bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–09–28
twenty-one papers selected by
Luca Bolliger, lxBio
  1. Advances in Adoptive Cell Therapies in Cancer: From Mechanistic Breakthroughs to Clinical Frontiers and Overcoming Barriers.
  2. Natural killer cells in adoptive cell therapy: current landscape of genetic engineering strategies.
  3. To c or not to c-KIT?: High toxicity and modest efficacy in CD117-directed CAR T cell therapy.
  4. Chimeric Antigen Receptor Cell Therapy: Current Status and Its Potential in Aging and Alzheimer's Disease.
  5. Animal models in preclinical evaluation of CAR-T cell therapy: Advantages and limitations.
  6. Designing immunity with cytokines: A logic-based framework for programmable CAR therapies.
  7. A Scalable Protocol for Ex Vivo Production of CAR-Engineered Human NK Cells.
  8. Patient and carer experience of chimeric antigen receptor T-cell therapy: a multicentre qualitative study.
  9. CAR T cell-mediated bone marrow inflammation causes hematotoxicity and favors clonal hematopoiesis.
  10. Predictors of Neurotoxicity in a Large Cohort of Italian Patients Undergoing Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy.
  11. Second signals for cancer immunotherapy.
  12. CAR-T Cell Therapies in B-Cell Acute Lymphoblastic Leukemia: Emerging Data and Open Issues.
  13. Cell avidity in CAR-T cell therapy.
  14. Mechanisms of Resistance to CAR T-Cells and How to Overcome Them.
  15. The Emerging Roles and Therapeutic Potential of Unconventional T Cells in Sepsis.
  16. The Oncology Drug Shortages and Its Impact on Community Hospitals.
  17. Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment.
  18. A systematic review of the applications of the real option value of medical technologies in oncology.
  19. RNA virus and DNA virus initiations of autoimmune diseases and/or dementias.
  20. Innate iNKT cells: from biological insight to clinical impact.
  21. History and Evolution of Innovations in Clinical Pharmacology.
  1. Med Sci (Basel). 2025 Sep 15. pii: 190. [Epub ahead of print]13(3):
    Advances in Adoptive Cell Therapies in Cancer: From Mechanistic Breakthroughs to Clinical Frontiers and Overcoming Barriers.
    Syed Arman Rabbani, Mohamed El-Tanani, Yahia El-Tanani, Rakesh Kumar, Shrestha Sharma, Mohammad Ahmed Khan, Suhel Parvez, Alaa A A Aljabali, Mohammad I Matalka, Manfredi Rizzo.
      Adoptive cell therapies (ACTs) have revolutionized cancer treatment by harnessing the specificity and potency of T lymphocytes. Chimeric antigen receptor (CAR)-T cells have achieved landmark successes in B-cell malignancies and multiple myeloma. Tumor-infiltrating lymphocytes (TILs) and T-cell receptor (TCR)-engineered T cells offer complementary strategies to target solid tumors and intracellular antigens. Despite these advances, ACTs face challenges including cytokine release syndrome, neurotoxicity, on-target/off-tumor effects, manufacturing scalability, and immunosuppressive tumor microenvironments. Innovative strategies, such as dual-antigen targeting, localized delivery, checkpoint blockade combinations, gene-editing, and machine-learning-guided antigen discovery, are being used to mitigate toxicity, enhance efficacy, and streamline production. As CAR-T, TIL, and TCR modalities converge with advances in manufacturing and computational biology, the next generation of "living drugs" promises broader applicability across hematologic and solid tumors, improved safety profiles, and better treatment outcomes for patients. This review details the evolution of ACTs from first-generation CAR constructs to next-generation "armored" designs. It also focuses on the development and clinical deployment of TIL and TCR therapies. Furthermore, it synthesizes mechanisms, pivotal clinical trial outcomes, and ongoing challenges of ACTs. It also highlights strategies that will drive broader, safer, and more durable applications of these therapies across hematologic and solid tumors.
    Keywords:  CAR; T cell; adoptive cell therapy; immunotherapy; multiple myeloma; solid tumors; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.3390/medsci13030190
  2. Oncoimmunology. 2025 Dec;14(1): 2563099
    Natural killer cells in adoptive cell therapy: current landscape of genetic engineering strategies.
    María Burón, Anne Etxebarria, Maite Álvarez, Irene Romayor, Cristina Eguizabal.
