bims-carter Biomed News
on CAR-T Therapies
Issue of 2025–10–05
27 papers selected by
Luca Bolliger, lxBio
  1. [Clinical development of genetically modified T cell therapies].
  2. Engineering scFv immunotherapies: From CAR T cells to bispecific antibodies.
  3. Optimizing CAR T cell therapy for solid tumours: a clinical perspective.
  4. [CAR-T cell therapy in clinical practice].
  5. In vivo chimeric antigen receptor (CAR)-T cell therapy.
  6. Immune-based cancer therapies: mechanistic insights, clinical progress, and future directions.
  7. Engineering adoptive cell therapy for solid tumors.
  8. An Indigenous Workflow for Generating CD19 CAR-T Cells.
  9. Global research trends in CAR-T cell therapy for glioblastoma: a bibliometric and visualized analysis.
  10. CAR T-cell therapy in autoimmune diseases: Opportunities and challenges, with implications for RA.
  11. Foundational Principles for the Quantitative Translation of T-Cell Therapeutics for Hematologic Malignancies and Immunology.
  12. Cell and gene therapy approvals in Asia: regulatory landscape, access and affordability.
  13. From Innate Power to Intelligent Design: The Evolution of NK Cell-Based Cancer Immunotherapy.
  14. Innovations in immunotherapy for autoimmune diseases: recent breakthroughs and future directions.
  15. Disparities in access to gene therapy in the European Union: ethical and regulatory challenges.
  16. Budget impact analysis of new drugs in oncology and haematology: Principles and practice.
  17. CD70-targeted CAR-T/NK therapy: Rationale, advances, and future directions.
  18. Automated vertical wheel bioreactor integrated with process analytics for T-cell manufacturing.
  19. Integrated scFv identification and CAR T cell generation for AML targeting in vivo.
  20. The Promise of Immunotherapies in T-Cell Lymphoma.
  21. Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.
  22. Predictors of response to CD19 chimeric antigen receptor T-cell therapy in large B-cell lymphoma: a consolidated review.
  23. Advances in microfluidic chip technology for cell analysis.
  24. Immunotherapy for precision medicine in colorectal cancer.
  25. HDAC inhibitor (SAHA) enhances B7-H3-specific CAR T cell cytotoxic efficacy against chondrosarcoma cells and prolongs survival in an orthotopic mouse model.
  26. Antibody-drug conjugates: Current challenges and innovative solutions for precision cancer therapy.
  27. Optimizing activation and culture conditions for the production of cord blood-derived CAR-T and natural killer cells.
  1. Rinsho Ketsueki. 2025 ;66(9): 1233-1240
    [Clinical development of genetically modified T cell therapies].
    Keisuke Watanabe.
      Genetically modified T cell therapies using a chimeric antigen receptor (CAR) or a modified T cell receptor (TCR) have emerged as an attractive approach to cancer treatment, especially for hematological malignancies, and are becoming an indispensable therapeutic option in clinical practice. CAR- and TCR-T cell development continues to face many challenges, including relapsed/refractory disease, adverse events, manufacturing failures, and cost. Nevertheless, several significant achievements have been made, including favorable clinical responses in CAR-T cell trials and the first approval of a TCR-T cell product for synovial sarcoma by the FDA. This review article will describe the current state and future outlook of gene modified T cell therapy development, and will briefly discuss the drug discovery ecosystem for cell therapy platforms, with a particular focus on Japan.
    Keywords:  Chimeric antigen receptor T cell therapy; Drug discovery; Gene-modified T cell therapy; T cell receptor T cell therapy
    DOI:  https://doi.org/10.11406/rinketsu.66.1233
  2. Int Immunopharmacol. 2025 Sep 29. pii: S1567-5769(25)01588-7. [Epub ahead of print]166 115597
    Engineering scFv immunotherapies: From CAR T cells to bispecific antibodies.
