bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–11–16
fifty papers selected by
Luca Bolliger, lxBio
  1. The potential of microfluidic cell analysis in CAR T cell therapy manufacturing.
  2. Regulatory T Cell-Based Adoptive Cell Therapy in Autoimmunity.
  3. Non-signaling but all important: how the linker, hinge, and transmembrane domains in the CAR hold it all together.
  4. CAR-T cell therapy in hepatocellular carcinoma: from mechanistic insights to clinical translation.
  5. Chimeric Antigen Receptor T-Cell Therapy and Autoimmune Diseases in the Nervous System.
  6. CAR-NK cell therapy in multiple myeloma: from preclinical and clinical landscape to joining the force for treatment strategies optimization.
  7. Recommendations for Defining Chimeric Antigen Receptor T-Cell (CAR T) Dose-Limiting Toxicities (DLTs) for Future Early-Phase CAR T Therapy Studies.
  8. Leucine Zipper-based Cell Sorting for Purification of Dual-vector-transduced Cells.
  9. Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
  10. CRISPR-Cas9 in leukemia immunotherapy: precision engineering of CAR-T cells and tumor-microenvironment modulation.
  11. A systematic scoping review of published economic analyses of public cord blood banking: Is it time to reassess?
  12. Advancing Hematopoietic Stem Cell Transplantation (HSCT) in Africa: A Pathway to Curing Hematological Disorders.
  13. SLAMF7: A Potential Target for CAR T-Cell Therapy in Multiple Myeloma.
  14. Chimeric antigen receptor T-cell therapy for stiff-person syndrome: bridging innovation and clinical challenges in neuroimmunology.
  15. Early access disparities in innovative therapies across the US, EU, China, and Japan.
  16. The interleukin-6 connection: Understanding cytomegalovirus reactivation following CAR-T-cell therapy.
  17. Injectable tert-butylphenylacetic acid/acrylated β-cyclodextrin-based hydrogels for co-delivery of CAR-T cells and IL-15 in solid tumor therapy.
  18. Bidirectional Regulatory Roles in the Immune Modulation, Organ Dysfunction, and Therapy of Sepsis.
  19. Development of production methodologies for scFv-Fc conjugated critical reagents to support CAR-T clinical programs.
  20. Access to anticancer and orphan medicines through compassionate use programs and named patient basis in seven European countries.
  21. Safety Assessment of Stem Cell-Based Therapies: Current Standards and Advancing Frameworks.
  22. A Notch too far: Treg plasticity in multiple sclerosis.
  23. Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma.
  24. CSF1R-CAR T cells induce CSF1R signaling and can promote target cell proliferation.
  25. Evaluation of several type of chemical cryoprotectants and combination towards cryopreservation of NK cell.
  26. Immune mediators as therapeutic targets in GvHD; cytokines, growth factors, chemokines, and co-stimulation /co-inhibition.
  27. Technological advancements in antibody-based therapeutics for treatment of diseases.
  28. Gut microbiota and acute graft-versus-host disease.
  29. Advances in integrating biomaterials with CAR-T cells for enhancing solid tumor therapy.
  30. Nanobody-based imaging: Advancing precision in molecular diagnostics.
  31. Nanotechnology-Microbiota Synergy in Cancer Immunotherapy.
  32. Surrogate Endpoints in Pivotal Clinical Trials for Drug Approval in Japan Compared to the United States.
  33. A personal perspective of patient-centred clinical trials.
  34. Microbial Primer: Artificial intelligence for microbiologists.
  35. Features of Peripheral T Cell Remigration into the Thymus.
  36. State-of-Art in Studying the Public Health Effects of Heat: A Literature Review.
  37. CAR T cells targeting B7H3 demonstrate potent preclinical activity against AML and ESCC.
  38. Nano-Conjugated Drug Delivery Systems for Enhanced Tumour-Specific Targeting.
  39. IFN-gamma in the tumor microenvironment: dual roles in cancer progression and therapy.
  40. Real-world clinical outcomes of CAR-T therapy from the Montefiore health system in the Bronx.
  41. Ibrutinib and PD-1 blockade potentiate mesothelin-targeting CAR-T cell therapy in preclinical models of pancreatic cancer.
  42. Organ-on-a-Chip: A Roadmap for Translational Research in Human and Veterinary Medicine.
  43. From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
  44. The power of genetics in decoding Sjögren's disease: current status and future development.
  45. The Environmental Impact of Biologic Therapy.
  46. Quantum dot: a next-generation tool for cancer diagnosis at an early stage.
  47. PredIG: an interpretable predictor of T-cell epitope immunogenicity.
  48. Antibody-Drug Conjugates in Oncology: A Spotlight on Overcoming Resistance.
  49. Optimization of the Use of Generic Medications in Oncology: Improving Safety and Therapeutic Quality.
  50. IL17-producing γδ T cells promote radioresistance via immunosuppression.
  1. Front Bioeng Biotechnol. 2025 ;13 1613836
    The potential of microfluidic cell analysis in CAR T cell therapy manufacturing.
    Aleksandra Nikoniuk, Koki Lilova, Michael Thomas, Nicolas Szita.
      Despite significant success in treating hematological cancers, Chimeric Antigen Receptor (CAR) T cell therapies must overcome several challenges to become accessible to a wide patient population. With the high cost of treatment stemming partly from the complexity of the manufacturing process, there is a need for radical innovation in the ways those therapies are made. A crucial aspect of the manufacturing process is quality control (QC), responsible for monitoring the quality of the drug product. The use of microfluidic technology, in which microchannels are designed and fabricated to achieve high control of liquids, can increase sensitivity, lower the Limit of Detection (LoD), and improve time-to-result of analytical assays. This review examines how recently developed microfluidic devices for T cell analysis fit the requirements of QC testing in CAR T cell manufacturing. A particular focus is on cell counting, cell phenotyping, and cytotoxicity assessments, where a range of microfluidic approaches have been taken to deliver reliable analytical assays. The review not only highlights current limitations of microfluidic devices that hinder their implementation in manufacturing, but also their potential to expand on current QC testing.
    Keywords:  CAR T cell; cell therapy manufacturing; critical quality attributes; microfluidics; process analytical technologies (PAT); quality control
    DOI:  https://doi.org/10.3389/fbioe.2025.1613836
  2. Int J Mol Sci. 2025 Oct 23. pii: 10340. [Epub ahead of print]26(21):
    Regulatory T Cell-Based Adoptive Cell Therapy in Autoimmunity.
    Eduardo Gozálvez, Adrián Lario, Guillermo Muñoz-Sánchez, Francisco Lozano.
      Regulatory T cells (Tregs) are a distinctive subset of CD4+ T cells critical in self-tolerance maintenance to prevent the development of autoimmunity. The mechanisms by which these cells provide immune regulation are numerous and, consequently, deeply involved in the pathogenesis of many autoimmune disorders. Treg-based adoptive cell transfer (ACT) therapy has generated interest as a novel, promising strategy to restore self-tolerance in autoimmunity. Polyclonal Treg-based ACT therapy was first implemented in clinical trials, presenting adequate safety profiles. Subsequent preclinical studies have shown antigen-specific Tregs to be safer and more effective than polyclonal approaches, so research has recently moved in this direction. Antigen-specificity can be conferred to Tregs by viral transduction of genes coding for engineered T cell receptors (eTCRs) or chimeric antigen receptors (CARs), with encouraging outcomes in different animal models of autoimmunity. This review focuses on the biology of Tregs, as well as on current preclinical and clinical data for Treg-based ACT in the field of autoimmunity.
    Keywords:  autoimmunity; chimeric antigen receptor (CAR); engineered T cell receptor (eTCR); regulatory T cells (Tregs)
    DOI:  https://doi.org/10.3390/ijms262110340
  3. Front Immunol. 2025 ;16 1664403
    Non-signaling but all important: how the linker, hinge, and transmembrane domains in the CAR hold it all together.
    Grace Bernard, Laura Evgin.
      The chimeric antigen receptor (CAR) is a synthetic and modular molecule composed of both signaling and non-signaling domains that allows a T cell to recognize cell surface antigens and trigger cytolytic functionality. It is appreciated that the non-signaling structural components, including the linker, hinge, and transmembrane domains, can dramatically alter how the CAR molecule interacts with itself and other endogenous molecules in the immune synapse. Herein, we describe the current understanding of how the structural domains can alter CAR T cell therapeutic efficacy and highlight how knowledge of the target antigen characteristics can inform CAR design choices.
    Keywords:  T cell; chimeric antigen receptor (CAR); hinge domain; linker region; transmembrane domain (TMD)
    DOI:  https://doi.org/10.3389/fimmu.2025.1664403
  4. Cancer Treat Rev. 2025 Nov 10. pii: S0305-7372(25)00168-9. [Epub ahead of print]141 103046
    CAR-T cell therapy in hepatocellular carcinoma: from mechanistic insights to clinical translation.
    Reza Elahi, Yassine Alami Idrissi, Anwaar Saeed.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed cancer immunotherapy, achieving durable complete remissions in hematologic cancers. Yet its translation to solid tumors like hepatocellular carcinoma (HCC), a leading cause of cancer-related deaths worldwide, faces formidable barriers, including immunosuppressive tumor microenvironments (TMEs), antigen heterogeneity, and risks of on-target/off-tumor toxicity. This review discusses the evolving role of CAR-T therapy in HCC across three domains: (1) foundational concepts in CAR-T design, mechanistic action, and antigen-targeting strategies; (2) breakthroughs from preclinical studies and early-phase clinical trials, such as glypican-3 (GPC3) and alpha-fetoprotein (AFP) directed CAR-T cells that have demonstrated preliminary safety and anti-tumor activity; and (3) innovative strategies to overcome TME-driven resistance, including metabolic reprogramming and stromal modulation. We highlight cutting-edge engineering solutions such as armored CAR-T cells engineered for cytokine support, dual-targeting constructs to mitigate antigen escape, and hypoxia-resistant designs alongside synergistic approaches combining CAR-T with immune checkpoint inhibitors or tyrosine kinase inhibitors. Furthermore, we dissect emerging tactics to disrupt TME immunosuppression. While CAR-T therapy holds promise for redefining HCC management, its success will depend on overcoming biological and logistical barriers through patient-tailored designs and robust translational pipelines. Future directions should prioritize biomarker-driven clinical trials, scalable manufacturing platforms, and integration with existing multimodal HCC therapies to maximize durable responses.
    Keywords:  Immunotherapy; chimeric antigen receptor (CAR); hepatocellular carcinoma (HCC); tumor microenvironment (TME)
    DOI:  https://doi.org/10.1016/j.ctrv.2025.103046
  5. Immun Inflamm Dis. 2025 Nov;13(11): e70298
    Chimeric Antigen Receptor T-Cell Therapy and Autoimmune Diseases in the Nervous System.
    Shun-Yu Yao, Miao-Qiao Du, Huan Yang, Qiu-Ming Zeng, Hao Zhou, Xiuli Zhang, Sugimoto Kazuo, Jia Liu, Lan-Xin Lin, Xu-Hui Kang, Dai-Yi Jiang, Yong Peng.
       INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapy, a revolutionary immunotherapy originally developed for hematologic malignancies, has recently gained attention for its potential in treating autoimmune diseases. Increasing evidence suggests that CAR-T cells can precisely target pathogenic immune populations, offering durable remission and immune homeostasis restoration in neuroimmunological disorders such as myasthenia gravis (MG), neuromyelitis optica spectrum disorder (NMOSD), and multiple sclerosis (MS).
    METHODS: Relevant publications and clinical trial data up to September 2025 were systematically reviewed to summarize the mechanisms, therapeutic targets, safety profiles, and translational applications of CAR-T therapy in autoimmune diseases of the nervous system.
    RESULTS: Preclinical and early clinical studies demonstrate that CD19- and BCMA-directed CAR-T therapies effectively deplete autoreactive B cells with significant symptom improvement and minimal cytokine release syndrome or neurotoxicity. Novel constructs such as chimeric autoantibody receptor (CAAR)-T and CAR-regulatory T (CAR-Treg) cells enhance specificity and immune tolerance. Innovations including allogeneic "off-the-shelf" CAR-T, in vivo CAR engineering, and CRISPR-based safety switches further optimize therapeutic potential and accessibility.
    CONCLUSION: CAR-T therapy represents a promising frontier for refractory neuroautoimmune diseases. By precisely modulating immune networks, it offers a pathway toward long-term remission and personalized immunotherapy in clinical neuroimmunology.
    Keywords:  CAR‐T therapy; Guillain–Barré syndrome; Myasthenia Gravis; autoimmune diseases; autoimmune encephalitis; multiple sclerosis; myelin oligodendrocyte glycoprotein antibody‐associated disease; neuromyelitis optica spectrum disorder
    DOI:  https://doi.org/10.1002/iid3.70298
  6. Cell Commun Signal. 2025 Nov 11. 23(1): 485
    CAR-NK cell therapy in multiple myeloma: from preclinical and clinical landscape to joining the force for treatment strategies optimization.
    Somayeh Yazdanparast, Mehdi Bakhtiyaridovvombaygi, Zeinab Davoodi-Moghaddam, Gelayol Asadi, Fatemeh Monjezi, Pegah Kiyamehr, Ahmad Gharehbaghian, Saeid Abroun, Nahid Moradi.
      Natural killer (NK) cells are specialized components of the innate immune system with an essential role in immune surveillance against multiple myeloma (MM). However, patients with MM often exhibit significant impairments in both the quantity and functionality of NK cells, particularly those who are refractory or have relapsed disease. Increasing evidence suggests that harnessing NK cells may provide a promising "off-the-shelf" therapeutic strategy for treating MM. Recent advancements in chimeric antigen receptor (CAR) engineering have enhanced the capabilities of NK cells, allowing them to target MM-associated antigens effectively. This innovative approach may help mitigate the off-target toxicities often associated with NK cells and address challenges such as the ability of MM cells to evade immune detection. CAR-NK therapy shows promise for B-cell malignancies, but its efficacy in MM has been less examined. This comprehensive review revealed that CAR-NK cells elicit a robust immune response against myeloma cells in preclinical studies conducted both in vitro and in vivo. Furthermore, the development of dual-CAR NK cell therapies indicates promise in overcoming myeloma escape mechanisms. Numerous clinical trials are currently underway to evaluate the efficacy and safety of CAR-NK cell therapy for individuals diagnosed with MM.
    Keywords:  CAR-NK cell; Chimeric antigen receptor; Multiple myeloma; Natural killer cell
    DOI:  https://doi.org/10.1186/s12964-025-02443-1
  7. Transplant Cell Ther. 2025 Nov 07. pii: S2666-6367(25)01554-4. [Epub ahead of print]
    Recommendations for Defining Chimeric Antigen Receptor T-Cell (CAR T) Dose-Limiting Toxicities (DLTs) for Future Early-Phase CAR T Therapy Studies.
    Frederick L Locke, Sarah Nikiforow, Matthew J Frigault, David G Maloney, Marco Davila, David B Miklos, Yi Lin, Judy Vong, Nirav N Shah, Sattva S Neelapu, John Welch, Eric Ng, Caron Jacobson, Marcela V Maus.
      Chimeric antigen receptor T-cell (CAR T) therapies have demonstrated potential to provide long-term remission in incurable hematologic malignancies, and novel approaches for CAR T therapy continue to be developed for treating cancer and other indications. Acute class-effect toxicities, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome, remain significant concerns despite their potential reversibility. Given the complexities of balancing safety and efficacy of CAR T therapies, the US Food and Drug Administration (FDA) recently published Guidance for Industry, which included suggested definitions for dose-limiting toxicities (DLTs) for clinical trials of emerging CAR T therapies. However, the DLT definitions in the guidance do not reflect what was used in the phase 1 and/or registrational studies for the approved CAR Ts; for example, these studies defined DLTs as treatment-related, included exceptions, and/or allowed for time to resolve the adverse event. Using DLT definitions from the guidance could have prematurely stopped the early-phase studies of the now approved CAR Ts. In 2023, while designing a first-in-human, phase 1 study of a logic-gated cell therapy, an expert panel of academic cell therapists collaborated with industry partners at A2 Biotherapeutics to assess the practical implications of the FDA guidance. This led the panel to draft the revised recommendations contained herein, which integrate the permissibility of reversible events during dose-escalation for trial sponsors, investigators, health authorities, and other parties who may be involved in future CAR T therapy trials. These expert recommendations balance the safety of patients in early-phase trials with the potential long-term therapeutic opportunities for patients with terminal malignancies.
    DOI:  https://doi.org/10.1016/j.jtct.2025.11.004
  8. J Vis Exp. 2025 Oct 24.
    Leucine Zipper-based Cell Sorting for Purification of Dual-vector-transduced Cells.
    Katerina Su, Bintao Wang, Adhithi Rajagopalan, Sophia Chen, Alexander P Boardman, Marcel R M van den Brink, Scott E James.
      Adoptive T cell therapies, including chimeric antigen receptor (CAR) T cells, have demonstrated impressive clinical activity against hematologic malignancies and are showing promise in treating solid tumor malignancies. Despite these successes, multiple mechanisms of resistance to T cell immunotherapy have been identified that limit therapeutic success, including loss of or weak expression of target antigens, development of T cell exhaustion, and the presence of an immunosuppressive tumor microenvironment. Multiple cell engineering strategies have been developed to overcome these mechanisms of resistance. However, multiple mechanisms of resistance can occur simultaneously, necessitating a combination of multiple engineering strategies to optimize anti-tumor activity. Vector packaging constraints limit the delivery of large amounts of genetic information to T cells and present a challenge in co-expressing multiple engineered constructs. Here, we describe a protocol for co-transducing T cells with two vectors to encode multiple transgenes, thereby increasing the number of engineered functions. By co-expressing a leucine zipper-based cell sorting methodology, termed Zip-sort, we direct selective immunomagnetic purification of dual-transduced cells that have incorporated two distinct vectors.
    DOI:  https://doi.org/10.3791/68628
  9. Front Immunol. 2025 ;16 1677548
    Reprogramming the tumor microenvironment to boost adoptive T cell therapy.
    Maria Fernanda Meza Pacheco, Lee-Hwa Tai.
      Adoptive T cell therapies (ACT) have revolutionized the management of hematologic malignancies; however, their efficacy in solid tumors remains limited. Accumulating evidence implicates the tumor microenvironment (TME) - a highly complex and immunosuppressive niche as a major barrier to their effectiveness. In this review, we propose that the next generation of ACT will require a fundamental shift from a reductionist focus on T cell engineering alone to an integrated approach that considers the interactions between immune cells and the TME. A comprehensive literature review identified several emerging strategies to enhance the efficacy of ACT, including reprogramming tumor vasculature, repolarizing immunosuppressive myeloid and stromal cells, leveraging oncolytic viruses to remodel antigen presentation, inducing acute sterile inflammation, and targeting the physical properties of the extracellular matrix. While many of these approaches remain in early-stage development, some have already progressed to clinical trials, indicating their potential for clinical translation. Additionally, we found that conventional therapies, such as surgery, chemotherapy, and radiotherapy, can be strategically integrated with ACT to improve therapeutic outcomes. These findings highlight a shift in the field toward more integrative approaches. Future advances will likely depend on reprogramming the TME to support T cell persistence and functions. Addressing these interconnected challenges will require closer collaboration between immunology, oncology, and bioengineering disciplines.
    Keywords:  CAR (chimeric antigen receptor) T-cell therapy; adoptive T cell immunotherapy; immunomodulation; immunotherapy; oncology; tumor infiltrating lymphocyte; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2025.1677548
  10. Mol Biol Rep. 2025 Nov 15. 53(1): 90
    CRISPR-Cas9 in leukemia immunotherapy: precision engineering of CAR-T cells and tumor-microenvironment modulation.
    Jingli Gong, Hamed Soleimani Samarkhazan, Mohammad Siavashi, Nazli Servatian, Farnaz Pirsavabi.
      Together with base editors, prime editors, and alternative nuclease platforms, CRISPR-Cas9 technology has transformed the field of genetic engineering by providing unprecedented precision in genome editing and creating new opportunities for therapeutic interventions. This technology comprises a versatile genome-editing toolkit for achieving a variety of therapeutic objectives. In the context of leukemia, a group of life-threatening hematologic malignancies, CRISPR-Cas9 has emerged as a transformative tool for immunotherapy. By enabling targeted modifications of immune cells, such as T cells, this technology enhances their ability to recognize and eradicate leukemic cells. CRISPR-Cas9 facilitates the disruption of immune checkpoint inhibitors, the insertion of chimeric antigen receptors (CARs), and the correction of genetic mutations that drive leukemia progression. These advancements have led to the development of more potent and personalized immunotherapies, such as CAR-T cell therapies, with improved efficacy and reduced off-target effects. Moreover, CRISPR-Cas9 allows researchers to model leukemia in vitro, providing deeper insights into disease mechanisms and accelerating the discovery of novel therapeutic targets. Despite challenges such as delivery efficiency and potential immunogenicity, the integration of CRISPR-Cas9 into leukemia immunotherapy represents a paradigm shift, offering hope for durable remissions and potentially curative outcomes. As clinical trials progress, this technology promises to redefine the standard of care for leukemia patients, ushering in a new era of precision medicine. This narrative review explores the revolutionary applications of CRISPR-Cas9 in redefining therapeutic strategies for leukemia.
    Keywords:  CAR-T cell therapy; CRISPR-Cas9; Genome editing; Immune checkpoint inhibitors; Leukemia immunotherapy; Precision medicine
    DOI:  https://doi.org/10.1007/s11033-025-11235-2
  11. Transfusion. 2025 Nov 14.
    A systematic scoping review of published economic analyses of public cord blood banking: Is it time to reassess?
    Luke E Allan, Risa Shorr, Matthew Seftel, Pierre J A Villeneuve.
       OBJECTIVES: Public banking of umbilical cord blood (UCB) remains important as a source of donor cells for hematopoietic cell transplantation (HCT). Given reductions in global cord blood transplant activity, the economic value of UCB banking may be questioned. We performed a scoping review to gain a full and current understanding of economic evaluations of public UCB banking.