      Among adoptive cell-based immunotherapies, chimeric antigen receptor (CAR) therapy has shown promising results in cancer treatment. Treatment with CAR-T cells has produced remarkable clinical responses, especially in cases of relapsed and refractory leukemia and lymphoma. However, CAR-T cell therapy still presents several limitations, including some safety concerns related to neurotoxicity and aggressive inflammatory responses. As an alternative to T-cells, natural killer (NK) cells have been developed as an attractive option for efficient cancer immunotherapy. As they do not express T cell receptor (TCR), NK cell-based therapies are not associated with cytokine release syndrome (CRS) or graft versus host disease (GvHD), which enables a safer therapy and the ability to generate an allogeneic "off-the-shelf" product. Despite the innate cytotoxic activity of NK cells against malignant cells, the therapeutic application of unmodified NK cells has been compromised by the inhibitory tumor microenvironment (TME), which is responsible for poor cell expansion, inactivation, insufficient tumor infiltration, and limited in vivo persistence, leading to the dysfunction of NK cells after infusion. Advances in the genetic modification of NK cells can address some of these limitations and improve their therapeutic efficacy. In this review, we describe the advances in the development of engineered NK cells for cancer immunotherapy. As such, we provide an overview of recent viral and non-viral approaches for the genetic modification of NK cells. We also discuss their current clinical status in the field of immunotherapy, and their use in other clinical applications.
    Keywords:  Natural killer cells; chimeric antigen receptor (CAR); genome engineering; immunotherapy; non-viral transfection; viral transduction
    DOI:  https://doi.org/10.1080/2162402X.2025.2563099
  3. Mol Ther. 2025 Sep 20. pii: S1525-0016(25)00749-X. [Epub ahead of print]
    To c or not to c-KIT?: High toxicity and modest efficacy in CD117-directed CAR T cell therapy.
    Isaac Gannon, Claire Roddie, Alex Rampotas.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2025.09.021
  4. Int J Mol Sci. 2025 Sep 16. pii: 9009. [Epub ahead of print]26(18):
    Chimeric Antigen Receptor Cell Therapy: Current Status and Its Potential in Aging and Alzheimer's Disease.
    Maria Carolina Jurcau, Carina Diana Iovanovici, Anamaria Jurcau, Marius Militaru, Radu Bogdan Udrea, Alexandra Comanescu, Vharoon Sharma Nunkoo.
      With an aging population, there is a worldwide increase in the prevalence of neurodegenerative diseases. Alzheimer's disease (AD) is the most prevalent form of dementia. Research focusing on aging has revealed a time-related accumulation of senescent cells that escape the cell cycle but remain metabolically active and spread the senescent traits to neighboring cells via the senescence-associated secretory phenotype. The accumulated senescent cells in various tissues are involved in the pathogenesis of several age-related conditions. As such, eliminating them would be an appealing anti-aging strategy. Following the high success rates of engineered chimeric antigen receptor (CAR)-T cells in hematological malignancies, the scientific community has tried to adapt the strategy to fight aging and age-related diseases. Research in this area is only in its infancy, but the results obtained from in vitro and animal models are encouraging. Due to the serious side effects of CAR-T cell therapies (cytokine release syndrome, immune cell-associated neurological syndrome) and because in AD the elimination of neurons with neurofibrillary tangles and amyloid aggregates should be avoided (given the limited regenerative potential of these cells), CAR macrophages, CAR regulatory T cells, or exosomes derived from these cells are a more promising approach.
    Keywords:  Alzheimer’s disease; CAR constructs; CRS; ICANS; NK cells; aging; immunosenescence; lymphocytes; macrophages; neuroinflammation
    DOI:  https://doi.org/10.3390/ijms26189009
  5. Biochim Biophys Acta Rev Cancer. 2025 Sep 18. pii: S0304-419X(25)00197-0. [Epub ahead of print]1880(6): 189455
    Animal models in preclinical evaluation of CAR-T cell therapy: Advantages and limitations.
    Lasse von Bornemann Fløe, Maya Graham Pedersen, Bjarne K Møller.