    Mohammad Chand Jamali, Amged Gaffer Mostafa Gaffer, Hakeem Ghani Hassan, Sana Abdul-Jabbar Ali, Mahaboob Khan Sulaiman, Anam Tariq, Nasrin Mansuri, Ashit Kumar Dutta, Mustafa Mudhafar.
      Single-chain variable fragments (scFvs) have become indispensable tools in cancer immunotherapy due to their high specificity, modularity, and cost-effective production. These engineered antibody fragments enable precise targeting of tumor antigens, driving innovations in chimeric antigen receptor (CAR) T cell therapy, bispecific T-cell engagers, immune checkpoint blockade, and nanoparticle delivery systems. Their compact size enhances tumor penetration compared to full-length antibodies, while recombinant production allows rapid customization. This review examines the expanding therapeutic applications of scFvs across multiple modalities, including their critical role in CAR-T cell engineering where scFv affinity determines efficacy and safety. We explore bispecific engagers that redirect T cells to tumors, checkpoint inhibitors that restore antitumor immunity, and targeted drug delivery platforms. Clinical successes in hematologic malignancies are highlighted alongside ongoing challenges in solid tumors, particularly regarding antigen heterogeneity and immunosuppressive microenvironments. Key advances in scFv optimization are discussed, focusing on half-life extension strategies, stability engineering, and combinatorial approaches to overcome limitations like rapid clearance and on-target/off-tumor toxicity. By synthesizing recent preclinical and clinical developments, this review demonstrates how scFv-based therapies continue to transform precision oncology through targeted immune modulation.
    Keywords:  Antibody engineering; BiTEs; CAR-T cell therapy; Immune checkpoint blockade; Tumor immunotherapy; scFv
    DOI:  https://doi.org/10.1016/j.intimp.2025.115597
  3. Nat Rev Clin Oncol. 2025 Oct 02.
    Optimizing CAR T cell therapy for solid tumours: a clinical perspective.
    Jiarui Li, Chang Liu, Panpan Zhang, Lin Shen, Changsong Qi.
      Chimeric antigen receptor (CAR) T cell therapy is revolutionizing the management of haematological malignancies but faces particular hurdles in the treatment of solid tumours. In this Review, we discuss important advances in refining CAR T cell therapy to provide practical clinical insights to address these challenges. We describe key strategies, including target antigen selection to enhance efficacy while minimizing on-target, off-tumour toxicities; early apheresis, rapid manufacturing and frontline application to preserve T cell fitness and ensure timely treatment; lymphodepletion to augment CAR T cell expansion; locoregional delivery to maximize local therapeutic concentrations and reduce systemic toxicity; and repeat infusions to prolong therapeutic effects. Furthermore, we discuss advanced response evaluation frameworks that will be essential for accurate assessment of the efficacy of CAR T cell therapies, and we highlight the need for robust toxicity management approaches to mitigate severe adverse events. By systematically addressing these multifaceted challenges, this Review provides a comprehensive guide for the optimization of CAR T cell therapy for solid tumours to enhance both efficacy and safety.
    DOI:  https://doi.org/10.1038/s41571-025-01075-1
  4. Rinsho Ketsueki. 2025 ;66(9): 1222-1232
    [CAR-T cell therapy in clinical practice].
    Tomoyasu Jo.
      Chimeric antigen receptor (CAR) T-cell therapy has demonstrated remarkable clinical efficacy in relapsed or refractory B-cell acute lymphoblastic leukemia, B-cell lymphoma, and multiple myeloma. In Japan, five CAR-T products have already been approved and have rapidly achieved widespread adoption in real-world clinical practice. CAR-T therapy involves multiple complex steps, including autologous T-cell collection, manufacturing, bridging therapy, infusion, and management of adverse events, each of which requires careful optimization. Disease relapse or progression after CAR-T therapy also remains common, which makes it crucial to accumulate clinical experience and evidence on post-treatment management. This review outlines the current clinical use of CAR-T cell therapy in Japan, discusses practical aspects of treatment delivery throughout the process, and examines its role relative to other emerging therapies.