    METHODS: We conducted a systematic search to June 2024 in Medline, Embase, Cochrane Central, Health Technology Assessment, Econlit, Scopus, and cumulative index to nursing and allied health literature (CINAHL) databases.
    RESULTS: Our search identified 13 studies published between 1999 and 2019, predominantly from the United States and Europe. Of these, five are classified as full economic evaluations, with two employing cost-effectiveness analysis, one applying cost-utility analysis and two applying cost-benefit analysis. Key findings reveal a shift from evaluating the optimal inventory size and costs associated with establishing cord banks, to the evaluation of strategies that increase usage and reduce costs of bank operations. Only two studies considered the societal gain from transplant survivors, noting many cord blood transplant recipients are pediatric with significant gain in quality-adjusted life years that offset the high costs of operating public cord banks. Studies addressing the needs of underrepresented populations were lacking.
    CONCLUSIONS: Our analysis highlights the evolving landscape of public UCB banking economic evaluations. Updated full economic studies are needed to understand the current landscape given potential usage by specific sub-groups of the population, reduced global usage for HCT, and the emergence of novel uses of cord blood.
    Keywords:  allogeneic; analysis; cost; economic; hematopoietic cell transplantation; public banking; umbilical cord blood; value
    DOI:  https://doi.org/10.1111/trf.18483
  12. Health Sci Rep. 2025 Nov;8(11): e71464
    Advancing Hematopoietic Stem Cell Transplantation (HSCT) in Africa: A Pathway to Curing Hematological Disorders.
    Tolulope Joseph Ogunniyi, Rodiat Remilekun Abdulkareem, Adeola Roqeebat Emiola, Toluwase Ruth Bamidele, Godsave Binlak Wazhi, Precious Opeyemi Arinde, Sarah Sokolabe Yisa, Oluwatoyin Makanjuola, Kesaobaka Batisani, Ayodele Ilesanmi.
       Background: Hematopoietic stem cell transplantation (HSCT) offers a curative option for numerous hematological disorders, notably sickle cell disease and thalassemia, which are highly prevalent in Africa. Despite its potential, access to HSCT remains limited due to infrastructural, economic, and socio-cultural challenges across the continent.
    Methods: This review synthesizes current literature and reports on the status of HSCT in Africa, analyzing data from existing transplant centers, national registries, and peer-reviewed studies to assess progress, challenges, and prospects for expanding HSCT services.
    Results: Out of 54 African countries, only seven perform HSCT, with considerable disparities in the number of procedures, donor availability, and infrastructure. Major barriers include inadequate healthcare infrastructure, limited trained personnel, scarcity of donors, high costs, cultural misconceptions, and poor documentation. Notably, progress has been made in Nigeria, Egypt, Morocco, Tunisia, South Africa, Tanzania and Algeria, but the overall transplant rate remains low. Emerging strategies such as regional collaborations, the development of African-specific donor registries, and technological innovations are being explored to improve access and outcomes.
    Conclusion: While HSCT in Africa is still in its infancy, strategic investments in infrastructure, capacity building, donor registry development, and regional cooperation hold promise for broader access. Integrating technological advances and policy support can accelerate progress, transforming HSCT into a sustainable, accessible curative therapy for hematological disorders across the continent.
    Keywords:  Africa; hematological disorder; hematopoietic stem cell transplantation; supportive care
    DOI:  https://doi.org/10.1002/hsr2.71464
  13. Cancers (Basel). 2025 Oct 29. pii: 3471. [Epub ahead of print]17(21):
    SLAMF7: A Potential Target for CAR T-Cell Therapy in Multiple Myeloma.
    Caterina Alati, Martina Pitea, Gaetana Porto, Erica Bilardi, Maria Bruna Greve, Iolanda Donatella Vincelli, Andrea Rizzuto, Giorgia Policastro, Maria Eugenia Alvaro, Giovanna Utano, Demetrio Gerace, Alessandro Allegra, Eugenio Piro, Marco Rossi, Massimo Martino.
      Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7) represents a potential target for CAR T-cell therapy in the treatment of multiple myeloma (MM), and it is a promising alternative to classic BCMA-CAR therapy. The receptor is expressed on immune cells, particularly natural killer cells and T cells, that can trigger both activating and inhibitory signals. It is highly expressed in MM cells at all disease stages, playing a crucial role in cell adhesion and communication between immune cells, and being involved in the development and progression of the disease. The target has a proven clinical success with Elotuzumab (anti-SLAMF7 antibody); it works by activating immune cells to kill myeloma cells, and limited expression on normal tissues, with, potentially, few side effects. SLAMF7's combination of specificity, stability, and clinical validation makes it an excellent target for current and future MM therapies. However, 'fratricide death', a phenomenon where the engineered CAR-T cells attack and kill each other, is a critical issue that requires safe engineering solutions. In this work, we will provide an overview on the field with a specific focus on SLAMF7 as an emerging CAR-T cell target in MM.
    Keywords:  BCMA; CAR-T cell therapy; SLAMF7; dual CAR-T; elotuzumab; multiple myeloma; new CAR-T targets
    DOI:  https://doi.org/10.3390/cancers17213471
  14. Ther Adv Neurol Disord. 2025 ;18 17562864251387930
    Chimeric antigen receptor T-cell therapy for stiff-person syndrome: bridging innovation and clinical challenges in neuroimmunology.
    Jonathan Wickel, Jeremias Motte, Ilya Ayzenberg, Benjamin Vlad, Ralf Gold, Christian Geis, Simon Faissner.
      Chimeric antigen receptor T-cells (CAR T-cells) have revolutionized the treatment of hematologic malignancies and are now being explored in autoimmune diseases, including neuroimmunological disorders. The first clinical applications of CAR T-cell therapy for autoimmune diseases have demonstrated promising efficacy, particularly in systemic lupus erythematosus and myasthenia gravis. While CAR T-cell therapy can induce profound B-cell depletion, leading to durable remission, concerns remain regarding cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. However, neuroimmunological conditions with lower target cell burdens may carry a reduced risk of these adverse events. Recent evidence suggests CAR T-cells could offer a transformative approach for stiff-person syndrome (SPS), a rare but debilitating autoimmune neurological disorder characterized by muscle rigidity and spasms. The first reported case of anti-CD19 CAR T-cell therapy in a treatment-refractory SPS patient resulted in substantial clinical improvement, including increased mobility and reduced dependence on symptomatic medication. A newly launched phase II clinical trial (NCT06588491) aims to further evaluate the safety and efficacy of anti-CD19 CAR T-cell therapy in SPS. In this review, we examine the current evidence supporting the use of CAR T-cells in neuroimmunological conditions, discuss the clinical picture and pathophysiological processes associated with stiff person spectrum disorders (SPSD), and elaborate on perspectives and limitations of CAR T-cell therapy in SPSD and beyond.
    Keywords:  CAR; CAR-T cell; CD19; GAD; PERM; SPS; SPSD
    DOI:  https://doi.org/10.1177/17562864251387930
  15. Front Med (Lausanne). 2025 ;12 1642882
    Early access disparities in innovative therapies across the US, EU, China, and Japan.
    Sanae Akodad, Michel Goldman, Hilde Stevens.
      Early access to innovative therapies offers a critical lifeline for patients with severe or life-threatening conditions, yet substantial disparities persist across the United States (US), the European Union (EU), China (CH), and Japan (JP). These disparities arise from diverging definitions of unmet medical need (UMN), heterogeneous timelines for regulatory review, and uneven implementation of Early and Expanded Access mechanisms. This policy review provides a comparative analysis of regional frameworks, emphasizing how clinical trial geography, eligibility rules, and access mechanisms interact to shape pre-approval opportunities for patients. While regulatory innovations such as the FDA's Breakthrough Therapy designation, the EMA's PRIME scheme, the PMDA's Sakigake program, and recent reforms in China have accelerated access in selected contexts, cross-border misalignments and fragmented health technology assessment (HTA) processes continue to generate inequities. The EU's new HTA Regulation (2021/2282) represents a step forward by embedding joint clinical assessment and real-world evidence, but persistent structural inconsistencies hinder timely and equitable uptake. This article argues for a paradigm shift from static approval models to adaptive licensing approaches, including live licenses and regulatory sandboxes. It calls for internationally coordinated benefit-risk governance that integrates early access planning into drug development from Phase II onward. By reframing uncertainty as a shared responsibility among regulators, developers, payers, clinicians, and patients, early access governance can be redesigned to promote equity, transparency, and responsiveness particularly for rare and high-burden diseases.
    Keywords:  early access; global health equity; health technology assessment (HTA); regulatory disparities; unmet medical need
    DOI:  https://doi.org/10.3389/fmed.2025.1642882
  16. Br J Haematol. 2025 Nov 12.
    The interleukin-6 connection: Understanding cytomegalovirus reactivation following CAR-T-cell therapy.
    Linghao Li, Zihao Wang, Chongsheng Qian, Jie Xu, Ziling Zhu, Guanghua Chen, Tianyu Lu, Ying Wang, Jia Chen, Suning Chen, Xiaowen Tang, Chengcheng Fu, Depei Wu, Sheng-Li Xue.
      Of 84 patients with acute lymphoblastic leukaemia, non-Hodgkin lymphoma or multiple myeloma, 22 developed cytomegalovirus (CMV) viraemia following chimeric antigen receptor modified T (CAR-T) cell therapy, resulting in a proportion of 26% and a median time to reactivation of 15.5 days. Sustained high level of interleukin-6 (IL-6) is a significant risk factor for CMV reactivation without significant interaction across subgroups of diagnosis and target. Other risk factors include ≥3 grade cytokine release syndrome (CRS), B-cell maturation antigen (BCMA)-directed CAR and high-dose corticosteroids. Excessive IL-6 during CRS play an important role in the frequent CMV reactivation following CAR-T-cell immunotherapy.
    Keywords:  cytokines; cytomegalovirus; immunotherapy; interleukins
    DOI:  https://doi.org/10.1111/bjh.70246
  17. Mater Today Bio. 2025 Dec;35 102421
    Injectable tert-butylphenylacetic acid/acrylated β-cyclodextrin-based hydrogels for co-delivery of CAR-T cells and IL-15 in solid tumor therapy.
    Yun-Cheng Zeng, Yi-Qun Sun, Xue-Qing Zhang, Shu-Jie Liang, Li-Li Chen, Kun-Yu Zhang, Zi-Dong Lu, Peilong Lai.
      Chimeric antigen receptor (CAR)-T cell therapy has shown great potential in treating hematologic malignancies, but its efficacy in solid tumors is limited by the immunosuppressive microenvironment and poor tumor infiltration. Hydrogels possess excellent local delivery capabilities, providing a supporting environment for adoptive cells and enhancing their tumor retention. Here, we report injectable supramolecular hydrogels composed of hyaluronic acid grafted with tert-butylphenylacetic acid (HA-TP) and acrylated β-cyclodextrin (AC-β-CD) for the co-delivery of CAR-T cells and IL-15. The hydrogels rapidly form a stable 3D network via host-guest interactions and acrylate photocrosslinking, providing a niche that retains and activates CAR-T cells. Interleukin (IL)-15 promotes CAR-T cell proliferation, leading to improved infiltration and antitumor cytotoxicity. In mouse models of B16-F10-ovalbumin (OVA) melanoma and B cell lymphoma, the hydrogels mediate the extensive infiltration of OVA-specific CD8+ T cells or CAR-T cells into tumors, effectively suppressing tumor growth. Furthermore, the hydrogels significantly promote the proportion of central memory T cells and effector memory T cells, which enables long-term antitumor effects. This hydrogel platform therefore provides a rational and effective approach to improve CAR-T cell therapy for solid tumors.