      Chimeric Antigen Receptor T (CAR-T) cell therapy is a promising new treatment category. Animal models have played a pivotal role in advancing CAR-T cell therapy. However, no animal model fully replicates human physiology, leading to unsuccessful translation from preclinical models to clinical trials. Understanding the advantages and limitations of various animal model choices requires insight into CAR-T cell mechanisms and their interactions across experimental contexts. CAR-T cell immunobiology differs between animal models and humans. This disparity is reflected in the limited translational capacity of pharmacological parameters and the absence of key immunological interactions in animal models compared to those seen in human trials. Additionally, the antigen specificity of the CAR introduces translational limitations. Differences in antigen density and expression among different cellular populations across species are critical factors to consider when interpreting preclinical results. Xenoreactivity, stemming from the original T-cell receptor repertoire, also limits experimental duration and timing in mouse models. Modeling human cancer in animal models requires many considerations. Cancer heterogeneity varies significantly between patient-derived xenografts and cell-line-based xenografts. Syngeneic models more accurately mimic interactions between CAR-T cells and other immune components, while xenograft models better reflect human tumor antigen expression. Beyond CAR-T-specific challenges, issues with standardization and replication in animal studies affect the reliability of the results. Furthermore, ethical guidelines should guide experimental planning to minimize animal use and prioritize humane treatment. This review explores the strengths and limitations of animal models preclinical CAR-T cell therapy research, while offering critical considerations for interpreting results and designing experiments.
    Keywords:  Animal models; CAR-T cell therapy; Experimental limitations; Immunobiology; Translational research
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189455
  6. Cytokine Growth Factor Rev. 2025 Sep 18. pii: S1359-6101(25)00132-7. [Epub ahead of print]86 40-55
    Designing immunity with cytokines: A logic-based framework for programmable CAR therapies.
    Saurabh Upadhyay, Kirti Upmanyu, Moustafa T Gabr.
      Adoptive cellular immunotherapy has transformed cancer care, with chimeric antigen receptor (CAR) T cells achieving unprecedented remission in hematologic malignancies. Yet solid tumor translation remains limited by antigen escape, hostile microenvironments, and life-threatening toxicities. Cytokines and chemokines are central to these barriers, shaping trafficking, persistence, and toxicity in ways that demand engineered solutions. This review introduces the first unified five-layer framework-Recognition, Navigation, Safety, Persistence, and Translation-that organizes CAR engineering through cytokine and chemokine logic. Innovations include dual-target and logic-gated CARs to counter heterogeneity, hypoxia- and chemokine-responsive circuits to enhance infiltration, inducible safety switches to mitigate IL-6/IL-1β-driven cytokine storm, and IL-7/IL-15 support to extend persistence. Beyond T cells, CAR logic is now ported into NK cells and macrophages, complementing adaptive memory with innate cytotoxicity and stromal remodeling, while iPSC-derived effectors offer scalable, standardized production. Together, these advances reframe cellular immunotherapy as a cytokine-guided, programmable immune ecosystem, providing a conceptual roadmap for therapies engineered not only for potency but also for safety, durability, and broad clinical integration.
    Keywords:  Adoptive cell therapy; CAR-NK cells; CAR-T cells; Cancer immunotherapy; Cytokines; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cytogfr.2025.09.004
  7. Methods Protoc. 2025 Sep 05. pii: 102. [Epub ahead of print]8(5):
    A Scalable Protocol for Ex Vivo Production of CAR-Engineered Human NK Cells.
    Supreet Khanal, Nirjal Bhattarai.
      Chimeric antigen receptor-expressing NK (CAR-NK) cells represent an advancing frontier in cancer immunotherapy, building upon decades of natural killer cell research and recent breakthroughs in CAR technology. While early CAR-NK manufacturing protocols have demonstrated feasibility, existing manufacturing methods, whether utilizing cord blood or peripheral blood sources, often require extended culture periods and intensive labor, creating bottlenecks for widespread therapeutic application. To address these manufacturing hurdles, we have developed an optimized protocol for ex vivo CAR-NK cell production from human peripheral blood that incorporates lessons learned from previous methodologies while introducing novel efficiency improvements. This protocol offers a practical solution for scalable CAR-NK cell manufacturing that can be readily adapted across different production facilities, potentially accelerating the clinical development of CAR-NK therapies.
    Keywords:  CAR-NK; G-Rex; cell manufacturing; chimeric antigen receptor; expansion
    DOI:  https://doi.org/10.3390/mps8050102
  8. BMJ Support Palliat Care. 2025 Sep 26. pii: spcare-2025-005371. [Epub ahead of print]
    Patient and carer experience of chimeric antigen receptor T-cell therapy: a multicentre qualitative study.
    Laura Barnes, Charlotte Stenson, Jennifer Vidrine, Rachel Stocker.
       OBJECTIVES: Chimeric Antigen Receptor T-cell (CAR-T) therapy is a complex, novel treatment for patients with relapsed/refractory haematological malignancies. Despite its advancement, research on the supportive care needs of this patient group and their caregivers is limited. This study aimed to explore the experiences of patients undergoing CAR-T cell therapy and their caregivers and identify any unmet needs of this group.
