bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–07–13
23 papers selected by
Luca Bolliger, lxBio



  1. Cell Mol Biol (Noisy-le-grand). 2025 Jul 06. 71(6): 80-88
      Chimeric antigen receptor (CAR)-T cell therapy, a breakthrough in hematological cancer treatment, is now being explored for autoimmune diseases like rheumatoid arthritis (RA). RA, characterized by chronic joint inflammation and autoantibody production, presents a compelling target for CAR-T cell therapy due to its potential for precise targeting of aberrant immune cells and restoration of immune tolerance. This review analyzes current strategies in CAR-T cell therapy for RA, focusing on molecular mechanisms and clinical implications. We discuss approaches such as CD19-targeted B cell depletion, simultaneous targeting of B cells and memory plasma cells, and the use of chimeric autoantibody receptors (CAARs) to target specific autoantigens. Furthermore, we explore the latest advancements in CAR-T cell engineering, including novel costimulatory domains, dual-targeting strategies, and the development of regulatory CAR-T cells (CAR-Tregs). This review provides insights into the efficacy and safety of CAR-T cell therapy for RA, highlighting its potential to revolutionize clinical applications and future directions in the field.
    DOI:  https://doi.org/10.14715/cmb/2025.71.6.11
  2. Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00174-6. [Epub ahead of print]394 197-212
      Chimeric Antigen Receptor (CAR) T-cell therapy represents a significant advancement in treating hematologic malignancies. However, its therapeutic efficacy against solid tumors remains hindered by several challenges, including suboptimal antitumor activity, high toxicity, and the emergence of resistance mechanisms. In recent years, the microbiome has emerged as a critical modulator of cancer immunotherapy outcomes. Yet, the precise molecular and cellular pathways through which the microbiome influences CAR-T cell efficacy remain largely unexplored. This chapter provides a comprehensive review of current knowledge regarding the interactions between CAR-T cell therapy and the microbiome, with particular emphasis on gut microbial dynamics. Additionally, it underscores the existing gaps in our understanding of these interactions and highlights key preclinical and clinical findings. We also discuss innovative strategies aimed at manipulating the microbiome to enhance CAR-T cell function, thereby presenting potential avenues for optimizing therapeutic outcomes.
    Keywords:  Antitumor effects; CAR-T cell therapy; Gut microbiome; Immunotherapies; Microbiome modulation
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.12.015
  3. Front Immunol. 2025 ;16 1606126
      Chimeric antigen receptor T cell (CAR-T) therapy has revolutionized cancer immunotherapy by overcoming intrinsic limitations in T cell activation, achieving remarkable success in treating relapsed or refractory hematologic malignancies in both pediatric and adult populations. Inspired by this success, researchers have turned their attention to natural killer (NK) cells-innate lymphocytes capable of recognizing and killing tumor cells without prior sensitization-and have begun designing CARs specifically adapted to NK cell biology. Unlike T cells, NK cells possess intrinsic cytotoxicity that does not solely rely on CAR-mediated activation. Moreover, NK cell-mediated antitumor responses can often be enhanced by simply increasing NK cell numbers, a strategy less effective in T cell-based therapies due to the complex mechanisms of tumor immune escape. This review explores the principles and strategies behind NK-adapted CAR design, critically examines whether CARs are essential for NK cell function, and discusses the opportunities and challenges in translating CAR-NK therapy into clinical practice.
    Keywords:  CAR-NK cells; NK cell activation; chimeric antigen receptor; immunotherapy; natural killer cells
    DOI:  https://doi.org/10.3389/fimmu.2025.1606126
  4. Biomed Pharmacother. 2025 Jul 07. pii: S0753-3322(25)00502-5. [Epub ahead of print]189 118308
      Cancer remains a leading cause of mortality worldwide. Extensive research is underway to discover appropriate therapeutic interventions for this disease. One such emerging approach involves the development of targeted drugs, including p53-targeted drugs and chimeric antigen receptor (CAR) T cell therapy. These therapies are the most effective for the treatment of cancer. Both are advantageous when used alone in the treatment of cancer; however, they have certain limitations. Therefore, it has been discovered that the combination of CAR T cells along p53-targeted therapy is beneficial against tumor cells. This review describes an in-depth analysis of both p53-targeted therapies and CAR T cell therapy, scrutinizing their mechanisms and clinical applications, and exploring the synergistic potential of both p53-Targeted Therapies and CAR T cell therapies. Furthermore, to provide a comprehensive consideration of their combined efficacy, a review discusses how the intermingling of CAR T cell therapy and p53-targeted medicines can lead to therapeutic conclusions. Furthermore, it also provides ample evidence on the development, challenges and forthcoming guidelines for both CAR T cell therapies and p53-targeted therapies, making it a vital resource for researchers. Furthermore, the molecular basis for how p53 controls the development and process of numerous components of the tumor microenvironment is described, along with the difficulties that combination therapy can provide, such as tumor heterogeneity, immune evasion, and potential side effects. This review offers valuable information on the potential synergies between p53-targeted medicines and CAR T cell remedies to produce more effective and enduring cancer management by closely examining preclinical and clinical research.