    Keywords:  B-cell acute lymphoblastic leukemia; B-cell lymphoma; Chimeric antigen receptor-T cell therapy; Multiple myeloma
    DOI:  https://doi.org/10.11406/rinketsu.66.1222
  5. Nat Rev Drug Discov. 2025 Sep 30.
    In vivo chimeric antigen receptor (CAR)-T cell therapy.
    Adrian Bot, Andrew Scharenberg, Kevin Friedman, Lin Guey, Robert Hofmeister, James I Andorko, Michael Klichinsky, Frank Neumann, Jagesh V Shah, Andrew J Swayer, Kyle Trudeau, Drew Weissman, Matthias T Stephan, Christian J Buchholz, Carl H June.
      Chimeric antigen receptor (CAR)-T cell therapy has transformed the outcomes of patients with haematological malignancies, yet its use is limited by labour-intensive manufacturing, constrained production capacity and variable clinical performance. In vivo CAR-T cell engineering, in which CAR-T cells are generated directly inside the patient's body, seeks to overcome these challenges by eliminating the need for ex vivo cell processing and complex logistics, as well as improve clinical performance. Recent advances in virology, RNA medicines and nanotechnology have catalysed a radical overhaul of this approach, which uses targeted delivery systems such as lentiviral vectors and lipid nanoparticles to introduce CAR-encoding genetic material into endogenous T cells. Early clinical studies have shown efficient transduction, sustained CAR expression and initial signs of antitumour activity, establishing proof of concept. This Review explores the underlying technologies - including RNA delivered by lipid nanoparticles and engineered viral vectors - and discusses how they are being adapted to develop more broadly applicable, scalable, safe and effective CAR-T cell therapies. By removing the need for ex vivo manipulation and chemotherapeutic conditioning, this strategy could enable the wider application of CAR-T cell therapies not just to blood cancers but to autoimmune diseases for which ex vivo CAR-T cell therapies have shown strong promise, such as systemic lupus erythematosus.
    DOI:  https://doi.org/10.1038/s41573-025-01291-5
  6. J Egypt Natl Canc Inst. 2025 Sep 29. 37(1): 62
    Immune-based cancer therapies: mechanistic insights, clinical progress, and future directions.
    Mahalakshmi Devaraji, Binoy Varghese Cheriyan.
      The field of cancer immunotherapy has evolved rapidly, offering new treatment paradigms by harnessing the body's own immune system to target and destroy malignancies. Various immunotherapeutic approaches, including immune checkpoint inhibitors, CAR-T cell therapy, cancer vaccines, cytokine therapies, and oncolytic viruses, have shown significant promise in treating different cancer types. This review provides a comprehensive examination of the historical development and recent advances in cancer immunotherapy. We discuss the mechanisms of action of key immunotherapeutic modalities, along with their clinical applications and innovative delivery techniques. In particular, we focus on immune checkpoint inhibitors, which have revolutionized the treatment of several cancers; CAR-T cell therapy, which has provided transformative results in hematological malignancies; and the potential of cancer vaccines, cytokine therapies, and oncolytic viruses. Additionally, the review addresses the current status of clinical trials and patents in the field, offering insight into the ongoing efforts to optimize these therapies for broader clinical use. Despite the promising results achieved, this review highlights significant challenges, such as immune-mediated toxicity, resistance to treatment, and the need for more effective delivery systems. While cancer immunotherapy has shown great potential in improving patient outcomes, overcoming existing obstacles such as toxicity and resistance remains a major challenge. This review offers a comprehensive overview of the state of cancer immunotherapy while also providing perspectives on its future directions and the ways in which these innovations may impact cancer treatment.
    Keywords:  CAR-T cell therapy; Cancer immunotherapy; Cancer vaccines; Cytokine therapies; Delivery modalities; Immune checkpoint inhibitors; Oncolytic viruses
    DOI:  https://doi.org/10.1186/s43046-025-00319-6
  7. Med Oncol. 2025 Sep 28. 42(11): 500
    Engineering adoptive cell therapy for solid tumors.