    METHODS: This multicentre, qualitative, longitudinal study recruited nine patients and five caregivers from three UK CAR-T therapy centres. Semistructured interviews were carried out between October 2021 and October 2022 and conducted in three phases: within 3 weeks of leukapheresis, mid-treatment and within 4 weeks of the first positron emission tomography scan (performed at 28 days postinfusion to assess treatment response). Thematic analysis was used to analyse interview data.
    RESULTS: Thematic analysis identified five distinct themes: the rollercoaster journey to reach CAR-T; balancing hope, realism and resignation; navigating CAR-T side effects and their impact; barriers to addressing uncertainty; and the tapestry of support. Notably, a high symptom burden and unique treatment toxicities were evident, alongside the need to navigate an uncertain (yet potentially curative) disease trajectory. Support from a dedicated CAR-T nurse specialist was crucial, and the potential of further palliative/supportive care provision was underscored.
    CONCLUSION: The experience of CAR-T therapy is characterised by often unique symptom burden, uncertainty and resilience. It is vitally bolstered by the support of professionals and carers. There is evidence of missed opportunities to support patients and caregivers with the challenges of navigating an uncertain future, and 'parallel planning' conversations may be a way to meet this need. Future research should focus on the involvement of collaborative palliative/supportive care to support this patient group.
    Keywords:  Haematological disease; Palliative Care; Supportive care
    DOI:  https://doi.org/10.1136/spcare-2025-005371
  9. Sci Transl Med. 2025 09 24. 17(817): eadu9790
    CAR T cell-mediated bone marrow inflammation causes hematotoxicity and favors clonal hematopoiesis.
    Myriam Ben Khelil, Ahmadreza Arbab, Janesa Srikanthan, Laura Marcos Kovandzic, Véronique Vergé, Arnaud Pagès, Jessica Rengassamy, Roula Amine-Hneineh, Marine Aglave, Rémy Jelin, Vincent Ribrag, Wassila Rahali, Paul-Auguste Goutebroze, Stéphane de Botton, Laurie Menger, Ileana Antony-Debré, Jean-Baptiste Micol, Christophe Marzac, Cristina Castilla Llorente, Camille Bigenwald.
      Although chimeric antigen receptor (CAR) T cells have shown excellent results in treating hematological malignancies, they also cause side effects. Patients treated with CAR T cells experience persistent cytopenia or hematotox. Here, using a fully immunocompetent mouse model, we recapitulated hematotox and demonstrated that a lymphodepleting regimen alone was insufficient to induce hematotox and required CAR T cell injection. Analysis of bone marrow (BM) samples from patients experiencing hematotox revealed a correlation between BM CAR T cells and hematotox severity. CAR T cells exhibited an activated program, leading to intense inflammation. In addition, we observed a high rate of clonal hematopoiesis in our patient cohort and the emergence of distinct hematopoietic clones in the months after CAR T cell injection. Our study provides insights into the pathophysiology of hematotox and highlights the need for long-term follow-up studies to determine the relevance of this intense BM inflammation in clonal selection.
    DOI:  https://doi.org/10.1126/scitranslmed.adu9790
  10. Brain Behav. 2025 Sep;15(9): e70891
    Predictors of Neurotoxicity in a Large Cohort of Italian Patients Undergoing Anti-CD19 Chimeric Antigen Receptor (CAR) T-Cell Therapy.
    Anna Modoni, Catello Vollono, Eugenio Galli, Luca Capriati, Federica Sorà, Stefan Hohaus, Serenella Servidei, Nicola Piccirillo, Paolo Calabresi, Simona Sica.
       BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is an innovative and effective treatment for patients with B-cell hematological malignancies. Despite its high efficacy, it has been associated with the development of acute toxicities that can be severe or even fatal. Indeed, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can induce significant morbidity and require close monitoring. Identification of clinical and laboratory markers able to predict the occurrence of ICANS may allow prompt recognition and more effective management strategies.
    METHODS: Here, we report a retrospective study on a cohort of 81 Italian adult patients treated in our hospital between September 2019 and April 2024. We reviewed all clinical, demographic, laboratory, and neurophysiological data in order to identify potential predictors.
    RESULTS: The results of the multivariate analysis confirmed that ICANS typically occurred less frequently in younger patients, especially when treated with 41BB co-stimulated CAR-T. Baseline EEG abnormalities are confirmed to be a fundamental predictor of neurotoxicity. Interestingly, we identified GammaGT as a new, statistically significant marker of ICANS. This represents a novel finding, probably related to the important role of GammaGT also in neuroinflammation.
