bims-carter Biomed News
on CAR-T Therapies
Issue of 2026–08–09
fifty-nine papers selected by
Luca Bolliger, lxBio
  1. Impact of cryopreservation on PBMC-derived CAR-T cell manufacturing outcomes: a systematic review.
  2. [Advances in the Study of Factors Influencing the Efficacy of CAR-T Cell Therapy in Hematologic Oncology Treatment--Review].
  3. Cascading Attrition of In Vivo CAR-T Therapy: From Systemic Delivery Failure to Functional Collapse.
  4. HSCT and CAR-T: a power couple-but who serves whom?
  5. Multi-antigen chimeric antigen receptor-T cell therapy for relapsed/refractory B cell lymphomas.
  6. CD19 CAR-T cell therapy in large B-cell lymphoma: clinical evidence, resistance, toxicity, and precision strategies.
  7. CD19-targeting CAR T cell therapy in five patients with systemic sclerosis unsuitable for autologous stem cell transplantation.
  8. CAR-T cell therapy for autoimmune diseases: from immune suppression to immune resetting.
  9. Locoregional and systemic adoptive cellular therapies for pediatric brain tumors: a systematic review of CAR‑T, TCR‑engineered T cells, and NK cell strategies.
  10. Cellular Therapy Essentials: An Overview of Cellular Therapy Products and Nursing Management.
  11. The landscape of genetic medicines for in vivo T cell reprogramming.
  12. Rethinking hemocompatibility standards: a critical appraisal of current regulatory frameworks for Advanced Therapy Medicinal Products (ATMPs) validation.
  13. Understanding FDA's reasons for nonapproval: A systematic review of complete response letters in cell and gene therapy.
  14. γδ T Cells as a Platform for Immunotherapy: From Biological Principles to Clinical Translation.
  15. The Rise of Generalist Foundation Models and Quantum Computing in Oncology.
  16. Clinical trial landscape and translational prospects of natural killer cell-based immunotherapy: an analysis based on the INFORMA database.
  17. Impact of Prior Bendamustine Exposure on Chimeric Antigen Receptor T-Cell Therapy Outcomes in Follicular Lymphoma.
  18. Swimming in the Sea of Real-World Evidence (RWE) Guidance: Why More Guidance Documents Are Needed to Help Researchers Swim.
  19. CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria.
  20. The Pharmacology of CAR T Cell Therapy for Autoimmune Disease.
  21. SOHO State of the Art Updates and Next Questions | Best of Stem Cell Transplant: Recent Advances in Allogeneic Hematopoietic Cell Transplantation.
  22. Engineering CAR-T cells for solid tumors: Overcoming the microenvironment through integrated design and clinical translation.
  23. The Multiple Criteria Qualitative Value-Based Pricing Framework "MARIE" for Novel Cell and Gene Therapy.
  24. Next-generation T cell engagers for cancer and autoimmune diseases.
  25. Chronic xenogeneic GVHD after CAR T cell therapy limits long-term safety assessment of CAR effects using NSG mouse model.
  26. Regulatory approval trends and market access implications: a multiregional comparative framework for New and supplemental Drug applications (2020-2025).
  27. What Does the Shape Space of T Cell Epitopes Look Like?
  28. Exosome-Inspired Nanocarriers in Cancer Therapy: Bio-Derived Nanotechnology Meets Nano Drug Delivery.
  29. Swimming in the Sea of RWE Guidance: Why More Guidance Will Not Help Researchers Swim.
  30. Can agentic AI dent Eroom's Law? Large reasoning models across the drug discovery and development pipeline.
  31. Tumor organoid-immune cell co-culture systems for precision oncology.
  32. Circadian rhythms in the tumor microenvironment: spatiotemporal immune regulation and chronotherapeutic opportunities.
  33. Co-delivery of lentiviral vectors and Cas9-containing virus-like particles enables rapid, scalable manufacture of gene-edited CAR T cells.
  34. Accelerating Translation of NK Cell Therapies to the Clinic: A European Perspective.
  35. CRISPR/Cas9 in cancer therapy: clinical translation, mechanistic strategies, and therapeutic directions.
  36. In Silico Strategies for Robust Process Development in Advanced Therapies: Poster Presented at PDA Week 2026.
  37. Global research trends and emerging frontiers of intratumoral microbiota in cancer immunotherapy: a bibliometric and visualization analysis.
  38. Why do AI projects fail in drug development and pharma? Insights from multi-year Pistoia Alliance studies.
  39. Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance.
  40. Past achievements and future perspectives of personalized vaccines and the role of dendritic cells.
  41. Natural killer cells against viral infection: from basic biology to immunotherapy.
  42. Hepatotoxicity in the Era of Precision Medicine: Toxicological Mechanisms and Management of Immune and Cell Therapy-Induced Liver Injury.
  43. Targeting regulatory T cell plasticity in gastric cancer: a unified bimodal model and precision immunotherapy paradigm: a hypothesis-generating review.
  44. A Counterintuitive Approach to Cancer Therapy.
  45. Critical complications in cancer patients admitted to the ICU in the era of immunotherapy: recognition, differential diagnosis, and management.
  46. Super-resolution imaging reveals altered actin architecture at CAR-T cell immune synapses.
  47. Nanomaterial Strategies for Pulmonary Delivery of Immunotherapeutics in Lung Cancer Treatment.
  48. Reframing NICE's Cost-Effectiveness Threshold: Technical Benchmark or Policy Signal? A Documentary Content Analysis.
  49. Validating medical digital twins for clinical decision support: beyond predictive accuracy.
  50. TSTScope Unifies Single-Cell Multi-Omics to Identify Functional T Cell States Predictive of Immunotherapy Response.
  51. Antibody Conjugation to Cell Surface Receptors.
  52. Empowering Clinical Development With Disease Progression Modeling: Recommendations From the Clinical Trials Transformation Initiative.
  53. Long-term complete remission following treatment with polatuzumab vedotin, rituximab, and bendamustine in a patient with mantle cell lymphoma relapsing after CAR-T cell therapy: a case report.
  54. Frontier research and clinical application prospects of microbiome biomarkers in autoimmune diseases.
  55. Directed evolution of chlorotoxin enhances MMP-2 recognition and improves CAR-T-cell activity in glioblastoma models in vitro.
  56. Drug type contributions to pharmaceutical innovation: A USA-China comparative analysis.
  57. Operationalizing Precision Medicine in Drug Development: Predictive Biomarkers, Companion Diagnostics, and Regulatory Pathways.
  58. Surrogate endpoints in cost-effectiveness analysis for use in health technology assessment - a qualitative analysis.
  59. The VIBE-HI framework: a conceptual model for evaluating vibe coding appropriateness, quality, and safety in health informatics.
  1. Front Immunol. 2026 ;17 1876909
    Impact of cryopreservation on PBMC-derived CAR-T cell manufacturing outcomes: a systematic review.
    Rama Amin Al-Wreidat, Sakhr Alshwayyat, Laith Ahmad Maharma, Maysa Al-Hussaini.
       Background: Chimeric antigen receptor T-cell (CAR-T) therapy is an established treatment for several hematological malignancies, with peripheral blood mononuclear cells (PBMCs) serving as the starting material for manufacturing. Cryopreservation of PBMCs may offer logistical flexibility, although its influence on manufacturing outcomes remains incompletely defined. This review aimed to compare the effect of fresh versus cryopreserved PBMC starting material on CAR-T cell manufacturing outcomes, including viability, fold expansion, and transduction efficiency.
    Methods: A systematic review was conducted following PRISMA guidelines. PubMed and Google Scholar were searched from inception through March 2026 for original studies comparing fresh and cryopreserved PBMCs in human CAR-T cell manufacturing. Methodological quality was assessed using the design-appropriate quality-appraisal tools, and findings were synthesized narratively due to heterogeneity in study design and protocols.
    Results: Five studies published between 2019 and 2025 met the inclusion criteria, comprising two clinical and three experimental analyses. Post-thaw viability and recovery of cryopreserved PBMCs ranged between 77% and 97%, slightly lower than fresh material. Fold expansion, transduction efficiency, and cytotoxic activity were generally comparable between groups, although some studies reported transient early differences including prolonged doubling times, mitochondrial dysfunction signals, and increased TIM-3 expression in cryopreserved-derived products.
    Conclusion: Cryopreservation can be considered a feasible approach in CAR-T manufacturing, with generally comparable outcomes despite early post-thaw cellular changes. These differences do not seem to consistently compromise the overall manufacturing performance. However, the current evidence remains limited and heterogeneous, and further studies are required to increase confidence in our initial findings.
    Keywords:  CAR-T cell; PBMC; cryopreservation; manufacturing; systematic review
    DOI:  https://doi.org/10.3389/fimmu.2026.1876909
  2. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2026 Jun;34(3): 910-916
    [Advances in the Study of Factors Influencing the Efficacy of CAR-T Cell Therapy in Hematologic Oncology Treatment--Review].
    Li-Mei Li, Xun Lai, Hong-Jing Yin.
      Chimeric antigen receptor T cell (CAR-T) therapy is a revolutionary progress in the current field of tumor treatment, especially showing remarkable potential in relapsed/refractory hematological malignancies. However, there are significant differences in efficacy among different patients, and such differences are affected by multiple clinical and biomedical factors. This review will discuss the current application status of CAR-T therapy in hematological malignancies, analyze the key factors influencing the efficacy, and summarize the latest research trends and development directions in this field, so as to provide references for clinical decision - making and scientific research innovation.
    Keywords:  chimeric antigen receptor T cell; hematological malignancy; efficacy; influencing factors
    DOI:  https://doi.org/10.19746/j.cnki.issn1009-2137.2026.03.040
  3. Crit Rev Oncol Hematol. 2026 Aug 05. pii: S1040-8428(26)00408-7. [Epub ahead of print] 105521
    Cascading Attrition of In Vivo CAR-T Therapy: From Systemic Delivery Failure to Functional Collapse.
    Haipeng Rao, Shichu Xu, Jiannan Chen, Zhigang Guo.
      Ex vivo chimeric antigen receptor (CAR)-T cell therapy demonstrates strong efficacy but remains limited by high costs and lengthy manufacturing. In vivo in situ reprogramming provides a scalable "off-the-shelf" alternative by directly engineering endogenous T cells; however, clinical translation is hindered by an efficacy-attrition paradox. Here we review the cascading loss of functional vector dose across multi-scale physiological barriers-from opsonin-driven sequestration and protein-corona formation in circulation, to metabolic checkpoints and nuclear transport restrictions within resting T cells. By comparing lentiviral vectors and lipid nanoparticles, we examine how each platform navigates these distinct hurdles. A key insight is that overcoming such stochastic failure cascades requires deterministic rather than incremental design: rational integration of synthetic biology tools-immune-cloaking surfaces, logic-gated circuits-enables precise navigation through complex in vivo microenvironments. This progress shifts the field from passive dose escalation toward engineered resilience, transforming in vivo CAR-T generation into a clinically viable platform for hematologic malignancies, solid tumors, and autoimmune diseases.
    Keywords:  Cascading Attrition; Delivery Barriers; In vivo CAR‑T; Lentiviral Vectors; Lipid Nanoparticles
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105521
  4. Front Immunol. 2026 ;17 1898336
    HSCT and CAR-T: a power couple-but who serves whom?
    Shuai Yao, Ran Zhang, Wenbin Mo, Zhenghua Liu, Heyang Zhang, Nan Su.
      Hematopoietic stem cell transplantation (HSCT) and chimeric antigen receptor T-cell (CAR-T) therapy are two major therapeutic approaches for hematologic malignancies. HSCT can provide durable disease control through conditioning-induced tumor cytoreduction, immune reconstitution, and graft-versus-leukemia effects, whereas CAR-T therapy provides antigen-specific antitumor activity and has reshaped the treatment landscape for relapsed or refractory leukemia, lymphoma, and multiple myeloma (MM). Despite these advances, both therapeutic approaches continue to face multiple challenges. HSCT is limited by disease relapse and transplant-related complications, while CAR-T therapy is challenged by antigen escape, limited persistence, and treatment-related toxicities. Increasing clinical experience suggests that HSCT and CAR-T therapy should not be viewed as competing strategies, but rather as complementary therapeutic approaches whose value depends on disease characteristics, depth of response, immune recovery, and transplant feasibility. On the one hand, CAR-T therapy can reduce tumor burden before transplantation, be incorporated into modified conditioning regimens, or be used after allogeneic HSCT (allo-HSCT) as prophylactic, preemptive, or salvage cellular therapy. On the other hand, HSCT can consolidate CAR-T-induced remission, provide hematopoietic support in selected settings, and create a post-transplant immune environment that may facilitate subsequent CAR-T-cell therapy. In this review, we summarize the current evidence for HSCT-CAR-T integration in leukemia, lymphoma, and MM. We discuss major integration strategies, including HSCT after CAR-T therapy, CAR-T-assisted conditioning, autologous stem cell transplantation (ASCT)-CAR-T sequential strategies, and CAR-T therapy after allo-HSCT. We aim to help match appropriate patients to the most suitable HSCT-CAR-T strategies and thereby improve clinical decision-making.
    Keywords:  CAR-T; allogeneic transplantation; autologous transplantation; conditioning regimen; hematologic malignancies; hematopoietic stem cell transplantation
    DOI:  https://doi.org/10.3389/fimmu.2026.1898336
  5. Front Immunol. 2026 ;17 1900443
    Multi-antigen chimeric antigen receptor-T cell therapy for relapsed/refractory B cell lymphomas.
    Toshali Pandey, Divya Samat, Saurabh Dahiya, Shyam A Patel.
      In the wake of the 10-year anniversary since the introduction of chimeric antigen receptor-T (CAR-T) cell therapies to the market, the field of B cell lymphoma has seen remarkable advances since these therapies first arrived at the bedside in 2017. Modern data from longitudinal readouts attests to the high depth and durability of response to CAR-T therapies in many patients with B cell lymphomas; however, approximately 50% of patients continue to have relapsed/refractory disease even after receipt of conventional CAR-T constructs. In this review, we discuss the mechanisms underlying primary and secondary refractoriness to conventional single-targeting CAR-T therapies for B cell lymphomas and explore the ongoing challenges with existing CAR constructs. We discuss the prospects for adaptable multi-antigen targeting via the use of bivalent CAR and bicistronic CAR functionalities as informed by recent advances in synthetic immunobiology. We explore contemporary efforts, mostly Phase 1 and 2 trials, involving bivalent CAR and bicistronic CAR constructs at the cutting edge of clinical translation. Finally, we propose evidence-based solutions to help improve the translational success of multi-antigen CAR-T therapy, including optimizing construct architecture, expanding the targetable antigen landscape, and improving scalability. These solutions for multi-antigen targeting in next-generation CARs may have substantial benefits in the coming years.