    Keywords:  CAR T cell therapy; Cancer; Tumor microenvironment; p53
    DOI:  https://doi.org/10.1016/j.biopha.2025.118308
  5. Front Immunol. 2025 ;16 1597512
      Cytokine release syndrome (CRS) is a severe complication following Chimeric Antigen Receptor T-cell (CAR-T) therapy, characterized by an excessive inflammatory response triggered by the activation of CAR-T cells. Clinically, approaches like tocilizumab and corticosteroids are commonly used to treat CRS. However, those methods might be insufficient, particularly in treating severe CRS patients (grade 3-4). Nowadays, therapeutic plasma exchange (PE) has been used as a promising adjunctive therapy to treat severe CRS, as it can rapidly remove circulating inflammatory cytokines and immune complexes which contribute to CRS progression. To summarize the characteristics and clinical usage of PE, we provide the experiences of 3 PE cases from our institution and 19 PE cases from relevant literature. In this review, we concluded that PE is effective in reducing elevated serum cytokine levels and alleviating CRS symptoms such as fever, hypotension, and neurotoxicity. Furthermore, we discuss the principles and development of PE and compare CAR-T-induced CRS with CRS caused by viral infections. In addition, PE demonstrates clear advantages over other blood purification techniques including hemofiltration (HF) and hemodiafiltration (HDF), particularly in its ability to remove large-molecular cytokines and immune complexes. To conclude, PE presents a promising therapeutic approach for managing severe CRS after CAR-T therapy, especially when standard treatments have failed.
    Keywords:  CAR-T; CRS; cytokines; hematological malignancies; plasma exchange
    DOI:  https://doi.org/10.3389/fimmu.2025.1597512
  6. Clin Cancer Res. 2025 Jul 07.
      The genetic reprogramming of T cells with chimeric antigen receptors (CARs), specifically targeting CD19 in B-cell malignancies or B cell maturation antigen (BCMA) for plasma cell tumors has achieved remarkable success. CAR-T cell therapy represents a revolutionary strategy in personalized cancer care, leveraging the immune system's precision to target cancer cells with unprecedented efficacy. However, challenges persist with resistance and relapse occurring in hematological malignancies. Understanding the intricate mechanisms governing response and resistance is crucial, emphasizing factors such as pharmacokinetics, product attributes, and tumor biology. This review focuses on biomarkers associated with CAR-T cell therapy in Mature B-cell Non-Hodgkin lymphoma (B-NHL) malignancies, underscoring the importance of pre-existing tumor immune contexture. Previous findings highlight strong correlation between early peak-levels of CAR-T cells post- treatment initiation and treatment response. Maintaining an optimal CAR-T cell to tumor burden ratio is essential for sustained responses. Systemic and tumor immune contexture impacts therapy outcomes, revealing pre-existing immunity's role in CAR-T cell efficacy. The mechanistic impact of CAR-T cells was investigated using pre- and post- treatment biopsies, revealing specific markers associated with treatment response in refractory large B-cell lymphoma (LBCL), across patients receiving CAR T-cell therapy in the second- and third-line setting, supporting precision medicine in developing next-generation cell therapies for hematological malignancies. The evolution of the tumor microenvironment (TME) with therapy lines was also demonstrated, supporting earlier intervention with CAR T cell therapy. Ongoing translational efforts, including single-cell omics analysis, aim to uncover additional factors that impact outcomes to develop more potent treatments.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-2267
  7. Int Rev Cell Mol Biol. 2025 ;pii: S1937-6448(24)00173-4. [Epub ahead of print]394 147-170
      Multiple innovative molecular techniques have established compelling connections between the gut microbiome and cancers. Studies have also revealed that the microbiome and microbiome-specific metabolites can significantly influence cancer treatments like chemotherapy, radiotherapy, and immunotherapy. Advancements in cancer immunotherapy driven by a targeted immune system approach have considerably improved the treatment landscape in cancer. However, the full potential of tumor immunotherapy remains to be explored, and many challenges need to be addressed. This review provides a summary of the current evidence regarding the presence of microbiota and how it can impact the response to Food and Drug Administration (FDA) approved cancer immunotherapies, such as immune checkpoint inhibitors (ICIs) or chimeric antigen receptor T (CAR-T) cell therapy. Additionally, it addresses the challenges and limitations of gut microbiome and cancer immunotherapy.
