highlights differing perspectives on digital health, the barriers to meaningful engagement, and the fragmented nature of data governance and technology adoption. Findings point not only to significant gaps in shared understanding, infrastructure, and policy but also to clear opportunities for collaboration, including early recommendations for building a more inclusive and patient-centered digital health ecosystem, one that supports sustainable innovation, trust, and systemwide impact.
    Keywords:  artificial intelligence in health care; cocreation; digital health; digital health literacy; digital therapeutics; health data governance; health technology; multistakeholder collaboration; patient engagement; patient-centered design; stakeholder perspectives; system-level impact
    DOI:  https://doi.org/10.2196/81463
  73. Cell Mol Immunol. 2025 Dec 10.
    Cis- and trans-binding chimeric costimulatory receptors enhance T-cell fitness and tumor control.
    Patricia Hernández-López, Caterina Riillo, Laia Gasull-Celades, Jairo G E Lommen, Sabine Heijhuurs, Jiali Zheng, Sascha van Bruggen, Marina Zintchenko, Simon M Brandl, Susana Minguet, Jürgen Kuball, Dennis X Beringer.
      T-cell-based therapies have shown remarkable success in combatting hematologic malignancies; however, their efficacy in solid tumors is hindered by the immunosuppressive microenvironment and restricted antigen availability. The use of chimeric costimulatory receptors (CCRs) has emerged as a strategy to improve T-cell function. However, most designs target antigens distinct from the primary antigen receptor, complicating their application across heterogeneous tumors. Here, we characterized the molecular requirements for a platform enabling costimulation in engineered T cells on the basis of dual targeting of a single antigen via a TCR and a CCR. We applied this strategy to the stress ligand BTN3A, which is broadly expressed in solid tumors and is a part of the antigen complex recognized by the γ9δ2TCR. Through structural modeling, alanine scanning, and antibody screening, we determined that 103-4-1BB, a BTN3A-specific CCR, bound to an epitope on BTN3A that was distinct from the γ9δ2TCR epitope. This epitope separation is critical for enabling synergistic coengagement of a single antigen, and the resulting increase in T-cell activation requires both γ9δ2TCR signaling and the trans-acting functionality of the anti-BTN3A-CCR. Moreover, the extracellular domain of 103-4-1BB stabilized T-cell-tumor cell interactions and increased γ9δ2TCR sensitivity, whereas its intracellular 4-1BB signaling domain drove robust proliferation, improved T-cell fitness, and mediated potent tumor control in vivo. Notably, cis-binding of the CCR to BTN3A on engineered T cells promoted survival in the absence of tumor cells, while transbinding to tumor-expressed BTN3A was required for infiltration, tumor clearance, and memory formation. These findings establish a modular framework for designing cis/trans-active CCRs that enhance T-cell function through single-antigen dual engagement, enabling broadly applicable strategies to improve solid tumor immunotherapy.
    Keywords:  Cancer immunotherapy; Chimeric costimulatory receptor; T cell; T cell engineering; Vγ9Vδ2-T cell
    DOI:  https://doi.org/10.1038/s41423-025-01373-9
  74. Chin Med J (Engl). 2025 Dec 12.
    Recipient-derived vs. donor-derived CAR-T-cell therapy in relapsed B-cell acute lymphoblastic leukemia patients after transplantation: A multi-center retropective study.
    Lichao Liu, Yongxian Hu, Ruihao Huang, Yuhua Li, Sanfang Tu, Shangjun Chen, Hai Yi, Qiuying Gao, Jian Zhou, Xu Tan, Cheng Zhang, Xiaoqi Wang, Xi Zhang.
       BACKGROUND: Chimeric antigen receptor T (CAR-T) cells have been demonstrated to be an effective treatment for relapsed B-cell acute lymphoblastic leukemia (B-ALL) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T cells for CAR-T therapy can be derived from the peripheral blood (recipient) of the patient or donor. Despite having identical genomes, the different maturation environments of these T cells can lead to functional differences. This study aimed to compare the clinical outcomes of CAR-T cells derived from these two sources.
    METHODS: This multicenter, retrospective cohort study collected clinical data from 36 patients who experienced B-ALL relapse after allo-HSCT and received CD19 CAR-T cell therapy between January 2016 and October 2023 across seven centers. The primary endpoint was complete remission (CR)/CR with an incomplete hematologic recovery (CRi) rate at 28 days post-CAR-T cell infusion. Secondary endpoints included the 2-year overall survival (OS) rate, 2-year event-free survival (EFS) rate, incidence of graft-versus-host disease (GVHD), cytokine release syndrome (CRS), and CAR-T cell-related encephalopathy syndrome (CRES).
    RESULTS: A retrospective analysis was performed on 36 patients: 12 in the recipient group and 24 in the donor group. The recipient and donor groups showed no statistically significant differences in CR/CRi rates (83.3% vs. 100.0%, P = 0.105), 2-year EFS rates (50.8% vs. 51.6%, P = 0.617), or 2-year OS rates (49.5% vs. 63.6%, P = 0.215). In addition, the incidences of GVHD, CRS, and CRES did not significantly differ between the two groups. Further analysis within the donor group revealed 12 matched sibling donors (MSDs) and 12 haploidentical donors (HIDs). The 2-year EFS rate was statistically significantly greater in the HID group than in the MSD group (75.0% vs. 30.7%, P = 0.043), whereas no significant differences were observed in the CR/CRi rates, 2-year OS, or the incidence of GVHD, CRS, and CRES between these subgroups.
    CONCLUSIONS: Both recipient-derived and donor-derived CD19 CAR-T cell therapies are effective treatment options for B-ALL relapsed post-allo-HSCT patients. HID-derived CAR-T cells offer a longer EFS and may be considered the optimal choice.
    Keywords:  Allogeneic hematopoietic stem cell transplantation; B-cell acute lymphoblastic leukemia; Chimeric antigen receptor T; Graft-versus-leukemia; Haploidentical donor; Matched sibling donor
    DOI:  https://doi.org/10.1097/CM9.0000000000003855
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