    Keywords:  B cell lymphoma; CAR--t; immunotherapy; lymphoma; multi-antigen targeting; tandem CARs
    DOI:  https://doi.org/10.3389/fimmu.2026.1900443
  6. Front Immunol. 2026 ;17 1903457
    CD19 CAR-T cell therapy in large B-cell lymphoma: clinical evidence, resistance, toxicity, and precision strategies.
    Congcong Wang, Jun Zhu, Jiaojiao Qiao, Huahua Wang, Xue Liang.
      CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed the management of relapsed or refractory large B-cell lymphoma (LBCL), producing durable remissions in a subset of patients whose disease previously had few curative options. Axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel established CAR T-cell therapy in the third-line setting, and randomized studies subsequently moved axicabtagene ciloleucel and lisocabtagene maraleucel into second-line treatment for primary refractory or early relapsed disease. This review provides a clinically anchored, mechanism-focused synthesis of CAR T-cell therapy in LBCL. We critically compare pivotal trials, long-term follow-up, patient-selection principles, and real-world evidence, emphasizing that apparent differences across products must be interpreted in light of eligibility criteria, analytic denominators, bridging therapy, manufacturing intervals, toxicity grading, and treatment crossover. We then examine resistance and relapse as systems-level phenomena arising from antigen modulation, tumor-intrinsic evolution, impaired CAR T-cell fitness, suppressive myeloid and stromal networks, systemic inflammation, metabolic stress, and incomplete immune recovery. The biological basis and clinical implications of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, prolonged cytopenias, infections, and late nonrelapse mortality are also reviewed. Finally, we discuss circulating tumor DNA, metabolic imaging, single-cell and multi-omic profiling, artificial intelligence, dual-target and armored constructs, allogeneic platforms, and in vivo CAR programming as components of precision cellular therapy. The central clinical challenge is no longer whether CAR T-cell therapy can work, but how to select patients, deliver treatment rapidly, anticipate failure, and preserve long-term immune and functional health.
    Keywords:  CAR T-cell therapy; CD19; CtDNA; clinical trials; diffuse large B-cell lymphoma; large B-cell lymphoma; precision immunotherapy; real-world evidence
    DOI:  https://doi.org/10.3389/fimmu.2026.1903457
  7. EULAR Rheumatol Open. 2026 Jun;2(2): 100008
    CD19-targeting CAR T cell therapy in five patients with systemic sclerosis unsuitable for autologous stem cell transplantation.
    Ann-Christin Pecher, Luca Hensen, Rebekka Schairer, Reinhild Klein, Wolfgang Bethge, Claudia Lengerke, Jörg Henes.
       Objectives: The efficacy of chimeric antigen receptor (CAR) T cell therapy in patients with systemic sclerosis (SSc) has been substantiated by a small number of case reports and series. An established treatment option for severe SSc is autologous stem cell transplantation (HSCT). The objective of this analysis was to assess the feasibility and safety of CD19-targeting CAR T cell therapy in patients with SSc who are unsuitable for HSCT.
    Methods: Five patients with SSc were treated between July 2023 and July 2024 with CAR T cells. The cells were produced in our academic Good Manufacturing Practice laboratory with a human anti-CD19 lentiviral construct and amplification in a CliniMACS Prodigy. The CAR T cells (1 Mio per kg) were reinfused on day 0, following lymphodepletion with fludarabine and cyclophosphamide.
    Results: All patients exhibited robust expansion of CAR T cells and B-cell depletion. No imminent cases of severe cytokine release syndrome, infection, or immune effector cell-associated neurotoxicity syndrome were recorded, and patients were treated as inpatients for a period of 2 to 3 weeks. Two patients were observed for a period of up to 12 months, 1 patient for 10 months, and 1 patient for 5 months. The observed outcomes indicated the presence of highly promising efficacy on the skin, lung, and gastrointestinal manifestations. One patient developed a fatal secondary haemophagocytic lymphohistiocytosis probably due to herpes simplex virus infection after an allergic reaction to acyclovir and consecutive massive CAR T expansion 2 months after therapy. We hypothesise an association with an underlying mutation in ten-eleven translocation methylcytosine dioxygenase 2, a protein that is mutated in various haematopoietic malignancies.
    Conclusions: The analysis of our 5 patients suggests that CD19-targeting CAR T cells are a feasible treatment option that can be used in patients who are ineligible for HSCT. Nevertheless, fatal side effects can occur, and we suggest a careful patient selection and screening for gene alterations in patients with abnormal blood count.
    DOI:  https://doi.org/10.1016/j.ero.2025.03.005
  8. Int Immunopharmacol. 2026 Aug 06. pii: S1567-5769(26)01077-5. [Epub ahead of print]187 117231
    CAR-T cell therapy for autoimmune diseases: from immune suppression to immune resetting.
    Mengting Zhang, Lianfeng Zhao, Tianyu Chen, Lu Ding, Lingfeng He, Zhigang Guo.
      Autoimmune diseases are heterogeneous disorders marked by immune dysregulation, loss of self-tolerance, autoantibody production, and chronic inflammation. Although immunosuppressants and biologics have improved disease control, incomplete remission, relapse after withdrawal, cumulative toxicity, and failure to restore immune homeostasis remain common. Chimeric antigen receptor T-cell (CAR-T) therapy offers a potential strategy for refractory autoimmune diseases by selectively eliminating pathogenic immune compartments and providing a theoretical pathway toward target-dependent immune remodeling and immune resetting. This review summarizes immunopathogenesis and therapeutic gaps in representative autoimmune diseases, compares CAR-T applications in malignancies and autoimmunity, and evaluates emerging response endpoints, target-selection strategies, and safety considerations in autoimmune settings. Early clinical evidence suggests rapid disease control, autoantibody reduction, and immunosuppression-free remission in selected B-cell- or autoantibody-driven diseases. However, reported remission duration and response proportions remain limited by small cohorts, short follow-up, and disease-specific heterogeneity. The central unresolved question is whether durable remission can be achieved without persistent immune deficiency. Cytokine release syndrome, infection, hypogammaglobulinemia, relapse, impaired vaccine responses, T-cell fitness, manufacturing barriers, and cost remain key challenges. Future studies should define optimal targets, standardized remission endpoints, durable remission biomarkers, long-term safety, and the role of T-cell engagers.
    Keywords:  Autoimmune diseases; B-cell targets; CAR-T cell therapy; CD70; Immune resetting
    DOI:  https://doi.org/10.1016/j.intimp.2026.117231
  9. Neurosurg Rev. 2026 Aug 07. pii: 519. [Epub ahead of print]49(1):
    Locoregional and systemic adoptive cellular therapies for pediatric brain tumors: a systematic review of CAR‑T, TCR‑engineered T cells, and NK cell strategies.
    Yaxel Levin Carrion, Jayant Bhasin, Sraavya Anne, Arman Sawhney, Caryn J Ha, Ibraheem Sharaf, Jacob Santana, Kevin Titkov, Marvens Jean, Drew Thibault, Alejandro Pando, Nemanja Novakovic, Nehal S Parikh, Morana Vojnic, Jonathan H Sherman.
      Adoptive cellular therapies may expand treatment options for pediatric brain tumors by focusing activity on tumor antigens and limiting off-tumor effects. We systematically reviewed preclinical and clinical evidence for CAR T cells, TCR-engineered T cells, and NK or γδ T-cell platforms directed against HER2, B7-H3 (CD276), EGFR806-reactive EGFR, GD2, IL13Rα2, and EphA2 or EphA3, with attention to delivery route, safety, persistence, and combination strategies. Following PRISMA, we searched PubMed, Embase, and Scopus from inception through September 17, 2025, restricted to English. The search yielded 324 records; 103 duplicates were removed; 221 titles and abstracts were screened; 180 full texts were reviewed; and 34 studies were extracted by two independent reviewers. We captured design, tumor and molecular features, product engineering, route and schedule, lymphodepletion, toxicities including cytokine release syndrome, immune effector cell associated neurotoxicity, and tumor inflammation associated neurotoxicity, radiographic or clinical response, survival, and correlatives such as persistence or trafficking in blood, cerebrospinal fluid, or tumor tissue, cytokines, and antigen dynamics. In vivo studies showed reproducible antitumor activity for HER2 in medulloblastoma, GD2 in diffuse midline glioma, and multi-antigen constructs incorporating IL13Rα2 and EphA2 in medulloblastoma and ependymoma, with significant survival advantages compared with controls. γδ T cells targeting the EphA axis selectively killed medulloblastoma with neural sparing; GD2 CAR NK-92 inhibited diffuse intrinsic pontine glioma growth. In early clinical programs, route shaped safety and pharmacodynamics. For GD2, low-dose intravenous induction followed by repeated intraventricular dosing produced objective radiographic regressions and manageable tumor inflammation associated neurotoxicity, while dose-limiting cytokine release syndrome was confined to higher intravenous doses. Intraventricular B7-H3 CAR T cells, given without lymphodepletion, enabled multi-cycle dosing with mainly grade 1 to 2 events and cerebrospinal fluid localized persistence. Weekly intracranial EGFR806 CAR T cells were feasible and well tolerated, with stable disease as the best response in a small cohort. Across trials, persistence and immune activation were most evident in cerebrospinal fluid, supporting cerebrospinal fluid centered pharmacodynamic monitoring. Mechanism-based combinations, including IGF-axis inhibition in diffuse midline glioma and epigenetic priming of GD2 with an integrated safety switch in medulloblastoma, enhanced activity. The evidence supports pediatric-centric antigen selection and a CNS-first, locoregional dosing approach to increase on-tumor exposure and reduce systemic toxicity. Priorities include multi-antigen strategies to prevent escape, incorporation of safety switches, earlier deployment when tumor burden is low, and prospective cerebrospinal fluid pharmacodynamics in multisite phase II studies.
    Keywords:  B7-H3 (CD276); CAR-T cells; Diffuse midline glioma (DMG/DIPG); GD2; Intraventricular delivery; Pediatric brain tumors
    DOI:  https://doi.org/10.1007/s10143-026-04437-0
  10. Clin J Oncol Nurs. 2026 Aug 03. 30(4): 309-313
    Cellular Therapy Essentials: An Overview of Cellular Therapy Products and Nursing Management.
    Christi Bell.
      Scientific advances have expanded cellular therapy beyond its association with stem cell transplantation to include a growing array of products that use a patient's own cells and genetic material to treat disease. Currently.
    Keywords:  CAR T-cell therapy; bispecific T-cell engager; tumor-infiltrating lymphocyte therapy
    DOI:  https://doi.org/10.1188/26.CJON.309-313
  11. Adv Drug Deliv Rev. 2026 Aug 03. pii: S0169-409X(26)00174-2. [Epub ahead of print] 115940
    The landscape of genetic medicines for in vivo T cell reprogramming.
    Jens B Simonsen, Viktor T Lemgart, Jayesh A Kulkarni, Dominik Witzigmann.
      In vivo reprogramming of T cells represents a transformative approach in immune-based therapies, with the potential to overcome the limitations of traditional ex vivo-engineered T cell products, such as autologous CAR-T therapies. While CAR-T cells have achieved remarkable success in treating hematological cancers with several FDA approved products, challenges like manufacturing complexity, costs, toxicity, and relapse rates persist. In this review, we first provide a brief background on T cell biology and CAR T cells, and then present a comprehensive overview of emerging strategies for direct in vivo T cell reprogramming. We discuss the key platform technologies, including lipid nanoparticles and viral vectors, and the targeting methods employed to enhance delivery and efficacy. Moreover, we evaluate the functional state of reprogrammed T cells and the role of different mouse models and reporter systems in assessing their therapeutic potential. We highlight key challenges related to the biodistribution, activation, and persistence of modified T cells, with an emphasis on the potential of these strategies for treating not only blood cancers but also solid tumors, autoimmune diseases, and beyond. Finally, we provide an outlook on future directions by highlighting recent non-human primate studies, ongoing clinical activities, and strategic acquisitions, representing key innovations and discuss remaining translational hurdles in the field.
    Keywords:  CAR-T cells; In vivo; LNPs; Non-viral vectors; RNA; T cell reprogramming; Viral vectors
    DOI:  https://doi.org/10.1016/j.addr.2026.115940
  12. Acta Biomater. 2026 Aug 05. pii: S1742-7061(26)00526-X. [Epub ahead of print]
    Rethinking hemocompatibility standards: a critical appraisal of current regulatory frameworks for Advanced Therapy Medicinal Products (ATMPs) validation.
    Hachem Bouarroudj, Constant Gillot, Miriam Cnop, Jean-Michel Dogné, Véronique Flamand, Isabelle Leclercq, Pauline Michaux, Jonathan Douxfils.
      Hemocompatibility, defined as the ability of a product to interact safely with blood components, is a critical requirement for therapies intended for intravascular administration. Current evaluation frameworks, primarily based on ISO 10993-4:2017, were initially developed for inert medical devices and rely on static assays assessing hemolysis, coagulation, platelet activation, and complement activation. However, these approaches remain limited when applied to Advanced Therapy Medicinal Products (ATMPs), which are dynamic and biologically active. Unlike conventional devices, ATMPs interact continuously with immune and hemostatic systems under flow conditions. Existing methodologies do not fully capture shear-dependent and time-evolving thrombo-inflammatory processes, may show variability, and have limited translational relevance. In addition, innate immune activation, an important contributor to ATMP-related adverse events, is not sufficiently considered. Regulatory guidance from major agencies, including the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA), remains indirect, leading to variability in practices and uncertainty in study design and interpretation. This review critically examines current hemocompatibility assessment strategies for ATMPs and highlights the need for adapted frameworks. It proposes redefining hemocompatibility as controlled blood-interaction and supports the integration of dynamic flow-based models and mechanistic assays within a risk-based, tiered approach to improve predictivity, standardization, and safety. Such an evolution is essential to implement more biologically relevant and clinically meaningful hemocompatibility standards for ATMPs. STATEMENT OF SIGNIFICANCE: Current hemocompatibility standards were primarily designed for inert medical devices and do not adequately address the biological complexity of advanced therapy medicinal products (ATMPs), such as cell and gene therapies. This review highlights important scientific and regulatory gaps in existing testing frameworks, particularly regarding thrombo-inflammatory and immune-mediated blood interactions. By analyzing current limitations and emerging technologies, including dynamic flow-based and microphysiological models, this work proposes a shift from the traditional concept of blood inertness toward controlled blood interaction. This perspective may help improve the predictive value of preclinical safety testing and support the development of more appropriate regulatory standards for next-generation advanced therapies.