    Keywords:  Adoptive T cell (ACT) therapy; CAR-T cell; Immune checkpoint inhibitors; Immune system; Immune-related adverse events (irAE); Immunotherapy; Microbiome
    DOI:  https://doi.org/10.1016/bs.ircmb.2024.12.014
  8. Front Med (Lausanne). 2025 ;12 1591287
      The fight against mortality in pediatric oncohematological diseases is a story of human rights, academia, innovation, and technological advancement-one in which women in science have played a pivotal role. With talent, perseverance, and sensitivity, they greatly contributed to research in new cellular therapies, expanding the frontiers of treatment and giving the most vulnerable patients the gift of more years of life. This review explores multipotent and unipotent cell therapies, focusing on hematopoietic stem cell transplantation (HSCT), mesenchymal stromal cell transplantation (MSCT), and chimeric antigen receptor (CAR)-T cell and natural killer (NK) cell therapy. HSCT remains the gold standard for high-risk and relapsed cases, with graft sources including bone marrow (BM), mobilized peripheral blood (MPB), and umbilical cord blood (UCB). Advances in MSCT highlight its role in hematopoiesis support and immunomodulation, reducing graft-versus-host disease (GVHD) risks. CAR-T cell therapy has revolutionized leukemia treatment, although challenges such as antigen escape, T-cell exhaustion, and treatment resistance persist. Emerging strategies, including CAR-NK cells, seek to enhance efficacy while minimizing toxicity. Despite these advancements, cell therapy remains complex and resource-intensive, necessitating further innovations for broader accessibility, particularly in developing regions.
    Keywords:  CAR-NK cells; CAR-T cells; HSC transplantation; MSC transplantation; pediatric hematological diseases
    DOI:  https://doi.org/10.3389/fmed.2025.1591287
  9. Z Rheumatol. 2025 Jul 10.
       BACKGROUND: Chimeric antigen receptor (CAR) T cell therapies were originally developed for the treatment of hematological malignancies; however, they are gaining increasing importance in the treatment of selected individuals with severe, treatment-refractory courses of neuroimmunological diseases. This article discusses the available treatment experiences to date and the potentially promising biotechnological developments in the context of the underlying neuroimmunological pathophysiology.
    OBSERVATIONS: The spectrum of immunopathology in neuroimmunological diseases ranges from classical autoantibody-mediated autoimmune diseases, such as myasthenia gravis to immunologically complex conditions like multiple sclerosis. The CAR T cell products currently in use target B cells, leading to complete B cell depletion, including autoreactive B cell clones. The therapeutic response, measured by disease activity and biomarkers, varies depending on the underlying immunopathology. The use of CAR T cells in different disease entities has shown a favorable safety profile concerning acute toxicity.
    CONCLUSION: Currently available and emerging CAR T cell therapy approaches open new therapeutic perspectives for neuroimmunological diseases. Larger studies are needed to assess safety, efficacy and long-term effects and to identify individual disease courses that may be suitable for the application of these forms of treatment.