    CONCLUSIONS: Our results need to be confirmed in a larger cohort of patients in order to eventually be integrated into current clinical practice and management of patients undergoing CAR-T.
    Keywords:  CAR‐T; EEG; GammaGT; ICANS; predictors of neurotoxicity
    DOI:  https://doi.org/10.1002/brb3.70891
  11. J Immunother Cancer. 2025 Sep 23. pii: e010530. [Epub ahead of print]13(9):
    Second signals for cancer immunotherapy.
    Scott H Olejniczak, Michael T Lotze, Dimitris Skokos.
      Recent years have seen renewed appreciation of the critical role played by the prototypic T cell co-stimulatory receptor CD28 in cancer immunotherapy. Inhibition of co-stimulation by direct competition, as exemplified by cytotoxic T-lymphocyte associated protein 4 (CTLA-4) competition with CD28 for B7 ligands, or interference with intracellular signaling, such as that mediated by SHP2 phosphatase recruited to programmed cell death protein-1 (PD-1), provides tumors with a means to avoid elimination by cytotoxic T cells. Reversing this inhibition or providing co-stimulation by alternative means-bispecific antibodies, chimeric antigen receptors, etc-is the mechanistic basis behind the success of many modern cancer immunotherapies. As such, understanding the complexities of T cell co-stimulation and the various receptors driving it has taken on new importance. In this commentary, we highlight recent studies in this space and discuss their contributions to our understanding of T cell co-stimulatory receptors in cancer.
    Keywords:  Immune Checkpoint Inhibitor; Immunotherapy; Major histocompatibility complex - MHC; T cell; co-stimulatory molecules
    DOI:  https://doi.org/10.1136/jitc-2024-010530
  12. Cancers (Basel). 2025 Sep 16. pii: 3027. [Epub ahead of print]17(18):
    CAR-T Cell Therapies in B-Cell Acute Lymphoblastic Leukemia: Emerging Data and Open Issues.
    Caterina Alati, Martina Pitea, Matteo Molica, Luca Scalise, Gaetana Porto, Erica Bilardi, Giuseppe Lazzaro, Maria Caterina Micò, Marta Pugliese, Filippo Antonio Canale, Barbara Loteta, Virginia Naso, Giorgia Policastro, Giovanna Utano, Andrea Rizzuto, Violetta Marafioti, Marco Rossi, Massimo Martino.
      CAR-T therapy has transformed the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL), particularly in pediatric and young adult patients. Many studies report one-year overall survival rates of between 60% and 80% following therapy. Event-free survival rates at one year are around 50-70%, with 40-50% of patients in remission after two years. Despite these impressive results, disease relapse remains a problem. Future CAR-T cell platforms should target multiple antigens, and the optimal design of such constructs must be determined. Modern trials should explore the role of CAR-T cell therapy as a consolidation treatment for patients with high-risk ALL, including those with persistent minimal residual disease at the end of induction/consolidation therapy, an IKZF1-positive gene expression profile, or a TP53 mutation or Ph-like gene expression profile. Improving the efficiency of gene-editing methods could lead to higher success rates in creating CAR-T cells, as well as reducing manufacturing time and costs. Producing universal CAR-T cells from healthy donors could significantly reduce production time and costs. These issues underscore the dynamic and evolving nature of B-ALL research. Ongoing studies and clinical trials are addressing many of these challenges in order to improve outcomes for B-ALL patients and expand the applications of CAR-T cell therapy.
    Keywords:  CAR-T as consolidation; CD19-directed chimeric antigen receptor T-cell; acute lymphoblastic leukemia; allogeneic CAR-T; gene-editing methods
    DOI:  https://doi.org/10.3390/cancers17183027
  13. Expert Rev Mol Diagn. 2025 Sep 24. 1-4
    Cell avidity in CAR-T cell therapy.
    Yayu Chen, Zhishuang Ye, William C Cho, Daniel Xin Zhang.
      
    Keywords:  Avidity; CAR-T; cancer; cell interaction; therapy
    DOI:  https://doi.org/10.1080/14737159.2025.2565274
  14. Methods Protoc. 2025 Sep 11. pii: 108. [Epub ahead of print]8(5):
    Mechanisms of Resistance to CAR T-Cells and How to Overcome Them.
    Luca Legato, Matteo Bisio, Filippo Fasano, Corrado Benevolo Savelli, Carolina Secreto, Chiara Maria Dellacasa, Barbara Botto, Alessandro Busca, Marco Cerrano, Roberto Freilone, Mattia Novo.