    Maryam Sanjary, Ameneh Shokati, Mahshid Akhavan Rahnama, Sanaz Khaseb, Mohammad Ahmadvand.
      Adaptive cell therapy (ACT) has emerged as a promising immunotherapeutic approach for cancer treatment by using engineered immune cells to recognize and destroy malignant cells. While ACT has shown remarkable success in hematologic malignancies, its application in solid tumors remains limited due to unique challenges such as limited immune cell infiltration, antigen heterogeneity, and the immunosuppressive tumor microenvironment. This review provides an overview of current strategies to enhance the efficacy of ACT in solid tumors, focusing on engineered T cells, including CAR-T, TCR-T, and tumor-infiltrating lymphocytes (TILs). We discuss recent progress in cancer immunotherapy, with a focus on tumor targeting, resistance to immunosuppressive signals, as well as strategies to overcome antigen escape. Moreover, we highlight the role of gene-editing tools such as CRISPR/Cas9 in designing next-generation immune cells with enhanced functionality and safety. By integrating novel engineering techniques and systems biology approaches, ACT holds the potential to become a key component of personalized cancer therapy for solid tumors.
    Keywords:  Adaptive cell therapy; CAR T cells; NK cells; Solid tumors
    DOI:  https://doi.org/10.1007/s12032-025-03067-8
  8. Methods Mol Biol. 2026 ;2959 189-201
    An Indigenous Workflow for Generating CD19 CAR-T Cells.
    Muthuganesh Muthuvel, Sunil Martin.
      FDA-approved CD19 CAR T cell therapy for treating B-cell lineage malignancies gave impetus to the adoptive immune/cell and gene therapy field. Although tested to a considerable extent, side effects such as immune effector cell-associated neurotoxicity syndrome (ICANS), immune effector cell-associated hematotoxicity (ICAHTs), the high cost of the therapy, and often complicated logistics make the accessibility of this CAR therapy far from the reach of many eligible patients. Therefore, the development of a safe, cost-effective, streamlined indigenous workflow for T-cell expansion, transduction, and CAR T-cell characterization is essential in a preclinical as well as clinical setting. We have optimized a method to develop CD19 CAR T cells from peripheral blood T cells from healthy donors. In this chapter, we describe an indigenous protocol for the generation and characterization of CD19 CAR T cells via lentiviral transduction to understand the immunology or possible downstream applications.
    Keywords:  Antitumor functions; CD19 CAR T cells; Flow cytometry; Lentiviral production
    DOI:  https://doi.org/10.1007/978-1-0716-4734-9_14
  9. Discov Oncol. 2025 Sep 29. 16(1): 1770
    Global research trends in CAR-T cell therapy for glioblastoma: a bibliometric and visualized analysis.
    Jian Li, Lichun Lu, Yu Duan, Guohui Huang, Xuhao Fang, Yao Deng, Feng Tang, Feng Jiang, Dongwei Dai.
       BACKGROUND: Glioblastoma (GBM) is the most aggressive and lethal primary malignant brain tumor in adults, characterized by extensive heterogeneity and a profoundly immunosuppressive microenvironment. Despite advances in surgery, radiotherapy, and chemotherapy, therapeutic outcomes remain poor. Chimeric antigen receptor (CAR)-T cell therapy has shown remarkable efficacy in hematologic malignancies and is now being explored for solid tumors such as GBM. Given the expanding research landscape, a systematic understanding of global trends and hotspots in this domain is urgently needed.
    METHODS: We conducted a comprehensive bibliometric and visualized analysis of publications related to CAR-T cell therapy in GBM from inception to December 31, 2024, using the Web of Science Core Collection. CiteSpace was used to analyze publication trends, country and institutional collaboration, author impact, journal co-citation, reference networks, and keyword co-occurrence, clustering, and bursts.