    Keywords:  Autoantibodies; B cells; Cell therapy; Immunopathology; Neuroimmunology
    DOI:  https://doi.org/10.1007/s00393-025-01676-2
  10. MAbs. 2025 Dec;17(1): 2531223
      T cell engagers (TCEs) are a promising class of cancer immunotherapy that re-direct T cells to kill tumor cells. However, their clinical application is limited by several challenges, including cytokine release syndrome (CRS), on-target off-tumor toxicity and overcoming immunosuppression in both hematological and solid tumors. This review explores recent innovations in TCE design aimed at improving their safety and efficacy. Key developments include optimizing geometry to facilitate effective immune synapses, affinity optimization of the anti-CD3/TCR domain and targeting of specific T cell subsets which both aim to reduce CRS. Logic-gated approaches such as dual-targeted and conditional TCEs activated by tumor microenvironment factors have the potential to reduce on target, off tumor toxicity and potentially increase the depth and durability of response. Additionally, leveraging costimulatory signaling offers the potential to further improve efficacy across hematological and solid tumor settings. The next generation of TCEs is expected to overcome some of the limitations of conventional TCEs, enhancing their therapeutic window and enabling combination therapies. As the field advances, TCEs are poised to become a cornerstone of cancer immunotherapy, potentially improving outcomes for a broader range of patients than the ones currently benefiting from conventional immunotherapy.
    Keywords:  Antibody engineering; Cancer immunotherapy; Conditional engager; Multi-specific antibodies; T cell engagers; T cells
    DOI:  https://doi.org/10.1080/19420862.2025.2531223
  11. bioRxiv. 2025 Jul 05. pii: 2025.07.02.662376. [Epub ahead of print]
      Chimeric antigen receptor (CAR) T cell therapies have shown promise in treating hematologic malignancies, but challenges remain due to immune suppression, antigen heterogeneity, and insufficient functional screening platforms. Here, we present a modular nanovial-based platform for high-throughput, single-cell functional screening of pooled CAR T cell libraries. Nanovials, hydrogel microparticles with nanoliter-scale cavities, were functionalized with recombinant HER2 antigen and cytokine-capture antibodies to simulate antigen-presenting cells and capture secreted interferon-γ (IFNγ). This system enabled the selective capture, activation, and functional profiling of CAR T cells based on antigen engagement and cytokine secretion. We screened a 32-variant CAR library with diverse intracellular signaling domains, using nanovials to isolate IFNγ-secreting cells at 3- and 12-hour timepoints. IL15RA-containing CARs, particularly IL15RA-CD28, were preferentially enriched in the sorted T cells after 3 hours of stimulation, consistent with early effector activation profiles. By 12 hours, IL15RA-containing constructs remained enriched while other CD40-containing domains showed delayed but substantial enrichment, suggesting prolonged signaling dynamics. The platform's high-throughput capacity (>2 million cells screened), compatibility with downstream sequencing, and tunable antigen presentation make it ideal of identifying CAR constructs associated with various time-dependent secretion phenotypes.
    DOI:  https://doi.org/10.1101/2025.07.02.662376
  12. Front Immunol. 2025 ;16 1640317
      
    Keywords:  adaptive cell therapy; chimeric antigen receptor (CAR); immunotherapy; oncoimmunology; resistance
    DOI:  https://doi.org/10.3389/fimmu.2025.1640317
  13. Leuk Lymphoma. 2025 Jul 06. 1-11
      Cellular therapies, including hematopoietic stem cell transplantation (HCT) and chimeric antigen receptor (CAR) T-cell therapy, have undergone significant advancements, leading to broader indications and improved patient outcomes. Despite the progress, access remains inequitable, driven by disparities related to socioeconomic factors, healthcare infrastructure, and limitations associated with the products themselves. This review provides an overview of the current state of access to cellular therapies in the United States, with a focus on identifying barriers and exploring potential solutions. Many of these barriers are shared globally, including in low- and middle-income countries, but are not necessarily mirrored in other developed nations, where healthcare systems and funding models differ. Addressing these disparities will require action at many levels, including expanding community-based access, innovation in the manufacturing process, enhancing financial support, and implementing equity-focused initiatives. As cellular therapies continue to evolve, ensuring equitable access must remain a central priority to foster inclusiveness in medical innovation.
    Keywords:  CAR T-cell; Cellular therapy; access; transplantation
    DOI:  https://doi.org/10.1080/10428194.2025.2513003
  14. Front Immunol. 2025 ;16 1612360
      Regulatory T cells (Tregs) play a pivotal role in modulating excessive immune responses and maintaining immune homeostasis in humans. Notably, therapeutic strategies employing autologous and allogeneic Tregs have shown promising signs of efficacy in the treatment and prevention of graft versus-host disease (GvHD), transplant rejection and autoimmune diseases. Treg cells are typically obtained from peripheral blood or umbilical cord blood, but the largely antigen-experienced memory state of peripheral blood Tregs and the limited number of Tregs that can be isolated from cord blood remain obstacles. However, recent studies have identified the thymus as a novel and promising source of Tregs, overcoming the abovementioned limitations. Currently, human thymus-isolated regulatory T cells (thyTregs) are being investigated in phase 1/2 clinical trials to assess their safety and efficacy in both autologous and allogeneic settings. This review provides a comprehensive overview of the different manufacturing processes for isolation and expansion of thymus-derived regulatory T cells, their clinical relevance and current ongoing clinical trials investigating the therapeutic potential of this novel class of Tregs.