    Keywords:  ATMPs; Advanced therapy; Hemocompatibility; Regulatory frameworks; Thrombo-inflammation
    DOI:  https://doi.org/10.1016/j.actbio.2026.08.003
  13. Cytotherapy. 2026 Jun 06. pii: S1465-3249(26)00887-X. [Epub ahead of print]28(10): 102926
    Understanding FDA's reasons for nonapproval: A systematic review of complete response letters in cell and gene therapy.
    Eugene Babcock, Cindy Riggins.
       BACKGROUND AIMS: Cell and gene therapy products face unique regulatory challenges due to their biological complexity and the stringent expectations for manufacturing control, analytical testing, and clinical assessment. As the pipeline grows, understanding the drivers of FDA non‑approval is increasingly important for improving first‑cycle success and reducing development delays. In this study, we aimed to characterize the frequency and impact of refuse‑to‑file actions, major amendments, and complete response letters issued for biologics licensing applications; and to identify recurring patterns of deficiencies contributing to delayed approval.
    METHODS: Publicly available documents were extracted from the FDA website. Data from each approved cell and gene therapy product's regulatory history-including complete responses, major amendments, inspection timing, and cited deficiencies-were compiled and categorized across clinical, quality, and labeling domains.
    RESULTS: Analysis showed that informational deficiencies were common across modalities. Major amendments occurred in roughly half of applications, and complete responses had the most significant impact. Quality deficiencies appeared in all complete responses and were the predominant barrier, while clinical and labeling issues were less frequent but meaningful when present.
    CONCLUSION: Overall, these findings highlight the need for proactive FDA engagement, comprehensive readiness, and early inspection preparation to reduce regulatory risk and improve first cycle approval outcomes.
    Keywords:  Biologics license application (BLA); cell therapy; chemistry, manufacturing, and controls (CMC); complete response; gene therapy; regulatory review
    DOI:  https://doi.org/10.1016/j.jcyt.2026.102926
  14. Immunol Invest. 2026 Aug 04. 1-29
    γδ T Cells as a Platform for Immunotherapy: From Biological Principles to Clinical Translation.
    Junjie Ni, Chao Xiong, Xian Wu, Zijun Yuan, Xingyue Wang, Yu Chen, Xu Wu, Mingxing Li, Fukuan Du, Yueshui Zhao, Zhuo Chen, Jing Shen, Xi He, Zhangang Xiao.
      Background: γδ T cells are emerging as a promising immunotherapy platform because they combine rapid innate-like effector activity with adaptive immune features and recognize stress-associated signals in a largely MHC-independent manner. Their clinical utility, however, is constrained by pronounced heterogeneity in subset composition, tissue localization, and functional state.Objective: This review aims to summarize the biological principles governing γδ T-cell development, classification, and antigen recognition and to examine how their context-dependent functions inform therapeutic design.Methods: We integrated current evidence on γδ T-cell biology across cancer, infection, and autoimmunity and evaluated the major translational strategies currently being developed.Results: Current strategies include in vivo activation, adoptive transfer, combination regimens, engineered γδ T-cell products, and cell-free approaches such as γδ T-cell-derived extracellular vesicles. However, clinical translation remains limited by product heterogeneity, insufficient expansion and persistence, and incomplete mechanistic resolution.Conclusion: Future development should prioritize mechanism-guided engineering, biomarker-informed development, and better-designed clinical studies.
    Keywords:  Adoptive transfer; CAR-γδ T cells; biomarker-guided translation; functional plasticity; immunotherapy platform; γδ T cells
    DOI:  https://doi.org/10.1080/08820139.2026.2711303
  15. Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261476208
    The Rise of Generalist Foundation Models and Quantum Computing in Oncology.
    Manish Kakar.
      In the field of oncology, Artificial intelligence (AI) and deep learning (DL) are an essential component of decision-support. However, traditional narrow-AI models have significant limitations in clinics with respect to narrow, task-specificity (TS), high data requirement and interpretability. Moreover, the absence of common clinical criteria and the lack of doctors in the co-development of explainable AI (XAI) have undermined the implementation causing conflict with general data protection regulation (GDPR), trust and ethical integration requirements. The application of AI/DL tools in clinics are often constrained by TS, heavy dependency on hyperparameter tuning and large data volume. This review fills in these gaps by creating a cohesive framework that links problem-driven clinical demands with emerging technologies, specifically, the convergence of Generalist Medical AI (GMAI) and Quantum Oncology (QO). Although GMAI's use foundation models, have high computational requirements and have inherent complexity in their validation pipelines, they are designed to be based on self-supervised learning from multimodal data to address a range of downstream clinical tasks. This review aims to critically discuss the potential of quantum computing (QC) to augment GMAI for more efficient data processing, medical imaging, drug discovery, and genomic analysis, owing to the inherent strengths of quantum superposition and entanglement that surpass the capabilities of classical AI/DL systems. Structural and technical trade-offs of this paradigm change are also discussed. We also give recommendations for safe bedside translation by facilitating a common assessment through clinician in the loop design, the CLAIM checklist, and the framework FUTURE-AI. Finally, this analysis outlines oncology and quantum convergence into quantum oncology (QO). This enables scalable, sustainable, and precision oncology while respecting ethics and privacy.
    Keywords:  AI; current; future; generalized models; oncology
    DOI:  https://doi.org/10.1177/15330338261476208
  16. J Immunother Cancer. 2026 Aug 07. pii: e016348. [Epub ahead of print]14(8):
    Clinical trial landscape and translational prospects of natural killer cell-based immunotherapy: an analysis based on the INFORMA database.
    Han Sun, Yanni Zhang, Ye Yuan, Dehua Liu, Jinhan Qiao.
      Natural killer (NK) cell-based immunotherapy is an increasingly important cancer treatment strategy because of its innate cytotoxicity, allogeneic potential, and compatibility with off-the-shelf manufacturing. We analyzed 287 clinical trials identified in the INFORMA database to characterize the global development of NK-cell therapies across phases, regions, indications, combinations, cell sources, product origins, and engineering platforms. Most trials were planned or early-phase, and combination regimens were more frequent than monotherapy. The USA, China, and South Korea led clinical activity. Hematologic malignancies remained the principal testing ground, while lung, colorectal, and other solid tumors reflected broader expansion. Platform-level analysis showed a predominance of allogeneic products and rapid growth of CAR-engineered NK-cell trials after 2020. These findings indicate a transition from proof-of-concept adoptive transfer toward standardized, genetically programmable, off-the-shelf platforms. The principal challenge is shifting from manufacturing feasibility alone to durable biological activity. Future development should align cell engineering, combination partners, translational endpoints, and biomarker-guided patient selection with specific barriers involving persistence, tumor delivery, microenvironmental fitness, and immune escape.
    Keywords:  Immunotherapy; Natural killer - NK
    DOI:  https://doi.org/10.1136/jitc-2026-016348
  17. Transplant Cell Ther. 2026 Aug 05. pii: S2666-6367(26)00599-3. [Epub ahead of print]
    Impact of Prior Bendamustine Exposure on Chimeric Antigen Receptor T-Cell Therapy Outcomes in Follicular Lymphoma.
    Danielle DeCicco, Sanjana Nethagani, Shanawar Waris, Salah Ud Din Safi, Aaron Cumpston, Lauren Veltri, Konstantinos Sdrimas.
      Prior bendamustine exposure impairs T-cell fitness and has been associated with inferior CAR T-cell therapy outcomes in large B-cell lymphoma, but follicular lymphoma (FL)-specific data are lacking. Using the TriNetX Research Network (107 healthcare organizations), we conducted a retrospective cohort study of adult patients with relapsed/refractory FL who received CD19-directed CAR T-cell therapy (axicabtagene ciloleucel, lisocabtagene maraleucel, or tisagenlecleucel). Propensity score-matched comparisons evaluated overall survival (OS) stratified by bendamustine exposure timing. Any prior bendamustine exposure was associated with inferior 2-year OS compared with bendamustine-naive patients (58.99% vs 76.73%; HR 1.855, 95% CI 1.003-3.432, p=0.046, n=89). Critically, bendamustine exposure within 1 year of CAR T-cell infusion was associated with significantly worse 2-year OS compared with exposure more than 1 year prior (40% vs. 68%; HR 2.277, 95% CI 1.117-4.644; p =0.020, n=46). In contrast, patients with bendamustine exposure more than 1 year before CAR T-cell had the same OS as bendamustine-naive patients (71% vs. 72%; HR 1.045; P = .914). A dose-response analysis demonstrated a consistent, statistically significant increase in mortality risk as bendamustine exposure approached the time of CAR T-cell infusion across all three measures of association (P < .05). Inpatient admission within 30, 60, and 90 days of CAR T-cell was significantly higher in patients with recent bendamustine exposure. These findings are hypothesis-generating and suggest a clinically actionable 12-month washout interval and support preferential use of non-bendamustine-containing regimens over bendamustine-based regimens in patients with FL who may require future CAR T-cell therapy. Extended Abstract BACKGROUND: Bendamustine-based chemoimmunotherapy is widely used in the treatment of follicular lymphoma (FL) but is associated with prolonged and profound T-cell suppression, which may adversely affect the efficacy of chimeric antigen receptor (CAR) T-cell therapy. Emerging data in large B-cell lymphoma suggest that recent bendamustine exposure negatively impacts CAR T-cell outcomes; however, disease-specific data in FL remain limited. Given the increasing use of CD19-directed CAR T-cell therapy in relapsed/refractory FL, understanding the impact of prior therapies on treatment outcomes is critical for optimizing patient selection and treatment sequencing.
    METHODS: We performed a retrospective cohort study using the TriNetX Research Network, a federated database of de-identified electronic health records from multiple healthcare organizations. Adult patients with relapsed or refractory FL who received CD19-directed CAR T-cell therapy, including axicabtagene ciloleucel, lisocabtagene maraleucel, or tisagenlecleucel, were identified. Patients were stratified according to prior bendamustine exposure and the timing of exposure relative to CAR T-cell infusion. Propensity score matching was conducted to balance baseline characteristics, including age, sex, and race, between comparison cohorts. The primary endpoint was overall survival (OS). Secondary analyses evaluated early post-CAR T-cell therapy toxicity and healthcare utilization. A dose-response analysis was performed to assess the relationship between the temporal proximity of bendamustine exposure and mortality risk.
    RESULTS: Prior bendamustine exposure was associated with inferior survival compared with bendamustine-naive patients, with a lower two-year OS (30.4% versus 55.7%) and an increased risk of mortality (hazard ratio [HR], 1.532; 95% confidence interval [CI], 0.895-2.622). The impact of bendamustine was strongly dependent on the timing of exposure. Patients who received bendamustine within one year prior to CAR T-cell infusion had significantly worse survival compared with those whose exposure occurred more than one year before infusion (two-year OS, 40% versus 68%; HR, 2.277; 95% CI, 1.117-4.644; P = .020). In contrast, patients with bendamustine exposure more than one year prior to CAR T-cell therapy had survival outcomes comparable to bendamustine-naive patients (two-year OS, 72% versus 72%; HR, 1.045; 95% CI, 0.469-2.328; P = .914). Dose-response analyses demonstrated a consistent increase in mortality risk as bendamustine exposure occurred closer to the time of CAR T-cell infusion (P < .05 across measures of association). In secondary analyses, patients with recent bendamustine exposure experienced higher rates of inpatient admission within 30, 60, and 90 days following CAR T-cell therapy, whereas rates of cytokine release syndrome and neurotoxicity were similar between groups.
    CONCLUSIONS: Recent bendamustine exposure is associated with significantly inferior overall survival following CD19-directed CAR T-cell therapy in patients with FL, whereas exposure beyond 12 months may not adversely affect outcomes.
    CLINICAL IMPLICATIONS: These results have immediate relevance for treatment sequencing in FL. Avoidance of bendamustine-containing regimens in patients who are potential candidates for CAR T-cell therapy, or ensuring an adequate washout period prior to leukapheresis and infusion, may optimize cellular therapy outcomes. Prospective studies incorporating immune profiling and CAR T-cell manufacturing metrics are warranted to validate these findings and further define the biological basis of this effect.
    DOI:  https://doi.org/10.1016/j.jtct.2026.07.039
  18. Value Health. 2026 Aug 06. pii: S1098-3015(26)02570-2. [Epub ahead of print]
    Swimming in the Sea of Real-World Evidence (RWE) Guidance: Why More Guidance Documents Are Needed to Help Researchers Swim.
    Sandipan Bhattacharjee.
      Real-world evidence (RWE) plays an expanding role in regulatory, health technology assessment (HTA), and lifecycle decision-making, prompting a rapid increase in guidance documents intended to support its generation and use. This commentary argues that additional guidance is not redundant; rather, it is necessary to sustain consistency, credibility, and confidence as RWE methods become more specialized and operationally complex. Recent advances, including pragmatic and registry-based trials, hybrid randomized-real-world designs, external control arms, artificial intelligence and machine learning applications, digital health data, synthetic controls, and data tokenization, have outpaced the scope of many existing frameworks. Although recent reporting initiatives and international harmonization efforts have improved transparency and reproducibility, important gaps remain in implementation-focused guidance on issues such as causal inference, dynamic borrowing, linkage validation, algorithm auditability, reproducibility, and distributed data environments. The need is further amplified by heterogeneity across regulatory and HTA agencies, where differing evidentiary expectations can create uncertainty and inefficiency, and by the limited availability of context-appropriate guidance for low- and middle-income countries, where structural data and infrastructure constraints may hinder RWE generation and use. Future progress should emphasize targeted, modular, and potentially "living" guidance that is updated as methods evolve, while also improving uptake of existing frameworks through clearer reporting expectations, education, and stakeholder collaboration. More guidance, when focused and implementation-oriented, can better translate methodological principles into decision-grade RWE.
    DOI:  https://doi.org/10.1016/j.jval.2026.07.006
  19. Front Oncol. 2026 ;16 1869826
    CAR T-cell therapy in pediatric brain tumors: a narrative review with comparative analysis of clinical trial eligibility criteria.
    Akshaya Srinivasan, Angeline Abraham, Aliya I Modak, Anugrah Pradeep, Nisrine L Nimachwala, Akshit V Chemmancheri, Aarifa Banu, Afnan A Azad, Ashly Abraham, Lika Khorbaladze.