    RESULTS: A total of 303 relevant publications were included. Annual outputs showed rapid growth beginning in 2015, with the United States and China leading in productivity and collaboration. Influential authors such as Christine E. Brown and Donald M. O'Rourke were identified as core contributors. Neuro-Oncology and Clinical Cancer Research emerged as key publishing and co-cited journals. Co-citation and keyword analysis revealed a shift from early focus on single-antigen CAR designs (e.g., IL13Rα2, EGFRvIII) toward dual-target constructs, "armored" CAR-T cells, and combinatorial immunotherapies. Recent research hotspots included immunomodulation, precision medicine, and novel delivery platforms such as nanoparticles and oncolytic viruses.
    CONCLUSIONS: This study maps the evolving scientific landscape of CAR-T cell therapy in GBM, highlighting key contributors, institutional collaboration, and emerging research frontiers. The transition from basic antigen targeting to multifunctional, immune-enhancing strategies reflects a maturing field with increasing translational focus. Our findings offer valuable insights that can inform strategic funding allocation by identifying high-impact institutions and authors, optimize clinical trial design by highlighting emerging combinatorial and delivery strategies, and guide novel target discovery through analysis of co-cited references and keyword bursts. By revealing global collaboration networks and thematic shifts, this study also supports the development of interdisciplinary research frameworks in CAR-T therapy for GBM.
    Keywords:  Bibliometric analysis; CAR-T cell therapy; Glioblastoma; Immunotherapy; Research trends
    DOI:  https://doi.org/10.1007/s12672-025-03285-6
  10. Tissue Cell. 2025 Sep 28. pii: S0040-8166(25)00446-X. [Epub ahead of print]98 103164
    CAR T-cell therapy in autoimmune diseases: Opportunities and challenges, with implications for RA.
    Mohamad Mahdi Hojati Shargh, Mahmoud Mahmoudi, Seyed Amir Asef Agah, Fatemeh Forouzanfar, Zahra Javanmardi, Afsane Fadaee, Dariush Haghmorad, Seyed-Alireza Esmaeili.
      Chimeric antigen receptor (CAR) T-cell therapy, initially developed for hematologic malignancies, is now being applied to autoimmune diseases. This review examines CAR T-cell applications in autoimmunity, focusing on rheumatoid arthritis (RA). We analyze CAR T-cell technology development, generational evolution, and manufacturing considerations. Clinical trials in systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and other autoimmune conditions demonstrate that single CAR T-cell infusions induce sustained, drug-free remission through selective pathogenic B-cell depletion and immune tolerance restoration. RA presents distinct challenges: disease heterogeneity, multi-cellular involvement (autoreactive T/B cells, synovial fibroblasts), and absence of universal target antigens. Preclinical approaches include HLA-DR1-targeted CARs for autoreactive CD4 + T cells and anti-FITC CARs for citrullinated peptide-specific B cells, though clinical optimization remains necessary. RA requires higher therapeutic precision than other autoimmune diseases due to established effective conventional treatments. Advances in allogeneic CAR T cells, dual-targeting constructs, and safety mechanisms (suicide switches) may facilitate clinical implementation. This review evaluates CAR T-cell therapy potential in autoimmune disease treatment and RA-specific therapeutic challenges.
    Keywords:  Autoimmune diseases; B-cell depletion; CAR T-cell therapy; Immune reset; Rheumatoid arthritis (RA)
    DOI:  https://doi.org/10.1016/j.tice.2025.103164
  11. Clin Pharmacol Ther. 2025 Oct 02.
    Foundational Principles for the Quantitative Translation of T-Cell Therapeutics for Hematologic Malignancies and Immunology.
    Peter Ashcroft, Sarah McFann, Alex Ferguson, Arthur Van De Vyver, Suzanne Gaudet, Eshita Khera, Jan-Frederik Schlender.