    Keywords:  Treg cell therapy; Treg isolation; ex vivo Treg expansion; in vitro Treg expansion; regulatory T cells; thyTregs; thymus
    DOI:  https://doi.org/10.3389/fimmu.2025.1612360
  15. Front Bioeng Biotechnol. 2025 ;13 1586912
       Background: Cell therapy is a promising field with the potential to improve outcomes for cancer and autoimmune disease patients. However, its complex and resource-intensive manufacturing requires costly infrastructure. Current processes, adapted from academic research, involve open handlings, manual processing, and repurposed equipment from biologics applications, raising quality and safety risks while increasing manufacturing costs. Closed, automated manufacturing systems can overcome these limitations.
    Methods: Allogeneic therapeutic natural killer (NK) cells can be generated from umbilical cord blood (UCB)-derived CD34+ hematopoietic stem cells in a closed, semi-automated process. Here, the automated CliniMACS Prodigy® system has been evaluated for reliability and performance in two unit operations, the enrichment of CD34+ stem cells from cord blood and the final product harvest and concentration. In this study, we report the outcome of these two processes across N = 36 different manufacturing runs performed during process development and GMP manufacturing for clinical release.
    Results: Efficiency of CD34+ stem cell enrichment was evaluated across cord blood units with low (<4.50E06 CD34+ cells/unit, N = 11), medium (4.50-7.00E06 CD34+ cells, N = 13) or high (>7.00E06 CD34+ cells, N = 12) content. Robust performance was observed in all groups, with average CD34+ cell recoveries of 68.18%, 68.46%, and 71.94%, respectively. Higher purity was achieved in the high group (69.73%), compared to low (57.48%) and medium (62.11%). Factors such as UCB age, total nucleated cell count, and platelet or red blood cell content had no significant impact. For the final harvest and concentration process, we analyzed batches with low (<2 L, N = 7), medium (2-5 L, N = 14) or high cell culture volume (>5 L, N = 8). Approximatively 20% cell loss was reported, with average yields of 74.59% for low, 82.69% for medium, and 83.74% for high volumes. NK cell purity was stable at over 80%, and B and T cell impurities content remained low or undetectable.
    Discussion: This study presents an agile solution using a single piece of equipment during two steps of a complex NK cell manufacturing process. This approach ensures closed system safety, automation, high consistency, and cost-effectiveness, enabling the successful delivery of high-quality allogeneic NK cell therapies to patients.
    Keywords:  CliniMACS Prodigy; GMP; NK cell therapy; allogeneic cell therapy; cell therapy manufacturing; closed system manufacturing; good manufacturing practice; process automation
    DOI:  https://doi.org/10.3389/fbioe.2025.1586912
  16. Curr Opin Oncol. 2025 Jul 08.
       PURPOSE OF REVIEW: The field of chimeric antigen receptor (CAR) T-cell therapies is rapidly evolving. The number of approved indications for the existing CAR-T products is increasing, and, in parallel, so too is the number of novel products and disease targets being evaluated. Being able to navigate the available evidence is a priority for every hemato-oncologist.
    RECENT FINDINGS: Long-term follow up from pivotal trials, as well as real-world studies of commercial products in a range of B-cell non-Hodgkin lymphoma (B-NHL) have confirmed their ability to produce durable disease control with a manageable toxicity profile in a significant proportion of patients, including populations generally excluded from clinical trials. Nonrelapse morbidity and mortality risk profiles have been better established with long-term follow up, and risk reduction via antimicrobial prophylaxis and monitoring of hematologic recovery are being integrated as part of standard of care for these patients beyond the first-year posttreatment.