      Pediatric brain tumors are the leading cause of cancer-related mortality in children, and current standard therapies like surgery, radiotherapy, and chemotherapy offer limited survival benefits and significant long-term morbidity. Chimeric antigen receptor (CAR) T-cell therapy is a transformative treatment for hematologic malignancies and is now being explored for pediatric brain tumors. This review summarizes the latest advances, preclinical and clinical findings, challenges of CAR T-cell therapy, and future directions in pediatric neuro-oncology. 18 studies that met the eligibility criteria were selected, consisting of preclinical models, early-phase clinical trials, and translational studies. A registry search of central nervous system (CNS) tumor trials from Clinicaltrials.gov, ISRCTN, and ANZCTR identified 12 active or completed interventional trials of CAR T-cell therapy in patients with CNS tumors, their eligibility criteria and parameters were compared. Preclinical studies consistently demonstrate that CAR T-cells targeting antigens such as B7-H3, GD2, HER2, IL13Rα2, and EphA2 can induce robust and specific tumor regression in models of medulloblastoma, diffuse intrinsic pontine glioma (DIPG), ependymoma, and high-grade gliomas. On the other hand, B7-H3 is a pan-pediatric target due to its high expression in multiple CNS tumors, including medulloblastoma, ependymoma, and glioma, whereas GD2 is highly relevant for H3K27M-mutant diffuse midline gliomas. Early-phase clinical trials confirm that CAR T-cells can traffic to CNS tumors, infiltrate tumor tissue, and mediate tumor regression. The ICV B7-H3 phase 1 trial in DIPG achieved noteworthy results, with a median survival of 19.8 months across 21 patients and 3 patients surviving more than 40 months. GD2-CAR T-cell therapy in H3K27 M-mutant gliomas showed partial clinical responses, with neurotoxicity and encephalopathy observed, whereas the HER2-targeted locoregional therapy showed no dose-limiting toxicities. Future interventions such as multi-antigen targeting, combinatorial CAR designs, and enhanced cytokine signaling are being developed to improve efficacy and safety. A comparison of 12 registered pediatric CAR T-cell trials showed heterogeneity in eligibility criteria, including age ranges, performance status thresholds, H3K27M mutation requirements, and geographic concentration bias. CAR T-cell therapy holds significant promise for improving outcomes in pediatric brain tumors, but its clinical translation is challenged by tumor heterogeneity, antigen escape, neurotoxicity, and the immunosuppressive tumor microenvironment.
    Keywords:  B7-H3; CAR T-cell therapy; CNS tumors; GD2; antigen escape; immunotherapy; neurotoxicity; pediatric brain tumors
    DOI:  https://doi.org/10.3389/fonc.2026.1869826
  20. Annu Rev Pharmacol Toxicol. 2026 Aug 03.
    The Pharmacology of CAR T Cell Therapy for Autoimmune Disease.
    Juliang Qin, Guangyu Zhang, Ning Zhao, Bing Du, Mingyao Liu.
      For decades, autoimmune disease treatment depended on long-term immunosuppression, which seldom yields lasting immune tolerance and carries cumulative toxic risks. Recent cell therapies, including chimeric antigen receptor (CAR) T cells, regulatory T cells, and mesenchymal stromal cells, have induced deep remission in refractory diseases, often persisting after treatment withdrawal and indicating benefits beyond short-term inflammation suppression. However, traditional dose-exposure-response pharmacokinetic/pharmacodynamic frameworks are insufficient to account for the in vivo expansion, trafficking, and phenotypic evolution of living cellular products. Here we propose that, in autoimmune diseases, cell-based therapies exemplified by CAR T cells should be reframed from exposure-control pharmacology to state-transition pharmacology. Through endogenous expansion and immune networks, therapeutic cells may shift the immune system from a pathological toward a tolerant steady state. Because toxicities may reflect the amplification or persistence of intended mechanisms, future work requires quantitative metrics of immune state transitions and programmable strategies for precise functional control.
    DOI:  https://doi.org/10.1146/annurev-pharmtox-060225-095155
  21. Clin Lymphoma Myeloma Leuk. 2026 Jul 15. pii: S2152-2650(26)00211-9. [Epub ahead of print]
    SOHO State of the Art Updates and Next Questions | Best of Stem Cell Transplant: Recent Advances in Allogeneic Hematopoietic Cell Transplantation.
    Molly Gilligan, Alexandra Gomez-Arteaga.
      Allogeneic hematopoietic cell transplantation is undergoing rapid transformation, propelled by a wave of practice-changing studies that are reshaping how donors are selected, how graft-versus-host disease (GVHD) is prevented, and how post-transplant relapse is managed. Here we review the major advances of the past several years, focusing on practice-changing studies from 2024 to 2026, and the questions they raise. The adoption of post-transplant cyclophosphamide (PTCy) as a near-universal GVHD prophylaxis backbone has diminished the long-standing primacy of human leukocyte antigen matching, enabling comparable outcomes with mismatched unrelated (MMUD) and haploidentical donors and expanding access for patients of non-European ancestry; contemporary guidelines now endorse concurrent donor searches and prioritization of younger donors. Building on the BMT CTN 1703 trial, PTCy-based prophylaxis has become a standard across conditioning intensities and donor types, while correlative studies illuminate both its mechanism and its trade-offs. Complementary strategies, including frontline and prophylactic ruxolitinib, adoptive regulatory T-cell (Treg) therapy, and the precision-engineered Orca-T graft, are broadening the prophylaxis repertoire and beginning to separate GVHD control from the loss of immune competence and graft-versus-leukemia activity. For FLT3-ITD AML, the MORPHO trial and subsequent analyses have established measurable residual disease-directed gilteritinib maintenance, advancing a molecularly individualized approach to relapse prevention. Together, these developments mark a decisive shift from a uniform transplant paradigm toward biomarker-guided, precision-based care, and they define the priorities for the next generation of clinical trials.
    Keywords:  Allogeneic hematopoietic stem cell transplant (allo-HCT); Graft-versus-host disease (GVHD); Measurable residual disease (MRD); Post-transplant cyclophosphamide (PTCy); Regulatory T cells
    DOI:  https://doi.org/10.1016/j.clml.2026.07.006
  22. Oncoscience. 2026 ;13 227-249
    Engineering CAR-T cells for solid tumors: Overcoming the microenvironment through integrated design and clinical translation.
    Samuel Obiosa Onyekweli, Gloria Osayamen Omoruyi, Christopher Oloruntoba Akintayo, Samuel Kehinde Olaniyi.
      Chimeric antigen receptor T-cell (CAR-T) therapy has produced remarkable therapeutic results in blood cancers, while its application to solid malignancies remains limited by a pooled objective response rate of approximately 9%. This gap stems from core biological obstacles: heterogeneous antigen expression, physical inaccessibility within dense stromal architectures, and immunosuppressive microenvironments that drive T-cell exhaustion through epigenetically fixed transcriptional programs. The period spanning 2024-2025 represents a pivotal turning point. GD2-targeting CAR-T cells delivered intracerebroventricularly achieved durable complete responses (including one sustained beyond 30 months) in H3K27M-mutated diffuse midline gliomas. CLDN18.2-targeting satricabtagene autoleucel demonstrated randomized superiority over physician's choice in advanced gastric cancer (progression-free survival HR 0.37). GPC3-targeting CAR-T cells armored with a dominant-negative TGF-β receptor achieved objective response rates of 50-57% in hepatocellular carcinoma, representing a three- to four-fold improvement over unarmored predecessors. These breakthroughs reflect a paradigm shift from potency-driven engineering toward resilience-based design: metabolic armoring via autocrine IL-10 and IL-15, epigenetic protection through DNMT3A disruption and c-Jun overexpression, logic-gated targeting via synNotch circuits, and microenvironmental shielding through dominant-negative receptors. Beyond the local microenvironment, emerging recognition of systemic neuroendocrine-immune dysregulation further informs CAR-T persistence and fitness considerations. This review synthesizes the mechanistic insights, engineering strategies, clinical evidence, and emerging platforms, including in vivo lentiviral CAR-T generation, that define the current landscape, and proposes a tiered framework for next-generation solid tumor CAR-T development, while explicitly acknowledging the limitations and unknowns that persist.
    Keywords:  CAR-T cell therapy; clinical translation; immunotherapy engineering; solid tumors; tumor microenvironment
    DOI:  https://doi.org/10.18632/oncoscience.666
  23. Clin Pharmacol Ther. 2026 Aug 04.
    The Multiple Criteria Qualitative Value-Based Pricing Framework "MARIE" for Novel Cell and Gene Therapy.
    Akina Takami, Ataru Igarashi.
      When setting the price of cell and gene therapies in Japan, the factors considered include the manufacturing and operating costs of the new drug or a comparator, leading to discrepancies between price and values, in particular those specific to cell and gene therapies. Here, we adapted our previously proposed value-based pricing framework "MARIE" for use in estimating value-based prices for cell and gene therapies. We adapted "MARIE" for use in pricing cell and gene therapies by adding "curative treatment" and "gene therapy" as value elements. The adapted framework determines prices of cell and gene therapies by multiplying the hypothetical daily price (determined from a drug price conversion table) and the efficacy period (rounded down to the nearest 6 months). We collected information, including on value elements, for new cell and gene therapies approved between 2015 and 2024 (n = 11) and compared estimated prices with actual list prices at the time of initial listing in the National Health Insurance Drug Price Standard. Overall, estimated prices tended to be similar to or higher than the list price. Estimated prices were 91.7% to 546.7% of list prices. We adapted our VBP framework "MARIE" for cell and gene therapies by incorporating elements specific to these therapies and estimated the prices using the information available at listing. Because certain factors, especially treatment duration, are uncertain at the time of initial listing, a system is needed that reevaluates and recalculates prices as additional evidence becomes available.
    DOI:  https://doi.org/10.1002/cpt.70417
  24. Front Immunol. 2026 ;17 1885909
    Next-generation T cell engagers for cancer and autoimmune diseases.
    Jennifer S Michaelson, Catherine C Henry, Karsten Sauer, Patrick A Baeuerle.
      T cell-engaging antibody constructs (TCEs) have emerged as a potent modality to treat cancer and autoimmune diseases. Twelve TCEs have been approved by the FDA and EMA for the treatment of hematological malignancies or solid tumors. Despite the varying designs and binding properties, they all lead to robust single-agent efficacy and approvals in refractory or relapsed leukemia, lymphomas, multiple myeloma (MM), small cell lung cancer, EpCAM-expressing cancers or uveal melanoma. Where comparisons can be deduced, TCEs appear to achieve response rates like those obtained with CAR-T cell therapies. Given the success of the first generation of TCEs, considerable attempts are underway to further improve upon this modality. With the goal of expanding TCEs into other malignant and autoimmune indications, and to further enhance efficacy and improve safety, a multitude of novel TCEs are currently in preclinical and clinical development. Here we review the current approaches to developing next-generation TCEs that can widen the therapeutic index, address heterogeneous target expression, and thereby potentially improve efficacy and safety.
    Keywords:  B cell depletion; T cell; T cell engager (TCE); autoimmune disease; bispecific antibody; conditional; costimulation; logic-gated
    DOI:  https://doi.org/10.3389/fimmu.2026.1885909
  25. Blood Adv. 2026 Aug 07. pii: bloodadvances.2025019559. [Epub ahead of print]
    Chronic xenogeneic GVHD after CAR T cell therapy limits long-term safety assessment of CAR effects using NSG mouse model.
    Wahed A Firoz, Michael K Sheng, Pedro Ruivo, Logan Vahid Vick, Craig P Collins, Ryan N Nielsen, Ravi K Shah, Lam T Khuat, Ying Xiong, Maneesh Dave, Sean J Judge, Robert J Canter, Arta M Monjazeb, Bruce R Blazar, Anthony Elston Zamora, William J Murphy.
      The clinical successes of chimeric antigen receptor (CAR) T cells represent a major shift in immunotherapy. However, there is also increasing emphasis on potential long-term effects of CAR T cell therapy, especially using preclinical xenogeneic models. It has been previously demonstrated that only naïve, and not memory, peripheral blood human T cells can mediate a rapid and acute xenogeneic graft-versus-host disease (xenoGVHD). Here, we demonstrate that simply by altering the donor T cells in the process of generating CAR T cells, in which they are all memory phenotype, that the xenoGVHD outcome was markedly altered. Following tumor clearance with CAR T cell administration, we observed a significantly delayed (up to 200 days post-transfer with some donors) occurrence of lethal xenoGVHD, marked by profound scleroderma and multi-organ pathology consistent with chronic, not acute, GVHD. Notably, this novel chronic xenoGVHD occurred in the absence of B cells, which are classically associated with mediating chronic GVHD pathology. TCR-repertoire constriction during disease and the lack of disease using MHCI/II double-knockout NSG recipient mice confirmed the observed pathology was xenoGVHD and mediated by human-TCR:murine-MHC interactions. Interestingly, despite the consistent expansion of CAR-positive T cells during early tumor-clearance, a later emergence of CAR-negative populations during xenoGVHD also resulted. Our findings highlight xenoGVHD as a problem that makes long-term assessment of CAR T efficacy or toxicity highly problematic in xenograft models due to the artefact of xenoreactivity which is not representative of autologous clinical usage, and the profound effect that T cell alterations have in GVHD pathophysiology.
    DOI:  https://doi.org/10.1182/bloodadvances.2025019559
  26. Expert Rev Pharmacoecon Outcomes Res. 2026 Aug 07.
    Regulatory approval trends and market access implications: a multiregional comparative framework for New and supplemental Drug applications (2020-2025).
    Mohit Bajaj, Mital Patel.
       BACKGROUND: Drug approval remains fragmented, governed by region-specific regulatory frameworks and review pathways. Despite international harmonization, the same product is often approved at different timelines and under different pathways across regions, complicating regulatory planning. Currently, there is no unified system that enables concurrent comparison of multiregional drug approvals.
    METHODS: Drug Approvals in the US, EU, Japan, and India were evaluated from Jan-2020 to June-2025. NDA approvals were assessed year-wise, review type, and by pharmacotherapeutic area to identify key focus areas. Supplemental approvals were analyzed year-wise, application categorywise, and by therapeutic area to understand post-approval patterns. This study analyses multiregional approval trends and addresses this gap through an integrated analytical framework. To enable integrated multiregional assessment, a web-based regulatory intelligence dashboard was developed.
    RESULTS: The dashboard consolidates approval data across regions and parameters into a harmonized interface for simultaneous visualization, comparison and assessment across multiple jurisdictions. For pharmaceutical manufacturers, the availability of such a platform enables monitoring of approval patterns, identifying unapproved or underexplored markets and supporting data-driven strategic planning for earlier market access. The dashboard provides regulatory authorities, sponsors, researchers and policy makers consolidated visibility into cross-regional activity.
    CONCLUSION: Overall, the dashboard enables data-driven comparison by addressing a gap in existing information systems.