      In the last few decades, chimeric antigen receptor (CAR) T-cell therapy has led to a paradigm shift in the treatment of hematological malignancies, including various subtypes of B-cell non-Hodgkin's lymphoma, B-cell acute lymphoblastic leukemia, and multiple myeloma. However, most patients experience refractoriness to CAR T-cells or relapse after treatment. Many efforts are underway to understand the mechanisms behind CAR T-cell failure, which are mainly related to CAR T-cell dysfunction, tumor-intrinsic resistance, an immunosuppressive tumor microenvironment, manufacturing issues, or patient-related factors. Several strategies are being developed to overcome these resistance mechanisms, including the engineering of more functional allogeneic CAR T-cell products, the targeting of alternative tumor antigens, and combination therapies with other drugs such as checkpoint inhibitors or small molecules to enhance CAR T-cell efficacy. In this review, we will provide an updated overview of the mechanisms of CAR T-cell failure and the therapeutic advances currently under development to address them.
    Keywords:  B-cell acute lymphoblastic leukemia; B-cell lymphoma; CAR NK; CAR T-cell resistance; CAR T-cells; allogeneic CAR T-cells; dual targeting; multiple myeloma
    DOI:  https://doi.org/10.3390/mps8050108
  15. J Inflamm Res. 2025 ;18 13139-13157
    The Emerging Roles and Therapeutic Potential of Unconventional T Cells in Sepsis.
    Shuaipeng Gu, Peidong Zhang, Cong Zhang, Tingxuan Tang, Teding Chang, Liming Dong, Wei Gao, Zhaohui Tang.
      Sepsis represents a dynamic, dysregulated host immune response to infection in which unconventional T cells-γδ T cells, mucosal-associated invariant T (MAIT) cells, natural killer T (NKT) cells, and double-negative T cells-actively shape the balance between early hyperinflammation and subsequent immune paralysis across time and tissues. These cells employ unique antigen recognition mechanisms to trigger rapid immune responses. γδ T cells facilitate early pathogen elimination and immune regulation, whereas MAIT cells detect microbial metabolites and modulate the systemic inflammation. NKT cells balance immune homeostasis through dual pro- and anti-inflammatory cytokine production. This review classifies these subsets and examines their sepsis-related functions alongside immunotherapies targeting them, such as cytokine manipulation, immunomodulators, and checkpoint inhibitors. Elucidating the precise mechanisms underlying sepsis could advance therapies that restore immune equilibrium and potentially improve clinical outcomes. Future studies should unravel the interactions between unconventional T cells and broader immune networks while translating the findings into practical treatments. Understanding the dynamic roles of these cells provides pathways for tailored interventions in sepsis management.
    Keywords:  double-negative t cells; immunotherapy; invariant natural killer t cells; mucosal-associated invariant t cells; sepsis; γδ T cells
    DOI:  https://doi.org/10.2147/JIR.S545532
  16. Cancer J. 2025 Sep-Oct 01;31(5):pii: e0794. [Epub ahead of print]31(5):
    The Oncology Drug Shortages and Its Impact on Community Hospitals.
    Lyndsey Reich, Kevin B Knopf.
      The ongoing shortage of oncology drugs, particularly generic chemotherapies like platinum agents, has had a disproportionate impact on community and safety net hospitals in the United States and globally. These institutions, often serving rural and underserved populations, face significant challenges due to limited financial resources. This article examines the practical implications of these shortages through the lens of a community hospital, where creative solutions were employed to maximize limited resources where drug shortages were concerned. This article also highlights the emergence of gray and black markets, raising concerns about drug quality, especially in low-income and middle-income countries. Broader market dynamics-including rising platinum prices and recent health care policy changes-threaten to deepen disparities in cancer care. Systemic reforms are required to improve supply chain resilience, ensure equitable drug access, and protect vulnerable institutions and populations from the consequences of ongoing and future drug shortages.
    Keywords:  cancer care disparities; community hospitals; drug shortage; rural hospitals; safety net hospitals
    DOI:  https://doi.org/10.1097/PPO.0000000000000794
  17. J Transl Autoimmun. 2025 Dec;11 100311
    Regulatory T cell therapy for Sjögren's disease: From pathogenesis to targeted treatment.
    Zhi Feng Sherman Lim, Alberta Y Hoi, Fabien B Vincent, Joshua D Ooi, Eric F Morand, Maureen Rischmueller, Yi Tian Ting.