    Keywords:  CAR-T cell therapy; Immunotherapy; Solid tumor therapy; Supramolecular hydrogels
    DOI:  https://doi.org/10.1016/j.mtbio.2025.102421
  18. Int J Nanomedicine. 2025 ;20 13527-13541
    Bidirectional Regulatory Roles in the Immune Modulation, Organ Dysfunction, and Therapy of Sepsis.
    Meng Zhang, Jiangang Xie, Peiyu Zhang, Linxiao Wang, Qianmei Wang, Wen Yin.
      Exosomes have emerged as central mediators in sepsis pathogenesis and therapy. Exosomes play an important role in cell communication by transferring functional proteins, metabolites, and nucleic acids to recipient cells. Recently, Low-immunogenic exosomes serve as novel biomarkers in sepsis, and they confer a 46% enhancement in survival benefit in animal models. However, exosomes drive the early inflammatory storm and late immune paralysis in sepsis. There are also limitations related to heterogeneity and translational barriers. Therefore, this review discusses the basic signaling pathways underlying the bidirectional effects of exosomes in the pathogenesis and treatment of sepsis, the interaction between organ dysfunction and exosomes in sepsis, the current progress in exosome therapy for sepsis, as well as the challenges and limitations faced in this field. In summary, exosomes have bright prospects in diagnosis and clinical translation, as well as the potential for standardized production.
    Keywords:  bidirectional regulatory roles; biomarkers; exosomes; extracellular vesicles; immunomodulation; sepsis
    DOI:  https://doi.org/10.2147/IJN.S542937
  19. Bioanalysis. 2025 Nov 14. 1-16
    Development of production methodologies for scFv-Fc conjugated critical reagents to support CAR-T clinical programs.
    Ellen O'Connor, Eric Lachacz, Jared Delmar, Bradley D'souza, Samuel Edwards, Christopher Griffin, Rosie Lin, Neil Mody, Alicia Salas, Natalia Schoch-Lopez, Mitali Shah, Ai Shih, Dewald van Dyk, Yueming Xu.
       INTRODUCTION: Routine conjugation protocols are typically used by bioanalytical laboratories for production of their assay critical reagents. Novel molecules can pose unique challenges to the production of high-quality conjugated critical reagents required for clinical bioanalytical assays. Using routine conjugation protocols, we observed gross instability of conjugated-drug surrogate material for use in antidrug antibody (ADA) assays in clinical autologous Chimeric Antigen Receptor (CAR)-T cell programs, thus halting assay development.
    METHODS: We highlight our approach in developing process conditions for CAR-T supporting conjugated critical reagents, where recombinant CAR scFv-hFc is the surrogate drug material to be conjugated. We show that when routine platform process approaches are not appropriate to produce conjugated novel molecule critical reagents, in-silico modeling can be used to determine conditions imparting repeatable generation of stable reagents. Implementing this modeling is advantageous as it decreases laborious efforts to develop stable novel critical reagent production methodologies.
    CONCLUSION: As a result of these studies herein, optimal stable conjugated critical reagents were produced which enabled successful development and validation of clinical CAR-T ADA assay. This work provides a framework that can be applied to the production of other bioanalytical assay critical reagents when platform conjugation approaches fail.
    Keywords:  Biopharmaceutical; CAR-T; conjugated critical reagent; ligand-binding assay; scFv
    DOI:  https://doi.org/10.1080/17576180.2025.2587001
  20. ESMO Open. 2025 Nov 12. pii: S2059-7029(25)01724-7. [Epub ahead of print]10(11): 105855
    Access to anticancer and orphan medicines through compassionate use programs and named patient basis in seven European countries.
    N Rosenberg, H C Post, T Schutte, S J de Visser, I Bartelink, A M G Pasmooij, H W M van Laarhoven, C E M Hollak.
       BACKGROUND: In the European Union (EU), anticancer and orphan medicines are often granted marketing authorization based on surrogate endpoints and limited clinical trial data. Driven by unmet medical needs and the urgency of providing access beyond clinical trials, there is growing interest in early access, such as compassionate use programs (CUPs) and named patient basis (NPB). Additionally, limited clinical evidence can hinder health technology assessments and, when combined with high costs, delay reimbursement negotiations and patient access. Hence, it is crucial to explore CUPs and NPBs including pricing and reimbursement aspects.
    DESIGN: This study includes a policy analysis to evaluate CUPs and NPBs in seven high-income European countries (Belgium, France, Germany, Netherlands, Norway, Switzerland, and the UK). We collected data on regulatory characteristics, including reimbursement aspects, from national health authority resources and direct consultations. In an in-depth examination, we assessed CUPs of anticancer and orphan medicines authorized in 2021 and 2022, focusing on availability, duration, and geographic distribution.
    RESULTS: Our analysis reveals variability in national regulations, with inconsistent reimbursement options for CUPs and NPBs. For NPBs, reimbursement was often unregulated. The in-depth examination of CUPs revealed disparities in availability and duration before and after EU marketing authorization. We identified 36 CUPs, with 3-9 CUPs per country. Each CUP was available in up to four countries.
    CONCLUSION: We recommend minimizing disparities between CUPs and NPBs across Europe to ensure equitable access for patients with high unmet medical needs. Reducing these differences is essential to protect patients from feeling compelled to travel abroad or bear the financial burden of obtaining medicines that are not authorized in their home country.
    Keywords:  anticancer medicines; compassionate use; early access; named patient; orphan medicines; pre-authorization access
    DOI:  https://doi.org/10.1016/j.esmoop.2025.105855
  21. Cells. 2025 Oct 23. pii: 1660. [Epub ahead of print]14(21):
    Safety Assessment of Stem Cell-Based Therapies: Current Standards and Advancing Frameworks.
    Georgy E Leonov, Lydia R Grinchevskaya, Oleg V Makhnach, Marina V Samburova, Dmitry V Goldshtein, Diana I Salikhova.
      Regenerative medicine is a rapidly evolving field of contemporary biomedical research that offers new therapeutic strategies for conditions previously considered untreatable. Cell therapy shows particular potential in this domain. However, rigorous biosafety measures are required in its development and clinical application. This review proposes a practice-oriented biosafety framework for cell therapy, translating key risks into operational principles: toxicity, oncogenicity/tumorigenicity/teratogenicity, immunogenicity, biodistribution; and cell product quality. For each principle, preclinical approaches and regulatory expectations are summarized. Criteria for immunological safety are addressed, including activation of innate immunity (complement, T- and NK-cell responses) and the need for HLA typing. Biodistribution assessment involves the use of quantitative PCR and imaging techniques (PET, MRI) to monitor cell fate over time. The risks of oncogenicity, tumorigenicity, and teratogenicity can be analyzed using a combination of in vitro methods and in vivo models in immunocompromised animals. Product quality assessment includes sterility, identity, potency, viability, and genetic stability, with alignment of procedures to regulatory requirements and an emphasis on quality-by-design principles to ensure safe and reproducible clinical use. Integrating toxicity and safety pharmacology data supports a balanced risk-benefit assessment and clinical trial planning.
    Keywords:  biodistribution; biosafety; cell product quality; cell therapy; immunogenicity; oncogenicity; regenerative medicine; toxicity; tumorigenicity
    DOI:  https://doi.org/10.3390/cells14211660
  22. Immunity. 2025 Nov 11. pii: S1074-7613(25)00471-6. [Epub ahead of print]58(11): 2615-2617
    A Notch too far: Treg plasticity in multiple sclerosis.
    Justine Fiefvet, Lidia Yshii.
      Regulatory T cells can play conflicting roles in autoimmune inflammation. In this issue of Immunity, Benamar et al. reveal that gut-microbiota-induced Notch3+ regulatory T cells migrate to the central nervous system in multiple sclerosis and transition to inflammatory Th17-like cells.
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.017
  23. Nat Commun. 2025 Nov 11. 16(1): 9914
    Engineered CXCR3-A expression enhances B7-H3-targeting CAR T cell migration and efficacy against diffuse intrinsic pontine glioma.
    Edward Z Song, Andrea Timpanaro, Michael Meechan, Leonel Elena-Sanchez, Lucy Z Li, Sophie Jamet, Davina S Lau, Lily I Winter, Matthew D Dun, Jessica B Foster, Myron K Evans, Siobhan S Pattwell, Vandana Kalia, Surojit Sarkar, Michael C Jensen, Matthew C Biery, Nicholas A Vitanza.
      Diffuse intrinsic pontine glioma (DIPG) is a fatal brainstem tumor desperately in need of better treatments. Chimeric antigen receptor (CAR) T cell therapies for DIPG have demonstrated clinical tolerability and bioactivity, but not universal benefit. A major obstacle is insufficient CAR T cell trafficking to the tumor. As our recent clinical trials have demonstrated locoregional elevation of CXCL10, a ligand of the chemokine receptor CXCR3, here we aim to leverage this CXCL10 upregulation to enhance cell trafficking by engineering our B7-H3-targeting CAR T cells to overexpress CXCR3 variants. We demonstrate that, compared to unmodified B7-H3 CAR T cells, CXCR3-A-modified CAR T cells migrate more efficiently toward CXCR3 ligands in vitro, and when delivered intracerebroventricularly in orthotopic DIPG mouse models, CXCR3-A-modified CAR T cells show enhanced trafficking into the tumor and improved therapeutic efficacy. Overall, our data support the potential for engineering CXCR3-A expression to enhance CAR T cell trafficking and efficacy against DIPG.
    DOI:  https://doi.org/10.1038/s41467-025-64861-6
  24. Sci Signal. 2025 Nov 11. 18(912): eadv4112
    CSF1R-CAR T cells induce CSF1R signaling and can promote target cell proliferation.
    Aurora Callahan, Xinyan Zhang, Amber Wang, Aisharja Mojumdar, Longhui Zeng, Xiaolei Su, Arthur R Salomon.