    Keywords:  Retrospective data analysis; decision support framework; drug lifecycle management; regulatory Web-based dashboard; regulatory approval trends
    DOI:  https://doi.org/10.1080/14737167.2026.2715979
  27. Immunol Rev. 2026 Aug;341(1): e70152
    What Does the Shape Space of T Cell Epitopes Look Like?
    Franka Buytenhuijs, Gijs Schröder, Johannes Textor.
      Shape space is a decades-old conceptual model of antibody-antigen interactions that underlies antigenic maps used to trace viral evolution. Here, we apply this concept to T cell receptors (TCRs) and the peptide-MHC complexes (pMHCs) that they recognize. We start by reviewing the history of shape space and its deep connections to concepts in statistical physics (energy landscapes) and computer science (complexity theory). Leveraging these connections, we propose a model in which TCR-pMHC binding relies on multiple, possibly conflicting, structural constraints-implying that pMHCs recognized by the same TCR occupy several disjoint, non-convex regions in shape space. Our model makes two central predictions: (1) even small pMHC structure alterations can have major effects on immunogenicity; (2) two pMHCs recognized by the same TCR can have very different structures. We show that published TCR-pMHC interaction data generated by mutagenesis assays lend some support for this idea. We conclude by discussing implications of a multispecific and non-convex T cell epitope shape space for the prediction of immune responses in cancer immunotherapy and other applications.
    DOI:  https://doi.org/10.1111/imr.70152
  28. Int J Nanomedicine. 2026 ;21 613224
    Exosome-Inspired Nanocarriers in Cancer Therapy: Bio-Derived Nanotechnology Meets Nano Drug Delivery.
    Bingya Zhang, Yihang Gao.
      Traditional cancer therapy has limitations due to a lack of specificity and efficiency in tumor-targeting, toxicity issues, and biological barriers, which affect the clinical efficacy of traditional agents as well as synthetically designed carriers. Exosomes have gained popularity as excellent biological carriers owing to their inherent biocompatibility, capability to overcome biological barriers, and ability to transport cargoes between cells naturally. This review discusses how engineering of exosomes, hybrid exosomes, and exosome mimics could be employed to deliver therapies, enhance tumor penetration, and enable multimodal treatment of cancers, including chemotherapy, gene therapy, immunotherapy, and theranostics. The biomimetic and hybrid platforms may overcome key limitations of native exosomes, particularly low production yield, heterogeneity, limited drug-loading efficiency, and scalability constraints, while preserving desirable biological functionality. Moreover, the review also emphasizes that the standardization in manufacturing, reproducibility in cargo, safety evaluation, and regulatory approval are the major obstacles to clinical application. Unlike many earlier reviews that were mainly centered on native exosomes, the current review discusses the engineering aspects of exosome-like nanoplatforms from a translational viewpoint.
    Keywords:  bio-derived drug delivery; cancer therapy; exosomes; extracellular vesicles; tumour microenvironment
    DOI:  https://doi.org/10.2147/IJN.S613224
  29. Value Health. 2026 Aug 06. pii: S1098-3015(26)02571-4. [Epub ahead of print]
    Swimming in the Sea of RWE Guidance: Why More Guidance Will Not Help Researchers Swim.
    Ashley Jaksa.
      The global use of real-world data (RWD) and real-world evidence (RWE) in regulatory and health technology assessment (HTA) decisions has led to a crucial need for alignment on what constitutes high-quality RWE. Regulators, HTA bodies, and professional societies have issued an abundance of guidance documents, resulting in a state of guidance oversaturation. The existence of multiple initiatives to track this guidance is itself indicative of the challenge researchers face in interpreting and aligning with decision-maker expectations. While the proliferation of guidance forces researchers into exhaustive 'compare and contrast' exercises, multiple publications have documented substantial alignment on core principles, including study design, data quality, the importance of fit-for-purpose data, and methodological rigor. For example, the fundamental requirements for RWD quality are similar between the FDA and EMA. This convergence suggests that additional, redundant guidance is not the answer to addressing remaining gaps. Instead of producing new, high-level guidance, future efforts should pivot toward two critical areas. First, global harmonization of existing guidance is necessary to reduce the resource burden on sponsors and prevent evidentiary fragmentation across jurisdictions. Second, a transparent, annotated repository of diverse case studies must be developed to build operational transparency in RWE use and decision-making. This repository should capture why specific data and methodological decisions were made, how the evidence was evaluated, and how it was ultimately used in decision-making. By shifting the focus from guidance to transparent, precedent-based learning and harmonized standards, the industry can establish a more predictable and efficient pathway for decision-grade RWE integration.
    Keywords:  guidance; real-world data; real-world evidence
    DOI:  https://doi.org/10.1016/j.jval.2026.06.026
  30. Drug Discov Today. 2026 Aug 04. pii: S1359-6446(26)00159-5. [Epub ahead of print] 104754
    Can agentic AI dent Eroom's Law? Large reasoning models across the drug discovery and development pipeline.
    Sheraz Khan, John G Samuelsson, Xuemei Cai, Kannan Natarajan, Subha Madhavan.
      Productivity in pharmaceutical R&D continues to fall despite deeper biological insight and steady gains in clinical development operations - a phenomenon termed Eroom's Law. Agentic AI workflows powered by reasoning-trained large language models (LLMs), increasingly described as large reasoning models (LRMs), could potentially dent this trend. Unlike earlier task-specific models, these systems couple multi-step reasoning with the ability to plan, invoke external tools and retrieve authoritative information, enabling them to decompose and execute complex scientific and operational tasks. This review discusses agentic AI applications across the drug development continuum, from target discovery to post-market surveillance, and highlights three near-term use cases: algorithmic drug repurposing, informed consent support and automated drafting of regulatory documents. For each, we outline plausible architectures, the current level of supporting evidence and the principal failure modes that constrain deployment. Realizing these gains, however, requires prospective validation, rigorous human oversight and governance frameworks that align algorithmic outputs with clinical, ethical, legal and regulatory standards. When implemented responsibly, agentic AI could transform human-AI collaboration in biopharma, improving R&D efficiency and accelerating delivery of safer, more-effective therapies.
    Keywords:  Agentic AI; Eroom’s Law; drug development; drug discovery; human-in-the-loop; large language models; large reasoning models; pharmaceutical R&D productivity; regulatory affairs; retrieval-augmented generation
    DOI:  https://doi.org/10.1016/j.drudis.2026.104754
  31. Front Cell Dev Biol. 2026 ;14 1865487
    Tumor organoid-immune cell co-culture systems for precision oncology.
    Lei Cai, Yunfeng Xiao, Feihong Xie, Zongke Yang.
      Three-dimensional tumor organoids, particularly patient-derived organoids (PDOs), recapitulate key morphological, genetic, and functional features of original tumors. Co-culture with immune cells enables studies of the tumor immune microenvironment (TIME) and holds promise for personalized immunotherapy. In this review, we critically evaluate established methodologies for tumor organoid-immune cell co-culture, including reductionist, holistic (tumor slice culture and air-liquid interface), and organoid-on-a-chip approaches. We provide quantitative benchmarking of success rates, immune cell persistence, and predictive accuracy, and discuss contradictory findings, reproducibility challenges, and technical barriers that limit clinical translation. We also analyze how these systems reveal mechanisms of antitumor immunity and immune escape, and assess their applications in immune checkpoint blockade screening, adoptive cell therapy (CAR-T, CAR-NK, γδ T cells), and emerging "organoid+" technologies including spatial transcriptomics, AI-assisted imaging, and machine learning. Finally, we address ethical, regulatory, and standardization issues. Despite substantial progress, current systems face major limitations-including batch variability, loss of native heterogeneity, insufficient vascularization, and lack of systemic immune modeling-that must be overcome before clinical adoption.
    Keywords:  immune cell co-culture; immunotherapy; patient-derived organoids; precision oncology; tumor immune microenvironment; tumor organoids
    DOI:  https://doi.org/10.3389/fcell.2026.1865487
  32. Front Immunol. 2026 ;17 1878388
    Circadian rhythms in the tumor microenvironment: spatiotemporal immune regulation and chronotherapeutic opportunities.
    RenJie Zhao, YuXuan Xiao, XingXing Fan.
      The tumor microenvironment (TME) is increasingly recognized as a temporally organized ecosystem rather than a static structural niche. Circadian rhythms, generated by transcriptional-translational feedback loops involving CLOCK, BMAL1, PER, CRY, REV-ERB, and ROR, coordinate systemic physiology and local cellular programs that are directly relevant to tumor initiation, progression, and therapeutic response. In this review, we summarized how circadian regulation shapes tumor rhythmicity across multiple biological scales, from central clock-mediated synchronization to peripheral clocks within epithelial cells, stromal cells, adipocytes, and immune populations. Emphasis is placed on the spatiotemporal regulation of antitumor immunity within the TME. At the same time, dendritic cell migration, antigen presentation, CD8+ T cell infiltration, and T cell exhaustion display time-dependent features that influence the efficacy of immune surveillance and immunotherapy. These findings supported a four-dimensional view of the TME, in which biological timing is a critical determinant of immune competence. We further discussed emerging therapeutic strategies that exploit circadian biology, including small-molecule clock modulators, rhythm-responsive nanomedicine, chronologically optimized CAR-T cell therapy, and time-of-day-dependent immune checkpoint blockade. Although most mechanistic evidence remains preclinical, and many clinical observations are retrospective, current data suggest that treatment timing may be a modifiable, low-cost parameter for improving anti-tumor efficacy while reducing toxicity. Finally, we highlighted future opportunities in microbiome-informed chronotherapy, multi-omics profiling, and digital twin modeling. Integrating temporal information into oncology may shift precision medicine from a static biomarker-driven framework toward a dynamic, time-resolved therapeutic paradigm.
    Keywords:  CAR-T therapy; chrono-pharmacology; circadian rhythm; immune checkpoint inhibitor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1878388
  33. Mol Ther Adv. 2026 Sep 10. 34(3): 201809
    Co-delivery of lentiviral vectors and Cas9-containing virus-like particles enables rapid, scalable manufacture of gene-edited CAR T cells.
    Francesca Ferrara, Matthew M Wielgosz, Jeoungeun J Park, Matthew Bauler, Chris Wincek, Nataly Mier, Yin Su, Li Tang, Brandon R Lowe, Jordan A Beard, Deanna M Langfitt, Sheng Zhou, Robert E Throm.
      Chimeric antigen receptor T cell immunotherapies are transforming therapies for hematological malignancies and solid tumors and can be enhanced by targeted gene knockout. Here, we report lentiviral-based virus-like particles that package and deliver Cas9 ribonucleoproteins to primary human T cells. Using distinct pseudotyping strategies for virus-like particles and for lentiviral or γ-retroviral vectors, we achieved chimeric antigen receptor expression and targeted gene disruption. Under optimized transduction conditions, more than 50% of T cells expressed a chimeric antigen receptor by flow cytometry, with vector copy numbers exceeding two. Editing efficiencies were above 70% at three different target loci tested: T cell receptor α constant chain, β2-microglobulin, and DNA methyltransferase 3α. When the editing efficiency of virus-like particles was directly compared to electroporation, electroporation achieved a higher editing efficiency (99% versus 70%-90%). However, virus-like particle treatment resulted in twice as many cells being recovered compared with electroporation with a 10% increase in cell viability. Furthermore, off-target editing in virus-like particle-treated cells was reduced compared to ribonucleoprotein electroporated cells. These results support the feasibility of using virus-like particle-mediated delivery of Cas9 ribonucleoprotein to disrupt genes of interest, enabling a more scalable and cost-effective process for generating T cell immunotherapies.
    Keywords:  CAR T; CRISPR; Cas9; gene editing; immunotherapy; lentiviral; manufacture; retrovirus; scalable; virus-like particles
    DOI:  https://doi.org/10.1016/j.omta.2026.201809
  34. Hum Gene Ther. 2026 Aug 03. 10430342261468974
    Accelerating Translation of NK Cell Therapies to the Clinic: A European Perspective.
    Lea Rebecca Knapp, Katharina Sophie Fischer, Janika Sosat, Jose Francisco Villena-Ossa, Pia Kluge, Dominik Schmiedel, Jürgen Kuball, Harry Dolstra, Susana Minguet, Tatjana I Cornu, Toni Cathomen, Evren Alici, Michael O'Dwyer, Winfried Stephan Wels, Karl-Johan Malmberg, Rizwan Romee, Eric Vivier, Ulrike Köhl, Adelheid Cerwenka, Evelyn Ullrich.
      Adoptive immunotherapies have emerged as a promising strategy in the treatment of hematological malignancies. To date, seven chimeric antigen receptor (CAR)-T cell products have obtained market authorization in Europe for B-cell malignancies, where they have revolutionized treatment for eligible patients. In addition, natural killer (NK) cells and γδ T cells are of particular interest for cell-based therapies due to their strong intrinsic cytotoxicity and favorable safety profile. Addressing challenges facing the clinical translation of NK cell therapies was one of the issues discussed in the NK & ILC Symposium that took place in Freiburg, Germany from March 11 to 13, 2026, as the annual meeting of the NK & ILC study group of the German Society for Immunology (DGfI). Topics ranging from basic immunological research to technological innovations and clinical trial results were discussed during the 3-day conference, spanning over 40 presentations and 100 posters. A highlight of the conference was a workshop featuring short presentations and a panel discussion that focused specifically on the current challenges and future prospects of the clinical implementation of NK cell therapies; the findings of this workshop are summarized in this opinion paper.
    Keywords:  NK cells; chimeric antigen receptor; immune cell therapy; translation
    DOI:  https://doi.org/10.1177/10430342261468974
  35. Front Oncol. 2026 ;16 1888734
    CRISPR/Cas9 in cancer therapy: clinical translation, mechanistic strategies, and therapeutic directions.
    Chu Xin Ng, Sakina Mustafa, Xin Yi Yap, Sau Har Lee.
      The advent of CRISPR/Cas9 genome editing has significantly transformed the landscape of cancer therapeutics by facilitating precise and programmable manipulation of disease-associated genetic modifications. This review comprehensively evaluates the current clinical and translational landscape of CRISPR/Cas9-based cancer therapies through an analysis of published literature and registered clinical trials. The current CRISPR/Cas9 applications in oncology are primarily centred on three mechanistic strategies: immune cell engineering for enhanced tumor recognition, direct targeting of oncogenic mutations, and modulation of tumor-supportive pathways. Analysis of 32 clinical trials indicates that CRISPR-based interventions have demonstrated encouraging safety profiles and early signs of clinical activity, particularly in ex vivo engineered immune-cell therapies. Notable examples include CRISPR-edited CAR-T cell products targeting CD19 and BCMA, which have achieved objective responses in relapsed or refractory hematological malignancies while demonstrating sustained persistence of edited cells in vivo. In contrast, clinical translation into solid tumors remains comparatively limited due to challenges associated with delivery efficiency, tumor heterogeneity, and the immunosuppressive tumor microenvironment. Technological advancements, including multiplex genome editing, base editing, and prime editing have expanded the precision and versatility of CRISPR-based interventions, while integration with immunotherapy and nanotechnology-based delivery systems continues to broaden therapeutic potential. Despite these advances, several significant challenges still need to be addressed, including off-target editing, manufacturing scalability, delivery limitations, and regulatory considerations. Overall, CRISPR/Cas9 represents a promising yet evolving platform in oncology, with its future clinical success dependent on achieving a balance between precision, safety, scalability, and long-term therapeutic durability.