      T-cell engaging antibodies (TCEs) and chimeric antigen receptor (CAR) T cells (CAR-T cells) are among precision medicine therapies that have revolutionized the treatment of hematologic cancers. Their success in oncology has piqued interest in translating this promise into additional indications, such as autoimmune disorders. This review discusses the foundational principles for mechanistic modeling to provide a unified assessment framework for cross-modality (i.e., CAR-T cells vs. TCEs) and cross-indication (i.e., oncology vs. immunology) translation. This framework captures the unique elements of each modality, such as CAR-T cellular kinetics, TCE pharmacokinetics, and complex formation with target cells, as well as shared elements such as B-cell kinetics and biodistribution across indications. We describe how this integrated approach can lead to informed decision making for more personalized and effective treatment strategies with these immune therapies.
    DOI:  https://doi.org/10.1002/cpt.70077
  12. Cytotherapy. 2025 Aug 22. pii: S1465-3249(25)00810-2. [Epub ahead of print]
    Cell and gene therapy approvals in Asia: regulatory landscape, access and affordability.
    William Ying Khee Hwang, Sudipto Bari, Shin Kawamata, Bryan Choi, Chaiyong Koaykul, He Huang, Pawan Gupta.
      Cell and gene therapies (CGTs) are revolutionizing the treatment paradigm for a range of life-threatening and rare conditions, offering curative potential where conventional therapies have fallen short. In Asia, the CGT landscape has matured significantly in recent years, driven by regulatory reforms, increased local development and a growing number of product approvals. This updated review presents a comprehensive analysis of CGT regulatory frameworks, product approvals, pricing trends and reimbursement policies across six key Asian markets: Singapore, Japan, South Korea, China, India and Thailand. Drawing upon updated data from 2023 to 2025, we examine differences in regulatory maturity, access pathways, affordability and local manufacturing capabilities. The review highlights how certain countries, such as Japan and South Korea, have successfully implemented fast-track regulatory pathways, while others, like India and China, have emphasized domestic innovation to drive down costs. Despite progress, affordability, scalability and sustainable reimbursement remain persistent challenges. By presenting an up-to-date comparative analysis and synthesizing emerging policy innovations, this article offers insights into opportunities for harmonization, equitable access and future policy planning in Asia's rapidly evolving CGT sector.
    Keywords:  Asia; CTGTP; approvals; funding; regulatory
    DOI:  https://doi.org/10.1016/j.jcyt.2025.08.005
  13. Crit Rev Oncol Hematol. 2025 Sep 29. pii: S1040-8428(25)00360-9. [Epub ahead of print] 104972
    From Innate Power to Intelligent Design: The Evolution of NK Cell-Based Cancer Immunotherapy.
    Israth Jahan Tuhin, Hong Jia Zhu, Masuma Akter Monty, Jin Wen Tan, Nan Xu, Jing Ye, Lei Yu.
      Natural killer (NK) cells have emerged as a promising platform for cancer immunotherapy due to their intrinsic cytotoxicity, lack of antigen restriction, and minimal risk of graft-versus-host disease, enabling the development of safe and scalable "off-the-shelf" therapies. However, their clinical efficacy, particularly in solid tumors, remains limited by poor in vivo persistence, inadequate tumor infiltration, and suppression by the immunosuppressive tumor microenvironment (TME). This review highlights the recent advances in genetic engineering strategies to enhance NK cell antitumor function. We discuss the optimization of chimeric antigen receptors (CARs) specifically for NK cells, the integration of immune checkpoint resistance, metabolic reprogramming, and the incorporation of cytokine support to improve survival and potency. In parallel, we explore combination strategies that synergize with NK cells, including monoclonal antibodies, oncolytic viruses, vaccines, and adoptive immune cell therapy. Additionally, we examine innovative platforms such as nanoparticle delivery systems and NK cell-derived exosomes to further enhance therapeutic outcomes. By systematically addressing the intrinsic and extrinsic limitations of NK cells through genetic precision and combinatorial immunomodulation, NK-based therapies are poised to transition from supportive to frontline modalities in cancer treatment. This review provides a comprehensive roadmap for the next generation of NK cell therapies with broad translational potential.
    Keywords:  Exosomes; Nanoparticles; Natural Killer cells; Oncolytic Virus; Tumor infiltration
    DOI:  https://doi.org/10.1016/j.critrevonc.2025.104972
  14. Front Immunol. 2025 ;16 1647066
    Innovations in immunotherapy for autoimmune diseases: recent breakthroughs and future directions.