      Chimeric antigen receptor (CAR) T cells have demonstrated unprecedented success in treating relapsed or refractory blood cancers. Previous studies of the mechanisms underlying the interactions and responses of CAR T cells and their targets have largely ignored the responses of tumors to CAR ligation. We compared the signaling of a second-generation, ligand-based CAR built from colony-stimulating factor 1 (CSF1) to target the CSF1 receptor (CSF1R) on target cells with a conventional, single-chain variable fragment-based CAR against the B cell antigen CD19. Using SILAC coculture with phosphotyrosine enrichment and LC-MS/MS analysis, we showed that ligation of CSF1R-expressing THP-1 cells with CSF1R-CAR T cells stimulated CSF1R-like signaling in the THP-1 cells. In contrast, no target cell signaling response was observed after the ligation of CD19-CAR T cells with target Raji cells. Using small-molecule inhibitors of the tyrosine kinase Lck, actin polymerization, and CSF1R, we found that CAR-induced CSF1R signaling in THP-1 cells depended exclusively on the kinase activity of CSF1R with no participation from T cell activation. Consistently, CSF1R-CAR T cells promoted THP-1 cell proliferation at low effector-to-target ratios but prevented THP-1 cell proliferation at high effector-to-target ratios. Our data provide evidence for CAR-induced signaling in target cells, an unintended consequence of CARs that may have implications for the choice of CAR antigen for optimal clinical efficacy.
    DOI:  https://doi.org/10.1126/scisignal.adv4112
  25. Cytotechnology. 2025 Dec;77(6): 187
    Evaluation of several type of chemical cryoprotectants and combination towards cryopreservation of NK cell.
    Takuya Kikuchi, Ippei Takeuchi, Hideto Yamaguchi.
      Natural killer (NK) cells are being developed as therapeutic agents targeting hematological malignancies and solid tumors. However, the lack of an optimal cryopreservation medium poses a significant challenge, as cryopreservation often reduces NK cell recovery, viability, and function, hindering their use in cellular therapies. This study investigated the effects of varying concentrations of Dimethyl sulfoxide (Me2SO), Proline, Trehalose, and Dextran 40 commonly used in cell cryopreservation on NK cell recovery, viability, and cytotoxic activity. Additionally, we conducted a screening of 19 cryoprotective agents (CPAs) to enhance NK cell cytotoxic activity after freeze-thawing. We found that reducing Me2SO concentration significantly decreased NK cell cytotoxic activity, and the combination of Proline, Trehalose, and Dextran 40 was insufficient to prevent this decline. A negative interaction effect between Trehalose and Dextran 40 on NK cell cytotoxic activity was also observed. Screening results identified Betaine, Glycine, Polyvinylpyrrolidone (PVP), α-tocopherol, Poloxamer 188, and Creatine as effective in enhancing NK cell cytotoxic activity after freeze-thawing. These findings provide new insights into the interaction effects of CPAs on NK cell cytotoxic activity and contribute to improving NK cell quality in pharmaceutical manufacturing.
    Supplementary Information: The online version contains supplementary material available at 10.1007/s10616-025-00865-w.
    Keywords:  Cryoprotectant; NK cell; NK cell cytotoxic activity
    DOI:  https://doi.org/10.1007/s10616-025-00865-w
  26. Transpl Immunol. 2025 Nov 12. pii: S0966-3274(25)00156-X. [Epub ahead of print] 102328
    Immune mediators as therapeutic targets in GvHD; cytokines, growth factors, chemokines, and co-stimulation /co-inhibition.
    Amir Rastegari, Fatemeh Mohebbi.
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) and emerging allogeneic T cell-based immunotherapies offer curative potential for hematologic malignancies, solid tumors, and selected non-malignant disorders through graft-versus-tumor (GvT) and immune reconstitution effects mediated by donor immune cells. However, their clinical success is constrained by graft-versus-host disease (GvHD) and other immune-mediated toxicities resulting from donor-host alloreactivity. Therefore, a central challenge is to develop personalized, safer allogeneic cellular therapies that preserve potent anti-tumor and immune-restorative functions while minimizing tissue injury. This review integrates the current understanding of acute and chronic GvHD immunopathogenesis, covering cytokine and chemokine networks, growth-factor signaling, and co-stimulatory/co-inhibitory pathways, and links these mechanisms to therapeutic strategies for selective immune modulation. Drawing on translational insights, we propose a framework for next-generation allogeneic cell-based therapies that are precision-tuned to donor/recipient biology, advancing individualized anticancer and immune-reconstitution outcomes with improved safety.
    Keywords:  Allogeneic hematopoietic stem cell transplantation; Chemokine; Co-inhibitory signal; Co-stimulatory signal; Cytokine; Graft-versus-host-disease; Graft-versus-tumor effect; Growth factor
    DOI:  https://doi.org/10.1016/j.trim.2025.102328
  27. J Biomed Sci. 2025 Nov 12. 32(1): 98
    Technological advancements in antibody-based therapeutics for treatment of diseases.
    Ruei-Min Lu, Hsiao-Ling Chiang, Joyce Pei-Yi Yuan, Hsiu-Hua Wang, Chi-Yung Chen, Sushree Shankar Panda, Kang-Hao Liang, Hung-Pin Peng, Shih-Han Ko, Hung-Ju Hsu, Monika Kumari, Yi-Jen Su, Yi-Ting Tse, Nai-Lin Chou, Han-Chung Wu.
      Monoclonal antibodies (mAbs) represent a major class of therapeutics with widespread clinical applications in oncology, immunology, hematology, neurology and infectious disease. Since the introduction of hybridoma technology in 1975, the field has been advanced by a succession of innovations including chimeric and humanized antibody engineering, phage display, transgenic mouse platforms and high-throughput single B cell isolation. These technological developments have enhanced the specificity, potency and safety of mAbs, resulting in 144 FDA-approved antibody drugs on the market and 1,516 worldwide candidates in clinical development as of August 2025. Engineering breakthroughs have led to new modalities of antibody-based therapeutics, such as antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs), and chimeric antigen receptor T (CAR-T) cell therapies. Each of these modalities has therapeutic utility across multiple disease domains. Recent advances in delivery strategies, notably mRNA-lipid nanoparticles (LNPs) and antibody-directed in vivo CAR-T cell reprogramming, can enable precision therapies while reducing off-target effects and manufacturing complexity. The integration of artificial intelligence (AI) and machine learning (ML), next-generation sequencing (NGS), and structural modeling tools has further accelerated antibody discovery, affinity maturation and immunogenicity prediction, allowing for more efficient and rational antibody design. The advances in antibody technology are reflected in the rapid market growth of antibody-based therapeutics, which had global sales exceeding USD 267 billion in 2024. This review provides a comprehensive update on recent developments in antibody discovery platforms, therapeutic formats and market trends, highlighting emerging strategies that are reshaping the landscape of antibody-based medicine. Furthermore, we discuss clinical translation, regulatory landscapes, and the integration of engineering, biology and informatics. Together, these aspects shape a dynamic and multidisciplinary future for the therapeutic antibody field, which is poised to address unmet clinical needs and global healthcare priorities.
    Keywords:  Antibody engineering; Antibody market; Antibody therapeutics; Antibody-drug conjugates (ADCs); Artificial intelligence (AI); Bispecific antibodies (bsAbs); Chimeric antigen receptor T (cell therapies CAR-T); New modalities
    DOI:  https://doi.org/10.1186/s12929-025-01190-2
  28. Chin J Cancer Res. 2025 Oct 30. 37(5): 657-666
    Gut microbiota and acute graft-versus-host disease.
    Zhile Chen, Lin Li, Diange Jin, Yanmin Zhao, Florent Malard, He Huang, Yishan Ye, Mohamad Mohty.
      Acute graft-versus-host disease (aGVHD) is an important complication which critically impacts the prognosis of patients undergoing allogeneic hematopoietic stem cell transplantation. Increasing evidence suggests that dysbiosis of the gut microbiota plays a key role in aGVHD pathogenesis. The biological process involves compromised intestinal barrier integrity, amplified inflammation driven by the translocation of microbial products like lipopolysaccharide, and finally the dysregulated immune response centralized by T cell activation and differentiation. Meanwhile, certain microbial metabolites such as short-chain fatty acids and secondary bile acids exert protective effects. The clinical relevance of these findings is underscored by studies establishing that specific gut microbial signatures, such as low diversity and single pathogen dominance, independently predict aGVHD morbidity and mortality. From a therapeutic perspective, the microbiome has emerged as an important therapeutic target for aGVHD. Fecal microbiota transplantation has shown significant efficacy in clinical trials for prophylaxis and treatment of aGVHD, providing definitive proof-of-concept for ecological restoration. This review synthesizes these foundational mechanistic insights, from metabolic disruption to host-microbe crosstalk at the mucosal barrier, and details the rapidly advancing clinical landscape of microbiome-targeted diagnostics and therapeutics for aGVHD.
    Keywords:  Gut microbiota; fecal microbiota transplantation; graft-versus-host disease
    DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.05.01
  29. Chin J Cancer Res. 2025 Oct 30. 37(5): 742-758
    Advances in integrating biomaterials with CAR-T cells for enhancing solid tumor therapy.
    Shuting Huang, Yan Zhao, Jie Shen.
      Chimeric antigen receptor T (CAR-T) cell immunotherapy has emerged as a transformative modality in immuno-oncology. However, the clinical translation of CAR-T therapy for solid tumors remains significantly limited by physical barriers, an immunosuppressive tumor microenvironment (TME), and treatment-related toxicities. Advances in biomaterials have demonstrated substantial potential to address these constraints through synergistic integration with CAR-T cells. This review systematically examines therapeutic applications of CAR-T cells combined with diverse biomaterial platforms, including nanoparticles, antibody-functionalized systems, and hydrogels. Critical analysis is provided on the multifaceted roles of biomaterials in enhancing CAR-T efficacy, specifically by promoting T cell activation and proliferation, improving tumor targeting, and reprogramming the immunosuppressive TME. Collectively, this review delivers a comprehensive analysis of CAR-T-biomaterial integration strategies, offering mechanistic and translational insights to advance solid tumor therapies.
    Keywords:  CAR-T; antibody; biomaterial; hydrogel; tumor microenvironment
    DOI:  https://doi.org/10.21147/j.issn.1000-9604.2025.05.07
  30. Biochim Biophys Acta Gen Subj. 2025 Nov 08. pii: S0304-4165(25)00129-1. [Epub ahead of print]1870(1): 130884
    Nanobody-based imaging: Advancing precision in molecular diagnostics.
    Zohre Eftekhari, Fatemeh Kazemi-Lomedasht.
      Molecular imaging is a cornerstone of modern medicine, enabling non-invasive visualization of biological processes at the molecular level. The emergence of nanobodies (Nbs), small single-domain antibody fragments derived from camelids, has transformed this field due to their superior tissue penetration, rapid clearance, and high target specificity compared to conventional antibodies. This review focuses on the integration of Nbs with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) two complementary molecular imaging modalities known for their high sensitivity, quantitative potential, and clinical relevance. Nb-based PET and SPECT imaging probes are emerging as powerful tools for detecting disease-associated molecular targets with exceptional precision. Their unique properties, including high affinity, specificity, and stability, make them ideal candidates for developing advanced radiotracers that enable early disease detection, monitoring of therapeutic responses, and evaluation of novel treatment strategies. Despite these advantages, several challenges remain, such as scalable Nb production, reduction of immunogenicity in clinical applications, and optimization of radiolabeling methods that preserve Nb integrity and function. This review highlights recent advances in Nb engineering, radiolabeling strategies, and preclinical and clinical applications of Nb-based PET and SPECT imaging, while outlining critical directions for future research. By addressing current limitations, Nb-based molecular imaging holds great promise for improving diagnostic accuracy, advancing personalized medicine, and expanding its clinical impact across diverse disease areas.