    Keywords:  CAR-T cell therapy; CRISPR/Cas9; cancer therapy; clinical trials; genome editing; precision oncology
    DOI:  https://doi.org/10.3389/fonc.2026.1888734
  36. PDA J Pharm Sci Technol. 2026 Aug 07. 80(4): 498-499
    In Silico Strategies for Robust Process Development in Advanced Therapies: Poster Presented at PDA Week 2026.
    Alyssa Burke.
      Robust process development enhances product quality while reducing time and cost across the product lifecycle. Systematic approaches are necessary to fully understand processes and control sources of variability; however, challenges increase when entering the field of autologous or personalized cell and gene therapies (ex. CAR-T) where each patient brings inherent biological variability. This presentation utilizes a simulated case study that combines Design of Experiments (DOE), mechanistic modeling, machine learning models, and Monte Carlo simulation to illustrate how complex processes can be analyzed in silico alongside benchtop experiments.A screening DOE study defined an efficient experimental space while mechanistic modeling generated critical quality attribute (CQA) outcomes to complement benchtop experimentation. These results trained regression and random forest models which were fed into Monte Carlo simulations. The simulations then quantify how patient-specific versus process-controlled variability contributes to overall outcome variance. Simulations can be repeated under different parameter constraints to ensure variability in patient-inputs can still lead to CQAs that are within acceptable limits.This integrated approach provides a more robust process development than DOE alone. This framework can aid in guiding process optimization and risk assessments both in early-stage process development and in continuous improvement during commercial production.
    DOI:  https://doi.org/10.5731/pdajpst.2026.26421
  37. Front Immunol. 2026 ;17 1865305
    Global research trends and emerging frontiers of intratumoral microbiota in cancer immunotherapy: a bibliometric and visualization analysis.
    Jiahe Zhou, Heyun Tao, Fuzhu Zou, Huiying Guo, Ruo Ding, Qing Lei, Xiaodie Zhou, Si Mei.
       Background: Intratumoral microbiota, an important component of the tumor microenvironment (TME), have attracted increasing attention in cancer immunotherapy. Emerging evidence links intratumoral microbiota to tumor immune microenvironment (TIME) remodeling, immune cell infiltration, and heterogeneous responses to immune checkpoint inhibitors (ICIs). However, the overall research landscape, knowledge base, and hotspot evolution in this field remain insufficiently characterized. This study aimed to systematically map this field through bibliometric and visualization analyses.
    Methods: Publications up to November 8, 2025, were retrieved from the Web of Science Core Collection, Scopus, and PubMed. After screening, deduplication, and data standardization, bibliometric analyses were performed using R, VOSviewer, CiteSpace, and Scimago Graphica to examine publication trends, collaboration networks, knowledge bases, and keyword evolution.
    Results: A total of 245 publications were included, comprising 141 original articles and 104 reviews. Since the first publication appeared in 2017, the field has grown exponentially, with a compound annual growth rate (CAGR) of 63.1% from 2017 to 2024. China ranked first in publication output, followed by the United States, while the United States occupied a more central position in total citations and international collaboration. Frontiers in Immunology was the most productive journal, whereas Science, Cell, and Nature constituted the major co-cited knowledge base, with 1,172, 729, and 670 co-citations, respectively. Keyword analysis showed that "intratumoral microbiota" was the most frequent term (90 occurrences), with excellent clustering quality (modularity Q = 0.6963; silhouette S = 0.9351). Research hotspots have gradually shifted from early explorations of gut microbiota, CD8+ T cells, and immune mechanisms toward immunotherapy resistance, microbial biomarkers, and microbiota-targeted interventions, including engineered bacteria, extracellular vesicles, and fecal microbiota transplantation.
    Conclusion: Research on intratumoral microbiota in cancer immunotherapy has rapidly developed into a distinct interdisciplinary field. Current hotspots are moving from mechanistic exploration toward response prediction and translational intervention. Future studies should prioritize standardized detection, spatial and multi-omics validation, and multicenter prospective evaluation to support the clinical translation of microbiota-based biomarkers and therapeutic strategies.
    Keywords:  bibliometric analysis; cancer immunotherapy; immune checkpoint inhibitors; intratumoral microbiota; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1865305
  38. J Comput Aided Mol Des. 2026 Aug 06. pii: 197. [Epub ahead of print]40(1):
    Why do AI projects fail in drug development and pharma? Insights from multi-year Pistoia Alliance studies.
    Vladimir A Makarov, Mario Sänger, Roman Saiz, Matthias Hartung, Nick Lynch.
      Artificial intelligence (AI) is playing an increasingly central role in drug discovery and the pharmaceutical industry more broadly. However, despite some high-profile success stories, many technically successful pilots do not translate into sustained business value. In this study, we analyze the determinants of successful AI adoption in the life sciences through three complementary approaches: (i) brainstorming workshops with senior industry professionals, (ii) a global executive survey, and (iii) a statistical analysis of a collection of AI/ML use cases collected by the Pistoia Alliance. Across all methods, a consistent pattern emerges: high strategic importance and demand for AI contrast with low organizational maturity, resulting in limited success rates for production deployments. Statistical analysis reveals that business success is associated with dimensions of organizational capability maturity, most notably project maturity, while technical factors such as data sources or model types show no significant association on their own. The findings reinforce that AI projects follow the same success drivers as other complex engineering initiatives and that organizational readiness, change management, and alignment between stakeholders are critical. Furthermore, trustworthiness encompassing reproducibility, explainability, and governance, is identified as a limiting factor for adoption, particularly in high-risk domains. We synthesize these observations into a set of recommended practices that emphasize fitness-for-purpose method selection, integration of AI into human workflows, and development of shared standards.
    Keywords:  Artificial intelligence; Drug discovery; Good machine learning practices; Governance; Organizational maturity
    DOI:  https://doi.org/10.1007/s10822-026-00894-3
  39. Front Immunol. 2026 ;17 1894658
    Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance.
    Renjie Pan, Dongdong Chen, Yilu Wu, Lancheng Zhang, Jing Zhang, Junjie Li, Qiuxia Zhao, Yan Tang.
      Immune checkpoint blockade has transformed cancer therapy, yet many tumors remain intrinsically resistant or acquire resistance after initial response. Increasing evidence indicates that this failure is not determined solely by PD-1, PD-L1, CTLA-4, or T-cell exhaustion, but also by metabolically suppressive states within the tumor microenvironment. Tumor-derived metabolites can function as metabolic immune checkpoints by limiting effector immune activity, promoting regulatory or myeloid suppressive compartments, and weakening immunotherapy efficacy. This mini review summarizes recent experimental evidence showing how lactate, adenosine, tryptophan-derived metabolites, and nucleotide-derived metabolites shape immune escape and resistance to immune checkpoint blockade. Lactate links tumor glycolysis to Treg recruitment, impaired T-cell function, and lactylation-associated therapeutic resistance. The CD73-adenosine axis suppresses CD8+ T cells and natural killer cells while reinforcing regulatory and myeloid immune programs. Tryptophan-derived metabolites extend beyond the classical IDO1-kynurenine-AhR pathway to involve non-classical checkpoints such as Siglec-15 and broader kynurenine/indole/serotonin networks. Emerging evidence further identifies nucleotide-derived UDP signaling as a driver of macrophage-mediated immunosuppression. Finally, we discuss how targeting metabolic checkpoints in combination with immune checkpoint blockade may improve therapeutic responses. Defining the spatial and cellular contexts of metabolite-mediated immune suppression may enable more precise strategies to overcome immunotherapy resistance.
    Keywords:  adenosine; immunotherapy resistance; lactate; metabolic immune checkpoint; tryptophan metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1894658
  40. Immunol Res. 2026 Aug 01. pii: 77. [Epub ahead of print]74(1):
    Past achievements and future perspectives of personalized vaccines and the role of dendritic cells.
    Mona Sadat Larijani, Anahita Bavand, Ladan Moradi, Amitis Ramezani.
      Personalized vaccines provide the advantage of patient-specific antigen selection to optimize immune responses, a strategy extensively explored in oncology through neoantigen-targeted peptide, mRNA, and dendritic cell platforms. Peptide vaccines provide simplicity and stability though often elicit limited cytotoxic T-cell responses. What is more, mRNA vaccines lead to rapid, multiplexed neoantigen delivery, endogenous antigen processing and eventually improved immunogenic coverage. Dendritic cell-based vaccines have the potency to prime potent T-cells although this technology requires labor-intensive manufacturing and extensive production timelines. Integration with immune checkpoint inhibitors, adoptive cell therapies, and oncolytic viruses further enhances efficacy, suggesting that rational combinations may be more effective than single modalities. Recent advances in sequencing, computational epitope prediction, and bioinformatics pipelines have facilitated neoantigen prioritization and DC vaccine design, enabling more rapid and precise personalization. Hybrid vaccination strategies, such as ex-vivo mRNA-electroporated dendritic cells and in-vivo DC-targeted platforms, bridge the gap between manufacturing feasibility and potent immune activation. Emerging technologies, including AI-driven neoepitope prediction, receptor-targeted antigen delivery, biomaterial-based modulation, and distributed mRNA manufacturing, seem to be promising approaches to accelerate personalized vaccine development in future. From another point of view, lessons learned from the COVID-19 pandemic accelerated the development, large-scale deployment, and validation of mRNA vaccine platforms for infectious diseases. Host HLA diversity, prior immune history, and viral evolution create heterogeneity in immune responses, highlighting opportunities for semi-personalized or adaptive strategies. In this review, we provide a landscape of personalized vaccines, with a focus on DC-based platforms, and explore translational lessons for viral pathogens. A conceptual framework linking cancer immunotherapy and infectious disease preparedness is proposed, emphasizing hybrid personalization approaches, rapid manufacturing, and AI-enabled epitope selection. This perspective highlights how convergence of immunology, computational biology, and advanced vaccine technologies could expand the scope of personalized vaccination, from oncology to future epidemic and pandemic scenarios as well as the current challenges.
    Keywords:  Cancer immunotherapy; MRNA vaccine platforms; Personalized cancer vaccines; Precision oncology; Tumor neoantigens
    DOI:  https://doi.org/10.1007/s12026-026-09812-z
  41. Precis Clin Med. 2026 Sep;9(3): pbag020
    Natural killer cells against viral infection: from basic biology to immunotherapy.
    Zicheng Zhang, Fangjie Wang, Rongjiao Liu, Lei Tian, Liang Cai, Youcai Deng.
      Natural killer (NK) cells, a pivotal component of the innate immune system, exert indispensable roles in antiviral immunity by directly eliminating virus-infected cells and modulating adaptive immune responses. This review systematically synthesizes the biological characteristics of NK cells and their multifaceted functions against viral infections. The bidirectional crosstalk between NK cells and viruses is elucidated, with a focus on NK cell adaptive features and viral evasion strategies during specific viral infections. Furthermore, potential therapeutic targets and cutting-edge immunotherapeutic strategies due to modulation of NK cell activities are summarized, including monoclonal antibodies, chimeric antigen receptor-modified NK cells, and adjuvant therapy with Chinese herbal medicines. Recent clinical evidence and preclinical advances are integrated to provide a comprehensive framework for understanding NK cell-mediated antiviral immunity, identifying novel insights to guide the development of precise, effective immunotherapies for combating refractory viral infections.
    Keywords:  immunotherapy; natural killer (NK) cells; viral infection
    DOI:  https://doi.org/10.1093/pcmedi/pbag020
  42. Med Res Rev. 2026 Aug 02.
    Hepatotoxicity in the Era of Precision Medicine: Toxicological Mechanisms and Management of Immune and Cell Therapy-Induced Liver Injury.
    Yujian Fan, Xiaokai Guo, Jiaying Lyu, Xinyu Wang, Fanjie Xu, Junzhen Yan, Yisheng He.
      Immune checkpoint inhibitors and adoptive cell therapies have revolutionized cancer treatment, yet their success is accompanied by immune-related hepatotoxicity that can range from asymptomatic enzyme elevation to life-threatening liver failure. Unlike conventional drug-induced liver injury, immune-mediated hepatotoxicity arises from complex, therapy-specific mechanisms that remain incompletely understood, creating critical knowledge gaps in risk prediction and prevention. This review incorporates current evidence on the clinical presentation, mechanistic pathways, and risk factors underlying hepatotoxicity across major immune and cell therapy platforms, with emphasis on translating mechanistic insights into actionable management strategies. We systematically examine hepatotoxicity patterns for immune checkpoint inhibitors, CAR-T cell therapies, bispecific T-cell engagers, and tumor-infiltrating lymphocyte therapy, integrating clinical trial data, real-world evidence, and mechanistic studies. Our analysis shows distinct injury mechanisms: T-cell-mediated hepatocyte destruction following checkpoint blockade, cytokine-driven bystander injury during cytokine release syndrome, and emerging on-target/off-tumor toxicity from engineered lymphocytes. Critical risk modifiers include pre-existing liver disease, concomitant hepatotoxic medications, gut microbiome dysbiosis from antibiotic exposure, and host pharmacogenomic variation. We propose three priority research directions: development of predictive biomarkers enabling pretreatment risk stratification, microbiome-directed interventions to preserve hepatic immune tolerance, and implementation of Safety-by-Design engineering strategies that integrate hepatotoxicity prevention into therapeutic design. This review provides a mechanistic framework for transitioning from reactive toxicity management to predictive, personalized prevention, essential for maximizing the therapeutic potential of immune and cell therapies while protecting patient safety in this rapidly expanding treatment landscape.
    Keywords:  CAR‐T cell therapy; drug‐induced liver injury; hepatotoxicity; immune checkpoint inhibitors; immune‐related adverse events
    DOI:  https://doi.org/10.1002/med.70093
  43. Front Oncol. 2026 ;16 1882680
    Targeting regulatory T cell plasticity in gastric cancer: a unified bimodal model and precision immunotherapy paradigm: a hypothesis-generating review.