    May A Alsayb.
      Millions of people worldwide suffer from chronic and devastating autoimmune disorders, challenging contemporary medicine. These disorders develop when the immune system attacks its own tissues, causing inflammation and damage. Traditional treatments have focused on widespread immunosuppression, which can relieve symptoms but has serious adverse effects and does not address immunological dysregulation. This review discusses the current and future trends in immunotherapy for the management of autoimmune diseases, including advancements such as CAR T-cell therapy, bispecific antibodies, next-generation immune checkpoint modulators, targeted cytokine therapies, and microbiome-based interventions. The discussion is grounded in current scientific literature, focusing on mechanisms of action, recent breakthroughs, limitations, and potential future directions. Each of the related sections presents cutting-edge advancements, current challenges, and future opportunities for research and clinical translation.
    Keywords:  CAR T-cells; autoimmunity; bispecific antibodies; checkpoint modulators; cytokine therapy; immunotherapy; microbiome interventions
    DOI:  https://doi.org/10.3389/fimmu.2025.1647066
  15. J Law Biosci. 2025 Jul-Dec;12(2):12(2): lsaf018
    Disparities in access to gene therapy in the European Union: ethical and regulatory challenges.
    Margaux Reckelbus, Riya Mohan, Phaedra Locquet, Eva Van Steijvoort, Isabelle Huys, Pascal Borry.
      Gene therapies represent a significant advancement in modern medicine, offering potential cures for untreatable genetic disorders. However, equitable access to these innovative therapies remains a critical ethical challenge within the European Union (EU). This paper examines the adequacy of the EU's centralized market authorization framework, supplemented by alternative pathways such as the Hospital Exemption and Compassionate Use Program, in addressing access disparities. While the centralized framework ensures high standards of safety, quality, and efficacy, its implementation reveals significant barriers related to affordability, geographical disparities, and fragmented national healthcare systems. High costs create financial obstacles for both healthcare systems and individuals, disproportionately affecting low-income countries and regions. Geographic disparities are further exacerbated by fragmented regulations and uneven healthcare infrastructures across member states, limiting patient access in rural areas. Alternative pathways, while designed to improve access, suffer from inconsistent national-level implementation. This paper argues that as the EU navigates the complexities of gene therapy regulation, it must focus on creating a more cohesive and inclusive framework. By doing so, it can ensure that the potential of gene therapies is realized in a manner that benefits all EU citizens, irrespective of their geographic or economic circumstances.
    Keywords:  European Union; access; affordability; ethics; gene therapy; regulation
    DOI:  https://doi.org/10.1093/jlb/lsaf018
  16. Br J Clin Pharmacol. 2025 Sep 30.
    Budget impact analysis of new drugs in oncology and haematology: Principles and practice.
    Javier Soto-Alsar, José L Revuelta-Herrero, Cristina Villanueva-Bueno, Carmen Cobos-Lama, Marc A Cañete-Muñoz, Andrés Muñoz-Martín, Pilar García-Alfonso, Javier Soto-Álvarez.
      Cancer is currently among the most prevalent and fatal diseases, so new, costly drugs for its treatment will be available in the coming years. Budget impact analyses (BIAs) are an essential component of the economic evaluation of new oncological and haematological drugs, and are increasingly required by health authorities in many countries as part of the pricing and reimbursement process. This article aims to provide updated guidance on the methodology for performing such analyses. In a BIA, the resource consumption in the reference scenario (before the new drug is introduced) is always compared with the resource consumption in the future scenario (after the new treatment is commercialized). The most important parts of a BIA include calculating the number of the existing patient population, the current mix of treatments and the expected mix after the coming of the new drug, the cost of the treatment mixes and other changes in cancer-related costs. The BIA's data sources should be drawn from the best available published evidence, such as clinical trials, observational studies, local epidemiological information, cost databases and expert opinion. Where possible, the decision maker's population and calculations for other parameter estimations should also be included. A deterministic analysis and a scenario sensitivity analysis should be carried out in every BIA. The BIA report must provide details of resource consumption and associated costs in the reference scenario and the future scenario. The difference between the 2 scenarios will represent the budget impact of introducing a new drug to the market.