    Keywords:  Diagnostic imaging; Molecular imaging; Nanobodies; Positron emission tomography; Radiolabeling techniques; Single-photon emission computed tomography
    DOI:  https://doi.org/10.1016/j.bbagen.2025.130884
  31. Crit Rev Oncol Hematol. 2025 Nov 12. pii: S1040-8428(25)00406-8. [Epub ahead of print] 105018
    Nanotechnology-Microbiota Synergy in Cancer Immunotherapy.
    Jihao Yang, Jia Li.
      The global burden of cancer continues to escalate, yet the efficacy of current targeted therapies and immune checkpoint inhibitors (ICIs) is often hampered by drug resistance and immune escape. The gut microbiota orchestrates tumor progression and ICI efficacy bidirectionally via the "microbiota-immune-tumor" axis. However, traditional interventions, including fecal microbiota transplantation and antibiotics, are limited by inherent drawbacks such as poor targeting. Nanotechnology can overcome this limitation: it not only enables precise targeting of the gut microbiota and reshapes the tumor immune microenvironment to synergistically enhance ICI efficacy but also reverses drug resistance in tumor chemotherapy, radiotherapy, and targeted therapy through multiple strategies. Additionally, it can synergize with probiotics, extracellular vesicles, and other agents to achieve tumor therapy. This review synthesizes current understanding of gut microbiota-immune crosstalk, the microbiota's role in regulating ICI efficacy, and the central applications of nanotechnology, thereby proposing novel synergistic strategies for cancer treatment.
    Keywords:  Extracellular Vesicles; Gut Microbiota; Nanotechnology; Probiotics; Tumor Immune Microenvironment; Tumor Therapy
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105018
  32. Clin Transl Sci. 2025 Nov;18(11): e70413
    Surrogate Endpoints in Pivotal Clinical Trials for Drug Approval in Japan Compared to the United States.
    Yuko Yamamoto, Harumi Kosaka, Hanami Nojiri, Hideki Maeda.
      Regulatory guidance documents exist on surrogate endpoints in the United States. In Japan, there are no established rules or guidance regarding the use of surrogate endpoints, and various aspects remain unclear. The aim of this study was to investigate the use of surrogate endpoints in Japan for drugs approved in Japan from 1999 to 2022, referring to the list established by the Food and Drug Administration. Precisely 2307 drugs were approved in Japan during the 24-year survey period. Of these, 1012 drugs (43.9%) were indicated for diseases for which surrogate endpoints were specified in the Surrogate Endpoint Table established by the Food and Drug Administration. After examining the endpoints used in clinical trials for 1012 drugs, 947 (93.6%) were approved based on the same surrogate endpoint as the Food and Drug Administration, whereas 65 (6.4%) were approved based on a different surrogate endpoint. In areas such as diabetes, there was a tendency to use surrogate endpoints established by the Food and Drug Administration, whereas for pharmaceuticals targeting pathogenic organisms, Japan's surrogate endpoints were typically used. Our findings demonstrate that several pharmaceuticals in Japan use surrogate endpoints similar to those of the Food and Drug Administration. These findings are expected to aid in the formulation of guidelines for the use of surrogate endpoints in clinical trials for future drug approvals in Japan.
    Keywords:  FDA; Japan; PMDA; drug approval; surrogate endpoint
    DOI:  https://doi.org/10.1111/cts.70413
  33. Oncotarget. 2025 Nov 14. 16 808-812
    A personal perspective of patient-centred clinical trials.
    Trevor Tyne, Elizabeth Ivimey, Leanne Duggan, Jia Liu.
      Key objective: To illustrate the first-hand journey of three early phase trial participants highlighting their benefits and challenges of participation and patient-centric innovations required to improve trial experience. Knowledge generated: Early phase trials have traditionally centred on dose-finding and toxicity. However as they have increased in number and improved in therapeutic intent, the patient experience becomes increasingly important. This article illustrates benefits of participation including access to novel therapies, support and close monitoring but challenges around eligibility criteria, finances, and communication. Proposed solutions including trial navigators, enhanced communication training, and greater flexibility in enrolment criteria to improve trials access.
    Keywords:  clinical trials; drug development; patient-centric care; precision oncology; tumor agnostic
    DOI:  https://doi.org/10.18632/oncotarget.28776
  34. Microbiology (Reading). 2025 Nov;171(11):
    Microbial Primer: Artificial intelligence for microbiologists.
    Hanqun Cao, Cesar de la Fuente-Nunez.
      Artificial intelligence (AI) and machine learning (ML) are reshaping microbiology, enabling rapid antibiotic discovery, resistance prediction and clinical diagnostics. For microbiologists, the goal is not to build new algorithms but to recognize when ML is appropriate, how to prepare data and how to interpret outputs responsibly. This primer takes that practical stance - driving the ML car rather than rebuilding the engine. At a high level, ML learns from complex patterns, often noisy data. In antibiotic discovery, ML models help identify compounds in biological data and design new ones from scratch using generative AI. In microbiome studies, where measurements are compositional, sparse and often confounded, ML helps uncover community structure and link taxa or functions to phenotypes. In pathogen genomics, supervised models map sequence-derived features (e.g. k‑mers, SNPs and gene presence/absence) to outcomes such as species identity, antimicrobial susceptibility or MIC. Unsupervised learning supports exploration, including clustering, latent gradients and dimensionality reduction for visualization. Across these settings, success hinges less on exotic architectures than on sound problem framing, careful preprocessing and experimental validation.
    Keywords:  artificial intelligence; machine learning; microbiology
    DOI:  https://doi.org/10.1099/mic.0.001629
  35. Int J Mol Sci. 2025 Oct 25. pii: 10391. [Epub ahead of print]26(21):
    Features of Peripheral T Cell Remigration into the Thymus.
    Anastasiia A Kalinina, Ludmila M Khromykh, Dmitry B Kazansky.
      The thymus, the central organ of T lymphopoiesis, is traditionally thought to exclusively export T cells. However, a great deal of studies has shown that mature peripheral T cells can return to the thymus and remain there. It is acknowledged that both CD4+ and CD8+ activated T cells can remigrate into the healthy adult thymus and accumulate predominantly in the medulla. In contrast, naïve T cells can actively populate the thymus of neonates and aged animals, potentially supporting the medulla's functioning. Still, the fate and functions of peripheral T cell remigrants are not fully understood as of today. This review presents experimental findings on peripheral T cell remigration, analyzes phenotypic and traffic features of remigrants, and considers possible effects of backmigration on thymus function.
    Keywords:  T cell; central tolerance; intrathymic selection; remigration; thymus
    DOI:  https://doi.org/10.3390/ijms262110391
  36. Glob Chall. 2025 Nov;9(11): e00381
    State-of-Art in Studying the Public Health Effects of Heat: A Literature Review.
    Lorenzo Gianquintieri, Enrico Gianluca Caiani.
      The impact of heat and heatwaves on human health constitutes a significant hazard, disproportionately affecting various regions worldwide and continuously exacerbating due to climate change. While human pathophysiology is well understood, addressing this challenge from a public-health perspective is essential to generate population-level insights and provide policymakers with evidence-based guidance. This calls for an interdisciplinary "environmental epidemiology" approach, which embraces multiple areas including (but not limited to) health sciences, geomatics, data-science, environmental analyses, and social sciences. Since the early 2000s, scientific production on this topic is increasing exponentially. This review aims to provide a narrative synthesis of the most relevant public-health studies, offering a comprehensive overview of prevailing perspectives within the scientific community. A key challenge highlighted is the lack of standardized thresholds, measures, and confounders, further complicated by variations in measurement methods, the urban heat island effect, and local disparities. The Distributed Lag Non-linear Model (DLNM) has emerged over the past decade as the gold-An standard for modeling heat-attributable health burdens. This approach enables risk stratification based on socio-demographic factors, evaluation of confounding variables, and scenario simulations. Numerous adaptation strategies are proposed, and with the support of emerging technologies, scientific research is increasingly shifting toward data-driven methodologies, unlocking new possibilities.
    Keywords:  DLNM; adaptation; climate change; heat; heatwave; literature review; risk assessment
    DOI:  https://doi.org/10.1002/gch2.202500381
  37. Int Immunopharmacol. 2025 Nov 09. pii: S1567-5769(25)01794-1. [Epub ahead of print]168(Pt 1): 115806
    CAR T cells targeting B7H3 demonstrate potent preclinical activity against AML and ESCC.
    Chang Liu, Jinping Zhao, Xuhua Zhang, Cheng Gao, Zhihao Wang, Huiting Wu, Mengjia Zhang, Tingting Wang, Lu Han, Yanan Jiang, Jing Lu, Tao Wang, Jing An, Xianlei Sun, Yurong Chai, Jimin Zhao, Kangdong Liu.
      T cells engineered to express chimeric antigen receptors (CARs) are a promising modality to treat refractory cancers. CD19 CAR-T therapy has achieved remarkable responses in against B-cell lymphomas, however, challenges persist for acute myeloid leukemia (AML) and solid malignancies. B7H3 is an immune regulatory molecule that is highly expressed in various tumor cells. Its abnormal expression in acute AML and esophageal squamous cell carcinoma (ESCC) is closely related to tumor progression. Here, we describe B7H3-targeted CAR-T cells constructed using the single-chain variable fragment (scFv) of an anti-B7H3 antibody and systematically evaluated their safety and efficacy in vitro and in mice models of AML and ESCC. Based on the monoclonal antibody targeting B7H3, namely A172 which screened according to phage antibody display library technology, we undertook humanization of the A172 antibody, resulting in A172-hu4, and further verified its affinity and cytotoxicity in the cell lines of AML and ESCC. The resulting A172-hu4-CAR-T displayed strong IFN-γ and IL-2 production and cytotoxic effects in vitro. We also identify that A172-hu4-CAR-T treatment could lead to more pronounced tumor suppression in AML and ESCC xenograft mouse models with no obvious toxic reactions to mice main organs. Accordingly, this study provides a novel target for CAR-T therapy in AML and ESCC to promote the development of clinical treatment strategies.
    Keywords:  Acute myeloid leukemia; B7H3; Cancer immunotherapy; Chimeric antigen receptor; Esophageal squamous cell carcinoma
    DOI:  https://doi.org/10.1016/j.intimp.2025.115806
  38. Pharm Dev Technol. 2025 Nov 12. 1-47
    Nano-Conjugated Drug Delivery Systems for Enhanced Tumour-Specific Targeting.
    Mirva Hirpara, Priyanka Ahlawat, Asha Patel, Shruti Patel, Drishti Panjwani.