    PengFei Zhou, DanYa Wang, HaiYa Zhang, FengLin Zhang, ZhiTong Li, HongQing Xi.
      In contrast to other solid tumors, gastric cancer exhibits a particularly high dependence on regulatory T cell (Treg)-mediated immunosuppression. This reliance represents a critical driver of both primary and acquired resistance to programmed death-1/ligand-1(PD-1/PD-L1) inhibitors. By integrating existing single-cell, spatial transcriptomic, and clinical evidence, this review proposes a unified bimodal model of the Treg tumor microenvironment. Within this framework, the immune status in gastric cancer is determined by the dynamic equilibrium between immunosuppressive stable-type Tregs and pro-inflammatory fragile-type Tregs. H. pylori is posited as the master upstream regulator of this balance, capable of driving Treg differentiation toward either stability or fragility through temporally specific signaling pathways. Based on this framework, we introduce the Treg Stability-Fragility(Treg-SF) score, which incorporates Treg functional state, H. pylori infection status, and CD8+T cell density as independently weighted variables within a unified model to predict immunotherapy efficacy. Furthermore, this review outlines three mechanism-based combination therapeutic strategies that target Treg plasticity, along with a detailed preclinical validation roadmap and risk-benefit analysis. These proposals provide an actionable translational roadmap to overcome Treg-mediated immune resistance and improve clinical outcomes in gastric cancer.
    Keywords:  Treg cell; fragile-like Treg; gastric cancer; immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2026.1882680
  44. Cancer Discov. 2026 Aug 03. 16(8): 1486-1488
    A Counterintuitive Approach to Cancer Therapy.
    René Bernards.
      Ever since immune checkpoint blockade showed activity in the treatment of cancer, the search has been on for combination regimens that make this therapy more effective. In this issue, Blagg and colleagues describe an unorthodox approach to increasing the effectiveness of cancer immunotherapy. See related article by Blagg et al., p. 1649.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-1039
  45. Front Med (Lausanne). 2026 ;13 1841937
    Critical complications in cancer patients admitted to the ICU in the era of immunotherapy: recognition, differential diagnosis, and management.
    Di Wang, Min Yu.
       Background: Immunotherapy has introduced a new spectrum of ICU-relevant complications in patients with cancer, including hyperinflammatory syndromes, neurotoxicity, severe pneumonitis, myocarditis, and overlapping infectious complications.
    Objective: To review the major life-threatening complications of cancer immunotherapy from an ICU perspective, focusing on recognition, differential diagnosis, and management.
    Content: We discuss the critical illness patterns associated with CAR-T therapy, immune checkpoint inhibitors, and bispecific T-cell engagers using a syndrome-based framework. Key topics include cytokine release syndrome and HLH/MAS, immune effector cell-associated neurotoxicity syndrome, respiratory failure related to pneumonitis and infection, cardiovascular emergencies such as myocarditis and arrhythmias, and other less common but ICU-relevant organ toxicities. We also summarize the major diagnostic conflicts in the ICU and propose general principles for organ support, immunomodulatory therapy, infection management, and multidisciplinary care.
    Conclusion: Immunotherapy-related critical illness is increasingly relevant in modern oncologic intensive care. Because these syndromes are often clinically overlapping yet potentially reversible, optimal management requires early ICU escalation, parallel diagnostic reasoning, and integrated supportive and syndrome-directed treatment.
    Keywords:  ICU; adverse effects; clinical complications; immunotherapy; toxicity
    DOI:  https://doi.org/10.3389/fmed.2026.1841937
  46. J Cell Biol. 2026 Oct 05. pii: e202506119. [Epub ahead of print]225(10):
    Super-resolution imaging reveals altered actin architecture at CAR-T cell immune synapses.
    Olivia P L Dalby, Efstratios Kirtsios, Hale-Seda Radoykova, Cecilia Zaza, Megan D Joseph, Persis J Amrolia, Alice Giustacchini, Sabrina Simoncelli.
      The actin cytoskeleton plays a key integrative role in immunological synapse (IS) formation during T cell activation, but how these dynamics are altered in chimeric antigen receptor (CAR)-T cells remains unclear. Here, we used stimulated emission depletion (STED) microscopy to perform the first super-resolution analysis of actin remodeling at the IS in single- and dual (CD19/CD22) CAR-T cells, activated on supported lipid bilayers across different time points. Quantitative imaging reveals that CAR-T cells form structurally distinct synapses to untransduced cells, characterized by reduced actin-depleted regions, fewer actin foci, and persistent microvilli-like protrusions. These features indicate incomplete cytoskeletal contraction and impaired actin network reorganization, leading to partial synapse maturation. Our findings highlight fundamental differences in actin dynamics between CAR- and TCR-mediated signaling and suggest that defective actin remodeling may contribute to unstable synapse formation, altered signaling integration, and dysregulated responses or off-target effects. These insights could inform future CAR-T engineering strategies to enhance safety and efficacy.
    DOI:  https://doi.org/10.1083/jcb.202506119
  47. Adv Healthc Mater. 2026 Aug 06. e71544
    Nanomaterial Strategies for Pulmonary Delivery of Immunotherapeutics in Lung Cancer Treatment.
    Han Zhang, Wei Tang.
      Organ-selective immunomodulation is increasingly viewed as a route to improve the therapeutic index of cancer immunotherapy, yet most agents are still delivered systemically, where limited tumor exposure and immune-related toxicities remain common. The lung is an attractive site for local intervention because it is directly accessible and immunologically specialized. However, effective pulmonary delivery is constrained by mucociliary clearance, airway mucus, alveolar macrophage uptake, and epithelial barriers. Nanomaterials can be rationally engineered to address these constraints, increasing pulmonary retention and concentrating immunotherapeutics within the lung tumor microenvironment while reducing systemic burden. This Review summarized the key physiological barriers for pulmonary immunotherapeutic delivery and discusses how nanomaterial properties shape deposition, retention, cellular partitioning, and downstream immune activation. We critically evaluate representative inhalable platforms across major immunotherapeutic modalities, including vaccines, immune checkpoint blockade, innate immune agonists (e.g., STING agonists), cytokine regulation, and emerging in situ immune-cell engineering strategies. We also highlight translational considerations. Together, these advances support inhalable immunotherapeutic nanomedicines as a complementary approach to current lung cancer treatment and a broader framework for pulmonary immune modulation.
    DOI:  https://doi.org/10.1002/adhm.71544
  48. Value Health. 2026 Aug 06. pii: S1098-3015(26)02567-2. [Epub ahead of print]
    Reframing NICE's Cost-Effectiveness Threshold: Technical Benchmark or Policy Signal? A Documentary Content Analysis.
    Hesam Ghiasvand, Seyran Naghdi.
       OBJECTIVES: To examine how governmental, industry, academic, consultancy, journalistic, and international health technology assessment (HTA) stakeholders framed the cost-effectiveness threshold (CET) uplift announced for the National Institute for Health and Care Excellence (NICE) in December 2025 during the early phase of policy debate.
    METHODS: A qualitative documentary content analysis was conducted using the READ framework. Twenty-seven publicly available documents published between October 2025 and March 2026 were purposively sampled across government, NICE, industry, academia, consultancy, journalism, civil society, and international HTA actors. Data were analysed through iterative coding and thematic synthesis.
    RESULTS: The 2025-2026 debate extended beyond technical discussions of cost-effectiveness and revealed five interrelated themes. First, government documents explicitly reframed the CET as an instrument of industrial policy, economic growth, and pharmaceutical competitiveness. Second, substantial disagreement emerged regarding HTA governance and ministerial involvement in threshold-setting. Third, stakeholders advanced competing interpretations of the consequences of the reform, with government and industry emphasising innovation access, while academic and public-interest sources highlighted opportunity costs, service displacement, and population-health impacts. Fourth, many documents situated the reform within broader geopolitical and pharmaceutical-policy dynamics, including trade negotiations, investment incentives, and potential international spillovers. Finally, stakeholders expressed contrasting views regarding transparency, consultation, and procedural legitimacy.
    CONCLUSIONS: The NICE threshold uplift was framed as a politically mediated reform with implications for industrial strategy, HTA governance, healthcare resource allocation, and public trust. The findings demonstrate how cost-effectiveness thresholds can become sites of broader political, economic, and institutional contestation, extending beyond their conventional role within health economic evaluation.
    Keywords:  NICE; cost-effectiveness threshold; health policy; health technology assessment; opportunity cost; pharmaceutical policy
    DOI:  https://doi.org/10.1016/j.jval.2026.07.004
  49. JAMIA Open. 2026 Aug;9(4): ooag160
    Validating medical digital twins for clinical decision support: beyond predictive accuracy.
    Alexandre Vallée.
       Objective: To clarify how validation requirements should be specified for medical digital twins used in clinical decision support, particularly when such systems are intended to compare interventions, treatment timings, dosages, or sequential care strategies.
    Perspective: Medical digital twins are heterogeneous systems that may combine prediction, simulation, mechanistic modeling, machine learning, data assimilation, uncertainty quantification, and decision-support functions. Their evaluation should therefore be driven by their intended use rather than by a single definition of what a digital twin is. For digital twins used primarily for visualization, monitoring, or short-term forecasting, predictive accuracy, calibration, discrimination, and robustness may be the central validation targets. However, when digital twins are used to support intervention-oriented clinical decisions, retrospective accuracy under historical clinical practice is insufficient on its own.
    Key message: Intervention-oriented digital twins address action-conditioned questions: what is predicted to happen under specified alternative actions, assumptions, time horizons, and clinical contexts. Their validation should therefore extend beyond scalar performance metrics to include uncertainty representation, updating stability, robustness under regime change, action-regime validity, counterfactual consistency, clinically weighted error, and decision-level consequences. This requires drawing on established traditions in forecast verification, causal inference, uncertainty quantification, model verification and validation, decision theory, control theory, and post-deployment monitoring. The level of causal or mechanistic support required should match the clinical claim being made, whether at the genotype, phenotype, physiological, or care-process level.
    Conclusion: The scientific-instrument framing is proposed as a pragmatic validation lens for intervention-oriented digital twins, not as a universal definition of digital twins. It helps define the scope within which their outputs can support clinical reasoning. Medical digital twins should be accompanied by explicit validation statements specifying their target population, prediction horizon, supported interventions, uncertainty bounds, and known failure conditions.
    Keywords:  causal inference; counterfactuals; digital twin; dynamical systems; epistemology; falsifiability; precision medicine; regulatory science; uncertainty; validation
    DOI:  https://doi.org/10.1093/jamiaopen/ooag160
  50. Adv Sci (Weinh). 2026 Aug 05. e76983
    TSTScope Unifies Single-Cell Multi-Omics to Identify Functional T Cell States Predictive of Immunotherapy Response.
    Shiwei Cao, Jinyu Cheng, Feng-Ao Wang, Chenxin Yi, Jiajun Chen, Keyue Wang, Lulu Liu, Junwei Liu, Yixue Li.
      Immune checkpoint blockade (ICB) can produce durable responses in cancer, but reliable predictors of benefit are still lacking. CD8+ tumor-specific T cells (TSTs) are essential for ICB efficacy, yet it remains unclear which functional states of these cells are associated with therapeutic benefit. To address this, we developed TSTScope, an interpretable deep learning framework that integrates single-cell transcriptomic and T-cell receptor sequencing data to generate unified representations of CD8+ T-cell identity. By applying TSTScope to non-small cell lung cancer (NSCLC) datasets, we characterized the gene programs defining tumor specificity and computationally inferred a population of potential TSTs (pTSTs). Our analyses show that clinical response is associated with the functional state of these cells rather than their abundance alone. We derived the major pathological response (MPR) score, a metric capturing this functional potential. In an independent validation cohort, the MPR score was associated with pathological response and recurrence-free survival and provided complementary information to selected response-associated biomarkers. Collectively, TSTScope identifies a distinct functional state of tumor-specific T cells linked to ICB response, providing an interpretable framework for studying receptor-linked T-cell function in immunotherapy cohorts.
    Keywords:  biology; blockade; cancer; cd8; computational biology; immune checkpoint; immunotherapy; lung cancer; t cell; transcriptome
    DOI:  https://doi.org/10.1002/advs.76983
  51. Methods Mol Biol. 2026 ;3009 129-151
    Antibody Conjugation to Cell Surface Receptors.
    Avani Parikh, Elisa Ruffo, Alexander Deiters, Jason Lohmueller.
      Here, we describe the covalent modification of cell surfaces with antibodies through bioconjugation to the self-labeling SNAP-tag enzyme. We apply this approach to the reprogramming of T cell signaling through the universal chimeric antigen receptor (CAR), "SNAP-CAR." Universal CARs are a highly programmable class of engineered receptors that interact with co-administered "adaptor" antibodies to recognize one or more antigens of interest to trigger receptor signaling. Universal CARs have promise for use in cell therapeutics and as research tools. SNAP-CAR covalently attaches to adaptor antibodies containing a benzyl guanine (BG) motif. The protocols presented here include methods for SNAP-CAR T cell and antibody adaptor generation using gamma retroviral transduction and BG-NHS ester conjugation, respectively. The chapter also describes methods to evaluate cell surface bioconjugate formation, including quantification of BG motifs on antibodies and co-incubation experiments to assay for antigen-directed SNAP-CAR T cell functions of target cell killing and SNAP-CAR T cell activation.
    Keywords:  Antibody conjugation; Antibody therapeutics; CAR T cell therapy; Synthetic biology; Universal CAR T cells
    DOI:  https://doi.org/10.1007/978-1-0716-5112-4_9
  52. Clin Transl Sci. 2026 Aug;19(8): e70686
    Empowering Clinical Development With Disease Progression Modeling: Recommendations From the Clinical Trials Transformation Initiative.
    Lindsay S Kehoe, Shu Chin Ma, Jiang Liu, Qi Liu, Herbert Pang, Bruce Burnett, Reem Yunis, Karthik Venkatakrishnan.
      Evaluating the benefit-risk profile of a medical product requires comprehensive evidence that integrates information across development stages. Technological advances and broader use of real-world data are enabling innovative quantitative paradigms characterized by greater efficiency, patient centricity, and sustainability. Despite regulatory recognition of model-informed drug development, disease progression modeling (DPM) remains underutilized compared with more established pharmacokinetic/pharmacodynamic modeling and simulation approaches. To inform adoption decisions by clinical, regulatory, and portfolio leaders, the Clinical Trials Transformation Initiative (CTTI) developed evidence-based, cross-sector recommendations that describe when and how to use DPM in medical product development and how to effectively communicate its impactful implementation across functions. In this article, we (i) define DPM and summarize its unique value in clinical development, (ii) describe CTTI's collaborative process to generate a set of nine DPM recommendations and a practical considerations framework, and (iii) present examples of strategic development questions showing how DPM can answer high-value questions about indication, population, endpoints, and dose selection. By providing a shared vocabulary and structured questions for decision makers and modelers, these recommendations may lower barriers to DPM implementation, support fit-for-purpose use of existing and new models, and enable more efficient, patient-focused, and sustainable clinical development.