    SUMMARY: A significant proportion of B-NHL patients can achieve long-lasting remission after CAR-T. Ongoing efforts have identified demographic and disease characteristics associated with optimal response and toxicity. Novel products targeting alternative B-cell antigens or utilizing an allogeneic platform might be an option for those whose disease recurs after anti-CD19 CAR-T, with multiple studies ongoing to define their role in the treatment algorithm.
    Keywords:  B-cell non-Hodgkin lymphoma; chimeric antigen receptor T-cell; diffuse large B-cell lymphoma; follicular lymphoma; immune effector cellular therapy
    DOI:  https://doi.org/10.1097/CCO.0000000000001169
  17. Adv Pharm Bull. 2025 Apr;15(1): 133-142
       Purpose: T cell-based immunotherapy, especially chimeric antigen receptor (CAR)-T cells, has emerged as an appropriate approach for treating hematologic malignancies and is currently under investigation in clinical trials for solid tumors. Despite significant improvements in CAR-T cell production processes, the isolation and expansion of CAR-engineered T cells continue to pose significant challenges. The aim of this research is to provide a simple and cost-effective method for the isolation and expansion of human CAR-T cells. This novel concept applies coated fetal bovine serum (FBS) culture plates and focuses on enhancing viability and functionality to improve the adherence of suspended T cells.
    Methods: This study evaluated a two-dimensional (2D) culture technique for isolating the CAR-T cells that target prostate-specific membrane antigen (PSMA) utilizing matrices pre-coated with 0.2% glutaraldehyde and FBS. Jurkat cells were transduced with a lentiviral vector encoding the anti-PSMA CAR construct. FBS-coated and commercialized Matrigel-coated matrices were used for single-cell isolation and clonal expansion. Functional tests were conducted to assess the activation and proliferation of CAR-T cells and the IFN-γ release assay subsequent to cloning and expansion.
    Results: Transfection efficiency markedly improved, with 88.4% of Lenti-X 293T cells demonstrating green fluorescent protein (GFP) expression. Among the Jurkat cells, 57.1% showed GFP expression post-transduction, of which 34.1% showed surface expression of anti-PSMA CAR. Clonal expansion on the FBS-coated matrix proved effective, yielding 92.1% GFP-positive isolated cells. Functional assays demonstrated that CAR-T cells co-cultured with LNCaP cells exhibited significantly enhanced proliferation, activation (as indicated by CD69 and CD25 expression), and cytokine release assay (IFN-γ) compared with those co-cultured with DU 145 and mock cells.
    Conclusion: This new approach is efficient, economical, and scalable for isolating specific homogenous T cells and promoting their clonal proliferation and expansion. Furthermore, this method improves T cell adherence, proliferation, and functional effectiveness, offering a potential foundation for advancing CAR-T cell therapies aimed at solid tumors. Future research should concentrate on optimizing culture conditions and testing this method in preclinical animal models to ensure its clinical applicability and efficacy.
    Keywords:  2D culture system; CAR-T cells; Cancer immunotherapy; Clonal expansion; FBS coating; Single cell isolation
    DOI:  https://doi.org/10.34172/apb.43798
  18. Cytotherapy. 2025 Jun 13. pii: S1465-3249(25)00745-5. [Epub ahead of print]
       INTRODUCTION: Chimeric antigen-receptor natural killer cells (CAR-NKs) offer a promising allogeneic immune effector cell therapy to treat malignant diseases. A systematic review is needed to understand the scope of current clinical studies and registered active trials to identify aspects of study design and cell product characterization that could accelerate greater clinical adoption.
    METHODS: A systematic review of all publications (to January 25, 2025) and registered clinical trials (to June 21, 2024) was conducted. We extracted information on study design, patient characteristics, outcome measures, and cell product characterization.
    RESULTS: A total of 150 patients in ten studies published between 2018 and 2025 were identified. Hematologic malignancies were examined most frequently (n = 6 studies). All published studies were uncontrolled, and only four reported on more than three patients. CAR-NK products were most frequently derived from the NK-92 cell line (four studies), umbilical cord blood (three studies), induced pluripotent stem cells (one study), or not reported (two studies). Considerable heterogeneity was observed regarding CAR-NK cell manufacturing methods and dosing. Complete response rates for patients with B cell lymphomas ranged from 25-85%, depending on lymphoma subtype. Responses were durable with median response not reached in the largest study and durable remission at 1-year in 70% of responders in a second study. Adverse events were uncommon with no cases of grade 3 or higher cytokine release syndrome and no cases of immune effector-cell mediated neurotoxicity or graft versus host disease reported. Among the 50 registered trials identified (n=2102 subjects to be enrolled), hematological malignancies (n = 34; 68%) were the most common diseases examined.