      Cancer remains among the major causes of death in the world, yet the treatment has been hampered and hindered by the issue of nonspecific drug toxicity, lack of selectivity and resistance. Drug delivery systems based on nanocarriers have become one of the promising platforms to enhance the precision and efficacy of therapeutic options. Of particular interest among them are glycan-functionalized nanocarriers since they can utilize cancer-related glycosylation patterns to achieve better tumor-specific targeting, greater biocompatibility, and lesser systemic toxicity. Precision nanomedicine is based on specific molecular markers, which are obtained through aberrant glycosylation in cancer including tumor-associated carbohydrate antigens (TACAs) including truncated O-linked glycans, abnormal N-glycan branching, and increased sialylation. This review discusses the importance of glycosylation in cancer biology, design and functionalization of nanocarriers; such as polymeric nanoparticles, liposomes, gold nanoparticles, dendrimers and quantum dots, application of the nanocarriers in overcoming biological barriers and improving therapeutic outcomes. Progress in glycoengineering, such as protein engineering and cell line engineering, is also described. Lastly, the opportunities and challenges regarding translating glycan-conjugated nanomedicines to clinical use are discussed in the review with emphasis on regulatory barriers, mass-produced manufacturing, and safety issues. Glycan-conjugated nanomedicine by combining the understanding of tumor-selective glycosylation with novel nanocarrier design has the capacity to revolutionize cancer therapy to achieve a more targeted, personalized and clinical viable approach to cancer therapy.
    Keywords:  Antibody-drug conjugates (ADCs); Glycosylation; Monoclonal antibodies (mAbs); Nano-conjugated drug delivery; Polymeric nanoparticles (PNPs); Tumor-associated carbohydrate antigens (TACAs)
    DOI:  https://doi.org/10.1080/10837450.2025.2587646
  39. EXCLI J. 2025 ;24 1352-1371
    IFN-gamma in the tumor microenvironment: dual roles in cancer progression and therapy.
    Jiahui Cui, Yi Zhang, Li Yang.
      Interferon-gamma (IFN-γ), as a pleiotropic cytokine, plays a pivotal role in antitumor immunity. Its remarkable immunostimulatory, antiproliferative, and pro-apoptotic effects make it a promising candidate for tumor immunotherapy. Here, we highlight the dual role of IFN-γ in the tumor microenvironment during tumor development and treatment. IFN-γ can enhance antigen presentation, boost cytotoxic T cell and natural killer cell activity, and inhibit angiogenesis, promoting tumor regression and correlating with favorable therapeutic outcomes. However, prolonged exposure may induce the upregulation of immune checkpoint molecules such as programmed death-ligand 1, trigger T cell exhaustion, and recruit regulatory T cells, phenomena associated with the development of treatment resistance in cancer therapy. This dual nature poses significant challenges for harnessing IFN-γ in tumor treatment, necessitating an in-depth understanding of its mechanisms within specific microenvironments. Although numerous studies have explored IFN-γ-based tumor therapies, their outcomes have been inconsistent. Thus, although IFN-γ-based therapeutic strategies hold considerable promise, their clinical translation requires precise modulation to fully exploit its antitumor effects while mitigating potential protumor risks. See also the graphical abstract(Fig. 1).
    Keywords:  IFN-gamma; immunoregulation; immunotherapy; tumor progression; tumor regression
    DOI:  https://doi.org/10.17179/excli2025-8617
  40. Ann Hematol. 2025 Nov 13.
    Real-world clinical outcomes of CAR-T therapy from the Montefiore health system in the Bronx.
    Sonya Henry, Ahmed Abbasi, Aiman Hafeez, Aditi Vichare, R Alejandro Sica, Tim Q Duong.
      Chimeric antigen receptor T-cell (CAR-T) therapy has transformed diffuse large B-cell lymphoma (DLBCL) treatment, but data in diverse urban populations remain limited. We report outcomes from a comprehensive cancer center in the Bronx. Montefiore Health System treated 79 DLBCL patients with CAR-T from March 2018 to July 2024. Demographics, comorbidities, socioeconomic factors, and acute complications, including immune effector cell neurotoxicity syndrome (ICANS), cytokine release syndrome (CRS), cardiotoxicity, and pulmonary events, were tabulated. Kaplan-Meier survival analysis was performed up to five years. Multivariate adjusted hazard ratios (aHR) were calculated for remission and 3-year mortality. CAR-T achieved complete remissions in 50.6%, partial remission in 16.5%, and progression in 22.8%. Cumulative mortality was 10.1% during treatment and 34.2% by five years. Complete remission reduced 3-year mortality (aHR 0.13; 95% CI 0.04-0.43). Complications included CRS (76.0%), ICANS (49.4%), neutropenic fever (58.2%), and sepsis (19.0%). ICANS correlated with CRS, ICU stay, and sepsis. Socioeconomic status was not linked to mortality, but comorbidities increased risk. CAR-T complete remission is an independent predictor of reduced mortality. High rates of complications, particularly CRS and ICAN, reinforce the need for vigilant monitoring and management strategies to enhance long-term outcomes.
    Keywords:  Blood cancer; Cytokine release syndrome; Immunotherapy; Neurological sequela
    DOI:  https://doi.org/10.1007/s00277-025-06727-x
  41. Clin Cancer Res. 2025 Nov 13.
    Ibrutinib and PD-1 blockade potentiate mesothelin-targeting CAR-T cell therapy in preclinical models of pancreatic cancer.
    Alexander Armstrong, Graziella van der Plancke, Sae Nishiguchi, Diego Salas-Benito, Amanda A Bouffard, Sadie Goncalves, Ashlyn T Merce, Christopher Kelly, Filippo Birocchi, Sangwoo Park, Mark B Leick, Nora Horick, Trisha R Berger, Marcela V Maus, Giulia Escobar.
       PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) remains refractory to chimeric antigen receptor (CAR) T cell therapies due to its immunosuppressive microenvironment and a dense extracellular matrix deposited by cancer-associated fibroblasts (CAFs), which impair CAR-T cell infiltration. To address these barriers, we previously developed a dual-targeting CAR-TEAM platform in which mesothelin-specific CAR-T cells secrete a FAP-targeting T cell engager antibody molecule (TEAM) to simultaneously kill tumor cells and CAFs. Here, we leveraged mesothelin-targeting CAR-T cells and tested rational drug combinations and optimal delivery strategies to enhance therapeutic efficacy and guide potential combinations that could be incorporated into a clinical study.
    EXPERIMENTAL DESIGN: Tumor mesothelin shedding by proteases and CAR-T cell dysfunction remain key obstacles to CAR-T cell efficacy. Using pre-clinical PDAC models, we tested mesothelin-targeting CAR-T cells in combination with agents that increase tumor mesothelin expression, promote T cell polarization and persistence, and support T cell function. Furthermore, we compared intravenous versus intraperitoneal delivery routes to treat peritoneal metastases.
    RESULTS: We demonstrated that ibrutinib enhanced CAR-T cell expansion, Th1 skewing, and anti-tumor activity in PDAC. PD-1 blockade synergistically improved CAR-T cell anti-tumor function in a patient-derived PDAC xenograft and intraperitoneal delivery proved superior against peritoneal disease. Conversely, while an ADAM10/17 inhibitor prevented mesothelin shedding and improved tumor killing in vitro, it did not enhance efficacy in vivo.
    CONCLUSION: These findings identify clinically actionable strategies to optimize CAR-T cell therapy against PDAC. A phase-I clinical trial testing meso-FAP CAR-TEAM T cells, alone or in combination with ibrutinib or PD-1 blockade is in development.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-2907
  42. Int J Mol Sci. 2025 Nov 05. pii: 10753. [Epub ahead of print]26(21):
    Organ-on-a-Chip: A Roadmap for Translational Research in Human and Veterinary Medicine.
    Surina Surina, Aleksandra Chmielewska, Barbara Pratscher, Patricia Freund, Alexandro Rodríguez-Rojas, Iwan Anton Burgener.
      In this review we offer a guide to organ-on-chip (OoC) technologies, covering the full experimental pipeline, from organoid derivation and culture, through microfluidic device fabrication and design strategies, to perfusion systems and data acquisition with AI-assisted analysis. At each stage, we highlight both the advantages and limitations, providing a balanced perspective that aids experimental planning and decision-making. By integrating insights from stem cell biology, bioengineering, and computational analytics, this review presents a compilation of the state of the art of OoC research. It emphasizes practical considerations for experimental design, reproducibility, and functional readouts while also exploring applications in human and veterinary medicine. Furthermore, key technical challenges, standardization issues, and regulatory considerations are discussed, offering readers a clear roadmap for advancing both foundational studies and translational applications of OoC systems.
    Keywords:  microfluidics; organ-on-chip; organoids; translational medicine; veterinary models
    DOI:  https://doi.org/10.3390/ijms262110753
  43. J Extracell Vesicles. 2025 Nov;14(11): e70192
    From Mitochondria to Immunity: The Emerging Roles of Mitochondria-Derived Vesicles and Small Extracellular Vesicles in Cellular Communication and Disease.
    Rostyslav Horbay, Vasyl Syrvatka, Artem Bedzay, Mikaela van der Merwe, Dylan Burger, Shawn T Beug.
      According to the endosymbiotic theory of mitochondrial origin, an α-proteobacterium entered a prokaryotic cell and, through symbiosis, evolved into the mitochondria-the powerhouse of the cell. Like other bacteria, the α-proteobacteria generate their own extracellular vesicles (EVs), a trait that was passed onto the mitochondria, enabling them to generate mitochondria-derived vesicles (MDVs). MDVs, similar to small EVs (sEVs), are vesicles ranging from 30 to 200 nm in diameter and carry cargo for degradation by lysosomes and peroxisomes. MDVs share several features with sEVs, including targeted cargo degradation, biogenesis, packaging into multivesicular bodies, nucleic acid and protein transportation, induction of immune responses, and surface antigen presentation. MDVs may also be released from the cell in a manner similar to sEVs, potentially influencing intercellular communication and immune responses. Furthermore, the presence of MDVs presents opportunities for early disease detection, including neurodegenerative disorders and cancer. In this review, we explore the differences and similarities between MDVs and EVs, including their roles in immunity.
    Keywords:  endosomal sorting complex required for transportation (ESCRT); endosome; lysosome; mitochondria‐derived vesicles (MDVs); mitophagy; multivesicular body (MVB); peroxisome; small extracellular vesicles (sEVs)
    DOI:  https://doi.org/10.1002/jev2.70192
  44. Curr Opin Immunol. 2025 Nov 10. pii: S0952-7915(25)00166-9. [Epub ahead of print]98 102690
    The power of genetics in decoding Sjögren's disease: current status and future development.
    Marcin Radziszewski, Kandice L Tessneer, Christopher J Lessard.
      Sjögren's disease (SjD) is the second most common systemic autoimmune disease in the United States. SjD patients are predominantly women 30-50 years of age and exhibit heterogeneous clinical manifestations, including symptoms of extensive dryness, chronic fatigue, and joint pain, and various major organ involvement. Late onset, clinical heterogeneity, and limited mechanistic understanding of its etiology frequently lead to delayed or misdiagnosis. Although the etiology of SjD is unclear, candidate gene studies and population-based genome-wide association studies suggest that SjD results from an interplay between genetics and environment. Defining the genetic susceptibility of SjD remains an important research focus to improve the understanding of SjD etiology and the development of diagnostic and treatment options. Unfortunately, the genetic understanding of SjD lags far behind that of other related autoimmune diseases. This review provides a brief history of key milestones in the field of SjD genetics and highlights several areas of future research that will bolster the discovery power of ongoing genetic studies and define the underlying mechanisms that drive disease etiology.