      Sjögren's disease (SjD) is a chronic systemic autoimmune disorder characterised by lymphocytic infiltration of the salivary and lacrimal glands, leading to the hallmark symptoms of dry eyes and dry mouth. Beyond glandular dysfunction, many patients experience systemic complications-including B cell hyperactivity, organ-specific inflammation, and a markedly increased risk of non-Hodgkin lymphoma-that are frequently under-recognised and poorly managed. Current treatments remain largely empirical and symptomatic, with limited efficacy in modifying disease progression or restoring immune tolerance. Recent advances have illuminated profound dysregulation in both innate and adaptive immunity, revealing novel therapeutic targets now under investigation in clinical trials, including type I interferon signalling, B cell activation, and co-stimulatory pathways. Central to this dysregulation is T cell-driven pathology: CD8+ T cell cytotoxicity, defective regulatory T cell (Treg) function, and HLA class II-mediated presentation of self-antigens to autoreactive CD4+ T cells are key mechanisms in disease initiation and persistence. A growing body of evidence implicates Ro autoantigens-Ro60 and Ro52-as central targets in SjD pathogenesis. Anti-Ro antibodies are present in approximately 70 % of patients and serve as both diagnostic markers and indicators of systemic involvement. Ro antigens and their corresponding antibodies are consistently detected in inflamed salivary tissues, underscoring their potential as compelling targets for antigen-specific therapy. This review examines the immunopathogenic role of Ro-specific T cell responses in SjD and outlines how engineered Treg-based therapies may enable precise immune modulation, restore tolerance, and provide durable disease control for patients with this complex autoimmune condition.
    Keywords:  Autoimmunity; Cell therapy; HLA; Regulatory T cells (Treg); SSA/Ro; Sjögren's disease (SjD)
    DOI:  https://doi.org/10.1016/j.jtauto.2025.100311
  18. J Manag Care Spec Pharm. 2025 Oct;31(10): 1062-1074
    A systematic review of the applications of the real option value of medical technologies in oncology.
    Kwame Adjei, Vakaramoko Diaby, Meng Li, Fatimah Sherbeny, Sandra Suther, Askal A Ali.
       BACKGROUND: Real option value (ROV) offers an innovative paradigm to evaluate the dynamic value of medical technologies, particularly in cancer, by capturing the value of extending patient survival to access future innovations. Despite its potential, the application of ROV in medical technologies in oncology remains underexplored.
    OBJECTIVE: To synthesize existing evidence on the application of ROV in medical technologies in oncology.
    METHODS: A comprehensive search of PubMed, ScienceDirect, and Web of Science was conducted to identify peer-reviewed studies published in English from January 2000 to May 2024. In the search query, a combination of keywords related to "real option value" and "cancer" was used. Key data extracted included study characteristics, objectives, ROV modeling technique, and primary findings. The Consolidated Health Economic Evaluation Reporting Standards 2022 checklist was used for quality assessment of the studies.
    RESULTS: A total of 13 of 165 studies assessed the ROV of medical therapies, with a primary focus on melanoma, lung cancer, and prostate cancer. ROV was modeled from the ex post and ex ante perspectives. The methodologies employed vary, with common forecasting approaches including the Lee-Carter model to project future decreases in mortality rates, fitting Cox proportional regression models on administrative claims data, or estimating the approval likelihood of early pipeline drugs based on data from early randomized clinical trials.
    CONCLUSIONS: The ROV represents a critical dimension in evaluating medical technologies in oncology, where innovation is rapid. The implications of ROV extend beyond oncology, with the potential to influence funding, pricing, and access decisions in other disease areas as well. However, challenges such as oversimplification of assumptions for forecasting, methodological consistency, and lack of standardized framework remain pervasive. This systematic review underscores the need to integrate ROV into Health Technology Assessment practices to inform resource allocation and policy decisions.
    DOI:  https://doi.org/10.18553/jmcp.2025.31.10.1062
  19. Drug Discov Today. 2025 Sep 24. pii: S1359-6446(25)00194-1. [Epub ahead of print] 104481
    RNA virus and DNA virus initiations of autoimmune diseases and/or dementias.
    Kevin Roe.
      There are viral pathogen pathways to initiate autoimmune diseases, such as multiple sclerosis, directly or indirectly, by reactivating latent viruses including human herpesviruses. After initial infections, these DNA viruses can enter latency but periodically reactivate into active infections following triggers: medical treatments inducing immunosuppressions; and infections by immunosuppressive pathogens including RNA viruses, stress or malnutrition. An indirect causation pathway for autoimmune diseases can utilize immune suppressions by RNA virus infections, which trigger reactivation of latent herpesviruses capable of directly causing autoimmune diseases. Although it is believed that general inflammation, not specific pathogens, causes autoimmune diseases, experimental evidence indicates autoimmune diseases are caused by herpesvirus reactivations. Such viral reactivations can be induced by immunosuppressions during severe pathogen infections, particularly by RNA virus infections.