    Keywords:  clinical trials; disease progression model; model‐informed drug development
    DOI:  https://doi.org/10.1111/cts.70686
  53. Ther Adv Med Oncol. 2026 ;18 17588359261472319
    Long-term complete remission following treatment with polatuzumab vedotin, rituximab, and bendamustine in a patient with mantle cell lymphoma relapsing after CAR-T cell therapy: a case report.
    Vincent Sunder-Plassmann, Barbara Kiesewetter, Markus Raderer.
      Mantle cell lymphoma (MCL) remains an incurable B-cell malignancy despite major advances in its therapeutic management. While Bruton tyrosine kinase inhibitors (BTKi) and, more recently, CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy have significantly improved outcomes in relapsed or refractory MCL, relapse after CAR-T therapy is associated with a dismal prognosis and represents a major therapeutic challenge. Here, we report the case of a 43-year-old male diagnosed with stage IV common-type MCL, who achieved long-term complete remission (CR) after treatment with polatuzumab vedotin, rituximab, and bendamustine (Pola-R-Benda) following relapse after CAR-T therapy. The patient had previously received standard first-line immunochemotherapy (R-CHOP alternating with R-DHAP) and autologous stem-cell transplantation, resulting in durable CR, followed by ibrutinib at first relapse in 2017 with sustained remission until 2021. Eleven months after CAR-T therapy with brexucabtagene autoleucel, the patient experienced systemic relapse. Enrollment into a Pola-R-Benda clinical protocol resulted in complete metabolic remission after three cycles, confirmed by positron emission tomography/computer tomography. Treatment was well tolerated except for mild grade 2 diarrhea. The patient remains in ongoing CR >20 months after initiation of Pola-R-Benda. To our knowledge, this is among the first reports of long-term remission with Pola-R-Benda following CAR-T failure in MCL, suggesting that antibody-drug conjugate-based therapy may represent an effective salvage option in this highly refractory clinical setting.
    Keywords:  case report mantle cell lymphoma; polatuzumab vedotin; salvage treatment
    DOI:  https://doi.org/10.1177/17588359261472319
  54. Front Immunol. 2026 ;17 1752840
    Frontier research and clinical application prospects of microbiome biomarkers in autoimmune diseases.
    Qianqian He, Pinjun Zhang, Zhenni Chen, Chengping Wen, Mingzhu Wang.
      The microbiome is increasingly recognized as a master regulator of immune homeostasis and a key environmental factor associated with the pathogenesis of autoimmune diseases (ADs). This review comprehensively synthesizes current knowledge on how microbial communities and their metabolites may contribute to ADs' development through microbial-immune interactions, dysbiosis, and the involvement of viral and fungal components within an integrated inter-kingdom ecosystem. We propose an operational definition of microbiome biomarkers as measurable microbiome-associated features reflecting disease susceptibility, activity, prognosis, or therapeutic response and categorize them into three classes: taxonomic, functional/metabolic, and host-microbiome interaction-derived biomarkers. We critically evaluate the evidence for specific microbial signatures as biomarkers for early diagnosis, disease monitoring, and prediction of therapeutic responses, incorporating evidence grading that distinguishes validated biomarkers from those that remain exploratory and discussing shared versus disease-specific signatures across ADs. The translational potential of microbiome-targeted interventions, including probiotics, prebiotics, and fecal microbiota transplantation, is examined within a personalized medicine framework, with barriers to clinical implementation explicitly addressed. Key confounding factors such as diet, geographic origin, and medication use are highlighted as critical variables shaping microbiome signatures independently of disease. Looking forward, the convergence of multi-omics technologies and artificial intelligence for biomarker discovery, multi-omics integration, and clinical validation promises to unravel the complex microbiome-immune crosstalk, enabling more accurate diagnosis, prognostic stratification, and ultimately, individualized microbiota-informed therapy.
    Keywords:  autoimmune diseases; biomarkers; clinical translation; microbiome; precision medicine
    DOI:  https://doi.org/10.3389/fimmu.2026.1752840
  55. Front Bioeng Biotechnol. 2026 ;14 1866928
    Directed evolution of chlorotoxin enhances MMP-2 recognition and improves CAR-T-cell activity in glioblastoma models in vitro.
    Anna Hajdara, Árpád Szöőr, József Murányi, Attila Brunyánszki, Gábor Z Rácz, Daniel Cioca, Ambrus Gordos, Natali Bata, Noémi Nagy, Imre Fedorcsák, László Sipos, Máté Kisgyörgy, Márton Megyeri, Zalán Péterfi, Sándor Farkas, Péter Hornyák.
       Background: Cysteine-rich miniproteins from venomous animals are promising therapeutic scaffolds due to their compact structure, high stability, and low immunogenicity. Chlorotoxin (CTX), a miniprotein derived from scorpion venom, selectively targets glioblastoma by binding matrix metalloproteinase-2 (MMP-2), an invasion-associated enzyme overexpressed in ∼80% of glioblastomas. CTX has been utilized in tumor imaging, drug delivery, and immunotherapy, including its incorporation into chimeric antigen receptor (CAR) constructs. CTX-based CAR show potent MMP-2-dependent cytotoxicity in glioblastoma models. We hypothesized that affinity maturation of CTX via phage display could enhance MMP-2 binding and improve CAR T-cell performance.
    Methods: A CTX-based phage display library (∼1.3 million variants) was screened against immobilized MMP-2. A lead variant, CTXA8, was recombinantly expressed and tested for binding specificity against a panel of off-target proteins. Its cellular uptake and localization were evaluated, followed by incorporation into CAR constructs in both single-unit and tandem formats (eCTXA8-CAR). The cytotoxicity of CTX-, CTXA8-, and eCTXA8-CAR T cells was assessed against glioblastoma cell lines and primary patient-derived tumor cells.
    Results: Screening identified CTXA8, which demonstrated a 4.4-fold increase in MMP-2 affinity and reduced off-target binding relative to CTX. Fluorescent CTXA8 showed 2.4-3.5-fold greater uptake in glioblastoma cells than CTX. Among the CAR constructs tested, eCTXA8 induced the highest IFN-γ release. eCTXA8-CAR T-cells consistently outperformed CTX-CAR and non-transduced T cells in cytotoxicity assays, especially at low effector-to-target ratios.
    Conclusion: This study demonstrates that directed evolution of CTX can produce high-affinity, selective MMP-2 ligands suitable for next-generation CAR T-cell therapies. CTXA8-based CARs offer enhanced anti-tumor efficacy, supporting their potential in overcoming challenges in solid tumor immunotherapy.
    Keywords:  CAR T-cell; MMP-2; chlorotoxin; glioblastoma; phage display; protein engineering
    DOI:  https://doi.org/10.3389/fbioe.2026.1866928
  56. Drug Discov Today. 2026 Aug 06. pii: S1359-6446(26)00165-0. [Epub ahead of print] 104760
    Drug type contributions to pharmaceutical innovation: A USA-China comparative analysis.
    Michael S Kinch, Aayan Alwani, Tyler Schwartz, Zachary Kraft.
      An analysis of experimental medicines entering clinical trials from 2000 to 2024 reveals divergent patterns of development activity between the USA and China. Whereas China's ascent was consistent in the most common therapeutic category: small molecules, its rise was most pronounced in biologics-oriented categories, particularly cell therapy and monoclonal antibodies. By contrast, the USA retained comparatively greater shares in emerging modalities such as nucleic acid therapeutics and gene therapy. These findings add resolution to the phenomenon of Chinese near-parity with the USA in overall pharmaceutical output. The convergence is not uniform across modalities but instead reflects differential growth by drug type. Causal attribution of these patterns to specific policy or investment decisions warrants further investigation.
    Keywords:  China; Drug discovery; USA; biologic; cell therapy; clinical trial; drug type; gene therapy; innovation; small molecule
    DOI:  https://doi.org/10.1016/j.drudis.2026.104760
  57. Clin Pharmacol Ther. 2026 Aug 06.
    Operationalizing Precision Medicine in Drug Development: Predictive Biomarkers, Companion Diagnostics, and Regulatory Pathways.
    Ingrid Holst-Laubjerg, José M A Moreira.
      Precision medicine offers the opportunity to improve the benefit-risk profile of new therapies by prospectively identifying patients most likely to respond or least likely to experience harm; however, its systematic integration into drug development remains inconsistent outside oncology. Key barriers include timely generation of robust predictive biomarker hypotheses (i.e., hypotheses regarding treatment-by-biomarker interactions), appropriate validation strategies, and coordinated development of companion diagnostics within increasingly complex FDA, European Medicines Agency, and In Vitro Diagnostic Regulation regulatory frameworks. This review presents a pragmatic operational framework to guide the incorporation of precision medicine into drug development across therapeutic areas. We outline structured approaches for early biomarker hypothesis generation and prephase II evidence development; define five clinical development scenarios based on the strength of the biomarker signal-front-loaded enrichment, precision-medicine-enabled phase II, adaptive phase II, adaptive phase III, and back-loaded confirmatory enrichment; and summarize regulatory and lifecycle considerations for companion diagnostics. Examples from oncology and emerging applications in cardiovascular and metabolic diseases illustrate evolving regulatory expectations and common industry challenges. We also discuss opportunities to extend precision medicine beyond predictive biomarkers to diagnostic, prognostic, and safety biomarkers, as well as digitally derived signatures. Treating precision medicine as a core component of drug development-rather than an optional enhancement-can improve clinical trial efficiency, support commercial viability, and ensure that patients derive meaningful clinical benefit. Early, structured biomarker planning; integrated clinical-diagnostic strategies; and iterative collaboration among sponsors, regulators, HTA bodies, payers, and patients are critical for translating biomarker insights into de-risked pivotal trials and aligned regulatory and market-access decisions.
    DOI:  https://doi.org/10.1002/cpt.70423
  58. Int J Technol Assess Health Care. 2026 Aug 07. 42(1): e69
    Surrogate endpoints in cost-effectiveness analysis for use in health technology assessment - a qualitative analysis.
    Laura Flight, Fatima Salih, Shane D Collins, Phyo Aung, Michael Coory, Daniel A Ollendorf, Marina Richardson, Zoe Garrett.
       OBJECTIVES: The use of surrogate endpoints poses challenges to health technology assessment (HTA) agencies and payers when informing the clinical and cost-effectiveness of health technologies. Decision makers often need to make recommendations in the absence of well-established evidence on their validation, particularly when the surrogate endpoint is novel without clear links to the longer-term outcome. This study explored the guidance needs of HTA agencies and identified how they have considered and dealt with surrogate endpoints in cost-effectiveness analysis.
    METHODS: A qualitative study was used to explore the professional experiences of international HTA staff and their collaborators. Data were collected using three focus groups with 29 participants representing 20 HTA agencies or associated organizations. Framework analysis was used to identify themes from the transcripts.
    RESULTS: HTA agencies frequently see submissions featuring surrogate endpoints. Issues they face include definitional concerns, absent or weak evidentiary links, and resource-intensive validation methods. Versatile guidance that is mindful of these challenges, such as those faced with rare diseases, is required. This would help to clarify expectations and help ascertain the required information from industry for economic modeling, on how to present the uncertainty arising from surrogate endpoints, and how to appropriately report the findings.
    CONCLUSIONS: Decision making using surrogate endpoints is a frequent and challenging problem faced by HTA agencies. These results provide the first-hand experiences and reflect the needs of HTA agencies globally. The resulting recommendations and considerations for the use of surrogate endpoints in economic modeling should benefit HTA agencies moving forward.
    Keywords:  health economic model; health technology assessment; surrogate endpoint; surrogate outcome
    DOI:  https://doi.org/10.1017/S0266462326103791
  59. Front Artif Intell. 2026 ;9 1882814
    The VIBE-HI framework: a conceptual model for evaluating vibe coding appropriateness, quality, and safety in health informatics.
    Ahmed Alqheedan, Saleh Alzughaibi.
       Background: Vibe coding-generating software through natural-language prompts to large language models without reviewing the underlying code-has moved rapidly from consumer technology into peer-reviewed clinical applications. By early 2026, clinicians had published vibe-coded teaching tools, a validated clinical nomogram, and an end-to-end omics platform built in under 10 minutes for under two dollars. Collins Dictionary named vibe coding its 2025 Word of the Year. No governance framework currently addresses the practice in healthcare.
    Objective: To introduce VIBE-HI, a health-informatics-specific framework for evaluating the appropriateness, quality, and safety of vibe coding across clinical contexts, and to specify its decision logic, quality constructs, and regulatory mapping in operational detail.
    Methods: VIBE-HI was developed as a conceptual framework through a structured, theory-informed narrative synthesis of three literatures-emerging biomedical vibe-coding reports, empirical software-engineering and security research on AI-generated code and established sociotechnical health-informatics theory and software-quality standards-following recognized conceptual-framework methodology. It was refined through illustrative application to four published clinician-built tools. This is a conceptual contribution; it is not a systematic review or a consensus (Delphi) study, and formal empirical validation is identified as the next step.
    Results: VIBE-HI organizes governance into three sequential layers. (1) Risk and Role Stratification assign one of four risk tiers-Green, Yellow, Orange, Red-and a matched clinician-developer role, from prototype to requirements analyst, using four criteria combined by an explicit dominant-criterion rule. (2) Quality and Validation extend ISO/IEC 25010:2023 with three measurable constructs-Code Provenance Transparency, Comprehension Coverage, and Hallucination Resilience-each with defined indicators and tier-dependent thresholds. (3) Compliance and Governance maps HIPAA, IEC 62304, FDA SaMD criteria, and the EU AI Act onto each tier and binds a named accountability owner. The framework treats comprehension abdication-the structural surrender of understanding to a generative system-as the core sociotechnical hazard distinguishing vibe coding from prior AI-assisted development, grounded in the automation-bias, responsibility-gap, and sociotechnical-systems literatures.
    Conclusion: Clinical vibe coding needs risk-stratified governance now, before largely invisible adoption outpaces the field's capacity to assess it. VIBE-HI offers an architecture institutions can apply immediately and provides a clear pathway for empirical validation, beginning with a modified-Delphi consensus study and stakeholder review.
    Keywords:  AI governance; clinical software safety; clinician-developers; comprehension abdication; health informatics; large language models; vibe coding
    DOI:  https://doi.org/10.3389/frai.2026.1882814
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