    CONCLUSIONS: The clinical outcomes and low adverse event rates following CAR-NK therapy in published studies are encouraging. Larger controlled trials are needed to confirm the safety and efficacy of CAR-NK therapy. We anticipate the completion of several such trials in the coming years.
    Keywords:  cancer; chimeric antigen receptor; clinical trials; natural killer cells; safety; systematic review
    DOI:  https://doi.org/10.1016/j.jcyt.2025.06.006
  19. Br J Haematol. 2025 Jul 05.
      The number of patients undergoing haematopoietic stem cell transplant (HCT) and cell therapies for non-malignant disorders is steadily increasing with more genetic diseases being identified and newer gene therapy products being introduced for various indications. By combining individualized conditioning, novel graft manipulation techniques, using cutting edge methods to monitor post HCT response and offering exceptional survivorship care, one can achieve excellent survival and improved quality of life for these patients.
    Keywords:  cell therapy; non‐malignant disorders; precision; stem cell transplantation
    DOI:  https://doi.org/10.1111/bjh.20245
  20. Br J Clin Pharmacol. 2025 Jul 05.
      Over the past 25 years, the UK has adopted health technology assessment (HTA) as a mechanism to ensure that new medicines, and new indications for existing medicines, are assessed in an open, objective and robust way so that when the UK National Health Service (NHS) adopts these therapeutic developments, it does so in a cost-effective manner, accepting those agents with an acceptable cost per quality-adjusted life year (QALY) or a discount that brings the cost below the threshold. Usually, pharmacoeconomic modelling is used to justify pricing, often relying on surrogate endpoints or extrapolation beyond the duration of existing trials data. Although cost-effectiveness is often based on robust clinical trials, there are other issues to consider, which require an understanding of clinical pharmacology and clinical judgement. Key considerations include the justification of use of surrogates and extrapolation, the appropriateness of any comparator drug studied, the difference between efficacy in trials and clinical effectiveness in real-world use, the additional costs of providing a service to deliver the medicine, and the cost of any important adverse effects that are likely to occur. Although the process in the UK is now well established, with support from clinicians and the public, there remain questions about whether the currently accepted cost/QALY is set too high, whether a special case should be made for some drugs commanding a higher cost/QALY (such as in cancer and end-of-life situations), and whether HTA should be used more broadly to assess other activities undertaken by the NHS.
    Keywords:  clinical pharmacology; cost‐effectiveness; health technology assessment; medicines; novel therapeutics; pharmacoeconomics
    DOI:  https://doi.org/10.1002/bcp.70157
  21. Curr Drug Res Rev. 2025 Jul 04.
       INTRODUCTION: Escalating healthcare costs and increasing demands on healthcare systems have increased the need for efficient resource allocation. Pharmacoeconomics is a vital field that quantifies and compares the value of therapeutic drugs or treatments. It provides a systematic framework for decision-makers in the pharmaceutical industry, government, and private sectors to optimize healthcare delivery and spending. This review aimed to explore the role of pharmacoeconomic models in assessing the economic and clinical value of therapies. It emphasizes the importance of cost-effectiveness, cost-utility, cost-benefit, and cost-minimization analyses in balancing costs with outcomes and guiding healthcare resource allocation.
    METHODS: Pharmacoeconomic methodologies involve evaluating costs, processes, and outcomes associated with therapeutic interventions. Key methods include cost-minimization, costeffectiveness, cost-utility, and cost-benefit analyses. These approaches are critical in regulatory compliance, reimbursement decisions, cost assessments, and sustaining pharmaceutical models.
    RESULTS: The review reveals that pharmacoeconomic tools such as Cost-Effectiveness Analysis (CEA), Cost-Utility Analysis (CUA), and Cost-Benefit Analysis (CBA) are widely used to guide healthcare policy decisions, particularly in resource-constrained settings. CEA is the most commonly applied method due to its simplicity, while CUA is gaining traction in advanced policy frameworks like Health Technology Assessment (HTA). In India, pharmacoeconomic research is emerging but faces barriers such as limited access to real-world data, the absence of national reimbursement systems, and high out-of-pocket costs. Innovative methods like machine learning and pharmacogenomics are being explored to improve the relevance and precision of these evaluations.