    DOI:  https://doi.org/10.1016/j.coi.2025.102690
  45. Dermatol Clin. 2026 Jan;pii: S0733-8635(25)00074-9. [Epub ahead of print]44(1): 137-143
    The Environmental Impact of Biologic Therapy.
    Andrea Leung, Georgia Marquez-Grap, Tina Bhutani.
      Biologic medications have revolutionized the treatment of many dermatologic diseases, but they also necessitate unique packaging and shipping requirements to maintain their stability, typically involving temperature-controlled environments, polystyrene, and single-use plastic injector pens, contributing significantly to medical waste and carbon emissions. It is essential to consider the environmental impact of these treatments. Collaborative efforts among pharmaceutical companies, specialty pharmacies, insurance companies, health care providers, and patients are essential to reduce waste and promote sustainability. Dermatologists, in particular, have a critical role in addressing the environmental impact of biologic therapies, by advocating for systemwide changes.
    Keywords:  Biologic therapy; Climate change; Environment; Waste
    DOI:  https://doi.org/10.1016/j.det.2025.08.011
  46. J Egypt Natl Canc Inst. 2025 Nov 09. 37(1): 73
    Quantum dot: a next-generation tool for cancer diagnosis at an early stage.
    Adhi Kesava Naidu Neelam.
       BACKGROUND: The convergence of biology and nanomaterials has propelled technological progress in biomedical sciences, offering transformative applications in diagnostics and therapy. Among these advancements, quantum dots (QDs) semiconductor nanocrystals activated by light have emerged as versatile tools due to their unique optical and electronic properties. Graphene quantum dots (GQDs), a subset of QDs, are nanoscale fragments of graphene that exhibit exceptional features, making them highly suitable for innovative biomedical applications. These include cancer detection, drug delivery, and imaging, areas where early diagnosis and effective treatment are crucial.
    MAIN BODY: The production of synthetic GQDs relies on two primary approaches: top-down methods, where larger carbon structures are broken into smaller fragments, and bottom-up methods, which involve assembling GQDs from smaller molecular units. Both methods offer advantages depending on the desired properties and applications of the GQDs. GQDs possess several beneficial characteristics, including high photostability, excellent biocompatibility, and tunable fluorescence, which make them particularly valuable for biomedical purposes. In cancer therapy, GQDs serve as efficient nano-delivery vehicles for drugs, offering enhanced targeting and reduced side effects compared to traditional chemotherapy. Furthermore, their fluorescence properties enable precise imaging and early detection of cancerous cells, providing a dual functionality in diagnosis and therapy. Current research highlights advancements in QD synthesis techniques, enhancing their scalability and application potential. These innovations underscore the role of GQDs in bridging the gap between experimental research and clinical applications.
    CONCLUSION: Quantum dots, particularly graphene quantum dots, represent a breakthrough in the field of nanomedicine. Their synthesis, functional properties, and dual roles in diagnostics and therapeutic delivery underscore their importance in advancing cancer treatment and early detection. With continued research and development, GQDs are poised to revolutionize drug delivery systems and expand the horizons of biomedical science.
    Keywords:  Chemotherapy; Graphene QDs; Nano-delivery vehicles; Nanomaterials; Novel treatment; Quantum dots (QDs)
    DOI:  https://doi.org/10.1186/s43046-025-00329-4
  47. Genome Med. 2025 Nov 12. 17(1): 140
    PredIG: an interpretable predictor of T-cell epitope immunogenicity.
    Roc Farriol-Duran, Christian Domínguez-Dalmases, Albert Cañellas-Solé, Miguel Vazquez, Eduard Porta-Pardo, Víctor Guallar.
       BACKGROUND: Cytotoxic T cells are key effectors in the immune response against pathogens and tumors. Thus, identifying those immunogenic epitopes driving T-cell activation conforms a fundamental goal for antigen-based immunotherapies. T-cell antigen discovery is challenged by immense epitope landscapes, unfeasible to screen ad hoc experimentally due to the high cost and low throughput of immunogenicity validations. Precedingly, immunoinformatic models, with orders of magnitude higher throughput such as HLA-I binding affinity tools, are used to predict the antigenic potential of T-cell epitopes. However, the resulting immunogenicity screening success rates (ISSR)-the capacity to rank truly immunogenic epitopes among top-scored candidates prioritized for experimental validation-have remained incremental and the immunological explainability underlying model predictions limited.
    RESULTS: PredIG is an interpretable predictor of T-cell epitope immunogenicity trained upon 17,448 peptide-HLA-I allele pairs (pHLAs) with reported immunogenicity in T-cell reactivity and binding assays. Upon pHLAs, PredIG integrates an in silico feature space of antigenic properties (proteasomal cleavage, TAP translocation, HLA-I binding affinity, and presentation), and physicochemical epitope descriptors, particularly focused on TCR-facing central residues. Leveraging this information, we built three antigen-specific XGBoost models to compute PredIG immunogenicity scores (PredIG-NeoAntigen, PredIG-NonCanonical, and PredIG-Pathogen). We then used Shapley Additive models (SHAP) to analyze their immunological interpretability pinpointing a balanced feature importance between antigenic and physicochemical properties. This highlighted the strong contribution of antigen processing likelihood and physicochemical characteristics, often overlooked in T-cell epitope predictions. Comparably, PredIG obtained cutting-edge ISSR performance in our pathogen and non-canonical cancer antigen held-outs versus immunogenicity, HLA-I binding, and pHLA stability predictors. In cancer neoantigens, we used PredIG to refine the success rates of HLA-I binding affinity predictions and to prioritize an additional set of immunogenic (neo)epitopes differing from top-binding candidates across the three antigen types tested.
    CONCLUSIONS: Overall, we demonstrate how PredIG immunogenicity scores are instrumental to refine and expand the prioritization of actionable T-cell (neo)epitopes in infection and cancer, including non-canonical antigens not seen during training. Furthermore, PredIG displays an unprecedented immunological interpretability determining important immunogenicity drivers beyond HLA-I binding affinity. Ultimately, PredIG enables large throughput antigen discovery in open-source containerized environments ( https://github.com/BSC-CNS-EAPM/PredIG ) and facilitates accessibility via a streamlined webserver ( https://horus.bsc.es/predig ).
    DOI:  https://doi.org/10.1186/s13073-025-01569-8
  48. Crit Rev Oncol Hematol. 2025 Nov 10. pii: S1040-8428(25)00403-2. [Epub ahead of print] 105015
    Antibody-Drug Conjugates in Oncology: A Spotlight on Overcoming Resistance.
    Xiaoxiao Xu, Tong Yu, Zhenxing Wang.
      Antibody-drug conjugates (ADCs), which combine precise monoclonal antibodies with cytotoxic payloads, represent a transformative class of anticancer therapeutics. Despite their clinical success, resistance mechanisms significantly limit their therapeutic utility. This review systematically summarizes the multifaceted mechanisms underlying ADC resistance, including antibody-related factors, aberrant intracellular trafficking, payload-related factors, and dysregulated survival signaling. We further evaluated strategies to overcome resistance, including third-generation ADCs, novel payloads, and multimodal combination therapies. By integrating preclinical insights and clinical advancements, this review provides a theoretical framework for optimizing ADC efficacy and overcoming therapeutic resistance in oncology.
    Keywords:  Antibody-drug conjugates; Cancer; Combination strategy; Mechanisms; Resistance
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.105015
  49. J Clin Med. 2025 Oct 24. pii: 7543. [Epub ahead of print]14(21):
    Optimization of the Use of Generic Medications in Oncology: Improving Safety and Therapeutic Quality.
    Diego Gómez Abreo, Daniel F Alarcón Cano, Fernando Ayala, Nelson Belalcázar Carvajal, Marie Claire Berrouet Mejía, Oscar Beltrán, Carlos Alberto Calderón-Ospina, Hugo Castro-Salguero, Diana Marcela Escobar Cárdenas, Mauricio Lema-Medina, Juan Ignacio Marín Zuluaga, Pilar Milla Bernabé, Rafael E Niño Velasco, Ruth Osorio Estévez, Jorge Mario Ortiz, Leonardo J Rojas-Melo, Marcela Urrego, Carlos Vargas, Andrés F Zuluaga.
      Introduction: Oncological diseases are one of the leading causes of mortality worldwide, with the high cost of therapies representing a critical barrier for health systems. Generic drugs have emerged as an alternative to reduce costs and improve access; however, their quality, safety, and efficacy remain a subject of regulatory and clinical debate. This issue is particularly sensitive in oncology, where generics often involve cytotoxic agents, narrow therapeutic indices, and complex formulations, all of which amplify the risks of therapeutic interchangeability. Materials and Methods: A multidisciplinary team composed of 19 experts in oncology, hepatology, gastroenterology, toxicology, endocrinology, and pharmacology was convened based on established academic contributions, clinical expertise, and participation in regulatory or guideline development. Evidence was synthesized through a non-systematic narrative review of PubMed, Embase, and regional databases. Consensus recommendations were developed using a two-round Delphi process, with agreement defined as ≥75%. Results: The Delphi panel produced six key recommendations: (1) stricter requirements for bioequivalence and bioavailability, tailored to oncology; (2) strengthened pharmacovigilance and real-world monitoring; (3) standardized protocols for therapeutic interchangeability, particularly for narrow therapeutic index agents; (4) active physician involvement in formulary decision-making; (5) harmonized regional regulatory frameworks, informed by FDA and EMA standards; and (6) expanded research on oncology-specific pharmacokinetic markers. While safety concerns dominated discussions, experts also acknowledged the potential of generics to reduce costs, improve equity, and enhance the sustainability of oncology care. Conclusions: The findings underscore the need for oncology-specific regulatory frameworks that extend beyond conventional bioequivalence standards. A balance is required: cost savings and equity gains offered by generics must be matched with robust safety mechanisms, regulatory harmonization, and physician-led oversight. Future research should expand expert representation, integrate real-world data, and address biosimilars in dedicated analyses to ensure safe and equitable integration of non-innovator therapies in cancer care.
    Keywords:  Delphi consensus; bioequivalence; generic drugs; oncology; regulation; safety and efficacy
    DOI:  https://doi.org/10.3390/jcm14217543
  50. Trends Cancer. 2025 Nov 12. pii: S2405-8033(25)00258-4. [Epub ahead of print]
    IL17-producing γδ T cells promote radioresistance via immunosuppression.
    Lorenzo Galluzzi, Toni Celià-Terrassa.
      IL17-secreting γδ T cells promote immunosuppression, metastatic dissemination, and resistance to treatment in various oncological settings. Recent findings from Deng et al suggest that DNA-containing extracellular vesicles released from irradiated lung cancer cells favor radioresistance by orchestrating the recruitment of IL17-secreting γδ T cells via a CCL20-dependent mechanism involving STING signaling in tumor-associated macrophages.
    Keywords:  CGAS; NF-κB; immune checkpoint inhibitors; myeloid-derived suppressor cells; three Cs; type I IFN signaling
    DOI:  https://doi.org/10.1016/j.trecan.2025.10.007
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