    Keywords:  Autoimmune disease; dementia; herpesvirus; latent infection; viral reactivation
    DOI:  https://doi.org/10.1016/j.drudis.2025.104481
  20. Front Immunol. 2025 ;16 1653183
    Innate iNKT cells: from biological insight to clinical impact.
    Antonia Rotolo, Nicola J Mason, Mark A Exley.
      Over the past 30 years, work of immunologists worldwide has phenotypically and functionally defined "Natural Killer T cells" (NKT) and their subsets, including "invariant Natural Killer T cells" (iNKT). NKT cells make up a substantial fraction of T cells that express NK cell markers and have TCRs restricted to either conventional MHC molecules or the monomorphic CD1d molecule. Among these, iNKT cells are CD1d-restricted and more common within NKT cells than T cells without NK markers. While the definition of NKT cells, whether based on phenotype, function, or both, remains a topic of debate, iNKT cells represent a distinct T cell population characterized by a recurrent, conserved TCR rearrangement (TRAV10-TRAJ18 in humans) paired with a limited Vβ repertoire (mostly encoded by TRBV25-1 in humans). iNKT cells are restricted by CD1d, which, unlike CD1a-c molecules, is expressed not only on professional antigen-presenting cells and thymocytes but also on certain non-hematopoietic somatic tissues, both normal and neoplastic. Like all CD1 family members, CD1d presents various lipid antigens by accommodating their long hydrophobic tails in deep binding pockets, in contrast to the shallow peptide grooves of conventional MHC molecules. However, the ligand repertoire of CD1d is distinct from that of CD1a-c. This review focuses on CD1d-restricted iNKT cells. Activation of iNKT cells via their semi-invariant TCR, often in synergy with NK receptors and other co-stimulatory molecules, triggers a rapid, polyfunctional response. Unlike conventional MHC-restricted T cells, individual iNKT cells can simultaneously produce both Th1- and Th2-type cytokines and exert cytotoxic activity in an immune synapse-directed fashion. Through this combination of direct cytotoxicity and cytokine-mediated immunomodulation, iNKTs can eliminate target cells while activating myeloid and other lymphoid populations to amplify immune responses. Their versatility has fueled growing interest in harnessing iNKT cells across inflammatory, infectious, and oncological diseases, where early-phase studies have demonstrated their safety and preliminary efficacy. Moreover, because they are restricted by the non-polymorphic CD1d molecule and possess immune-regulatory properties, iNKT cells lack graft-versus-host potential, making them ideal candidates for allogeneic, off-the-shelf therapies. This review summarizes how iNKT cells are being reimagined as innovative tools for immune intervention across a range of clinical settings.
    Keywords:  CD1; CD1d; COVID-19; NKT cell; allogeneic cells; graft versus host disease (GVHD); invariant natural killer T (iNKT) cell; off-the-shelf cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1653183
  21. Clin Pharmacol Ther. 2025 Sep 24.
    History and Evolution of Innovations in Clinical Pharmacology.
    Lawrence J Lesko, Piet H van der Graaf.
      Foundational scientific discoveries and inventions, with some dating back nearly 80 years laid the groundwork for many of today's innovations in clinical pharmacology. Beginning in the 1970 to 1980's, these discoveries began to rapidly mature, leading to widespread adoption in new and generic drug development and in regulatory decision-making. Over time, there has been a gradual transition toward a greater focus on quantitative modeling and simulation technologies, reinforced by enormous improvements in data collection in preclinical studies with translational bridges to relevant information derived from early phase human clinical trials. These innovations have opened the door to may improvements such as more precise assessments of dosage form performance, optimized dose selection to maximize the benefit-to-risk of numerous therapies, more in-depth understanding of drug-drug interactions, and informed dosage adjustments in specific populations. This review traces the history and evolution of innovations in clinical pharmacology through the lens of the interconnected pharmaceutical industry-regulatory agency relationship. It discusses three categories of innovations: established, in progress, and emerging, and discusses how specific innovations have played out, or are expected to shape, the future of the drug development and regulatory science enterprise tasked with bringing effective, safe, and needed new and novel therapies to the marketplace.
    DOI:  https://doi.org/10.1002/cpt.70048
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒28 at 9:28.