    DISCUSSION: While pharmacoeconomic models offer valuable insights for healthcare decisionmaking, their real-world impact is limited by inconsistencies in data quality and variations in implementation standards. In India, fragmented governance, low public health spending, and a lack of coordination among stakeholders further hinder effective application. Addressing systemic challenges-such as establishing interoperable data systems, standard treatment guidelines, and equitable healthcare access-is crucial. Tailored approaches, including localized utility values and digital health initiatives, are essential to make pharmacoeconomics a practical and influential tool in policy formulation and resource allocation in India and similar settings.
    CONCLUSION: Pharmacoeconomic studies evaluate clinical efficacy, adverse effects, and production costs while incorporating perspectives from patients, providers, payers, and communities. For India, unique challenges such as limited rural healthcare access, infrastructure disparities, and high out-of-pocket expenses necessitate tailored adaptations. Strategies such as integrating accessibility metrics, localized data, equity considerations, preventive care, tiered pricing, and public-private partnerships can enhance healthcare delivery. Pharmacoeconomic models are essential for improving health outcomes, ensuring equitable resource allocation, and addressing the diverse needs of India.
    Keywords:  Indian healthcare system; Pharmacoeconomics; equitable healthcare; models.; resource allocation; tiered pricing
    DOI:  https://doi.org/10.2174/0125899775394503250626070441
  22. J R Soc Interface. 2025 Jul;22(228): 20240710
      Immunotherapies are designed to exploit the immune system to target pathologies such as cancer. Monoclonal antibodies (mAbs) are an important class of immunotherapies that induce anti-tumour effects. Fundamental to the success of mAbs in cancer treatments are their interactions with target antigens. For example, binding multiple antigens, increasing binding affinity, termed the avidity effect, has been shown to impact treatment outcomes. However, there has been limited theoretical analysis addressing the impacts of antibody-antigen interactions on avidity, potency and efficacy. Hence, our aim is to use a mathematical model to develop insight on these impacts. We analyse an ordinary differential equation model of bivalent, monospecific IgG antibodies binding to membrane antigens and show that the ratio of antibody to antigen number impacts quantities that contribute to mAb potency and efficacy, such as antigen occupancy, and whether an antibody can bind both its antigen-binding arms. A global parameter sensitivity analysis shows that antigen occupancy and the ratio of bound antibody to total antigen number are sensitive to the antibody-antigen binding rates only for high antibody concentrations. We also identify parameter ranges in which the avidity effect is predicted to be large. These results could be used in the preclinical development of mAb therapies by predicting conditions that enhance mAb potency, efficacy and the avidity effect.
    Keywords:  antibodies; avidity; immunotherapies; mathematical model
    DOI:  https://doi.org/10.1098/rsif.2024.0710
  23. Front Med (Lausanne). 2025 ;12 1623689
       Introduction: The study examines the impact of regulatory tools, including PRIority MEdicines (PRIME) scheme, on the marketing authorization (MA) timeline of advanced therapy medicinal products (ATMPs) approved by the European Medicines Agency (EMA).
    Methods: A retrospective analysis of EMA-approved ATMPs was conducted using publicly available European public assessment reports. Timelines from submission to approval, regulatory pathways, frequency of scientific advice (SA), and use of supportive mechanisms such as PRIME and Orphan designation were analyzed.
    Results: A total of 27 ATMPs were approved in the EU, 52% of which received PRIME designation and 74% held orphan status. PRIME participation was associated with a 42.7% reduction in time to MA (p = 0.001), and orphan designation with a 32.8% reduction (p = 0.021). PRIME-designated products also had fewer and shorter clock stops and more frequent scientific advice interactions.
    Discussion: The PRIME scheme facilitates earlier MA by supporting developers in addressing regulatory requirements more efficiently, shortening time to approval by approximately one year. The study underscores the value of early and frequent engagement with regulatory authorities and the need for tailored regulatory frameworks to support smoother approval processes. These insights can help developers better plan and optimize regulatory strategies. By demonstrating the measurable benefits of PRIME, this research supports its continued use to accelerate access for patients with high unmet medical needs.
    Keywords:  PRIME scheme; advanced therapy; gene therapy; marketing authorization; somatic-cell therapy; tissue engineering
    DOI:  https://doi.org/10.3389/fmed.2025.1623689