    Keywords:  budget impact analysis; economic evaluation; guideline; methodology; oncohaematological drug
    DOI:  https://doi.org/10.1002/bcp.70303
  17. Transl Oncol. 2025 Oct 02. pii: S1936-5233(25)00286-4. [Epub ahead of print]62 102555
    CD70-targeted CAR-T/NK therapy: Rationale, advances, and future directions.
    Sijia Yan, Xiaojian Zhu, Yi Xiao.
      Chimeric antigen receptor T and natural killer (CAR-T/NK) cells is a rapidly evolving cellular immunotherapy technology that has made great achievements in the treatment of hematologic diseases. CD70, as a surface antigen expressed on tumor cells in a variety of hematologic malignancies, including acute myeloid leukemia, non-Hodgkin lymphoma, multiple myeloma, etc., and solid tumors such as renal cell carcinoma, osteosarcoma, and glioma, is a potential target for CAR-T/NK cells. Several preclinical studies and clinical trials on CAR-T/NK cells targeting CD70 are currently underway, bringing new hope for the treatment of CD70-positive tumors.
    Keywords:  Chimeric antigen receptor T cell; Chimeric antigen receptor natural killer cell; D70; Hematological malignancies; Solid tumors
    DOI:  https://doi.org/10.1016/j.tranon.2025.102555
  18. Cytotherapy. 2025 Aug 31. pii: S1465-3249(25)00813-8. [Epub ahead of print]
    Automated vertical wheel bioreactor integrated with process analytics for T-cell manufacturing.
    Bryan Wang, Bharat Kanwar, Annie C Bowles-Welch, Walker Byrnes, Paloma Casteleiro Costa, Caroline Filan, Reginald Tran, Theresa Kotanchek, Francisco Robles, Krishnendu Roy, Stephen Balakirsky.
       BACKGROUND AIMS: Biomanufacturing of cell therapies involves highly complex and labor-intensive processes, where process parameters and biological variabilities can significantly influence product quality, reproducibility and therapeutic efficacy. Here, we developed a vertical wheel-based bioreactor platform with automated controls and in-line process analytical technologies (PAT) to demonstrate successful closed-system T cell biomanufacturing.
    METHODS: By identifying the critical process parameters (CPP), a process development strategy was optimized for expanding primary human unmodified and chimeric antigen receptor (CAR) T cells using multiple activation systems, including degradable microscaffolds.
    RESULTS: Spent media analysis combined with symbolic regression identified CPPs, which were validated through small-scale experiments and large-scale expansions in the bioreactor platform. Closed-loop automation with analytics such as real-time imaging also was integrated into the bioreactor platform for continuous monitoring and process control.
    CONCLUSIONS: This integrated bioreactor platform provides a proof-of-concept design for multiplexed PAT integration, process optimization and feedback-controlled intelligent automation to enable discovery, monitoring and control of critical quality attributes and critical process parameters for cell therapy manufacturing.
    Keywords:  T cells; automation; bioreactor design; cell therapy manufacturing; process analytical technology; process development
    DOI:  https://doi.org/10.1016/j.jcyt.2025.08.007
  19. Int J Cancer. 2025 Oct 02.
    Integrated scFv identification and CAR T cell generation for AML targeting in vivo.
    Yi Liu, Annika Lauk, David Sedloev, Josephine Brysting, Ela Cetin, Chunan Liu, Maximilian Mönnig, Thomas Luft, Haiyang Yun, Michael Schmitt, Tim Sauer, Fengbiao Zhou, Christian Rohde, Carsten Müller-Tidow.
      Cancer immunotherapy has witnessed remarkable advancements, particularly in the development of chimeric antigen receptor (CAR) T cell therapy. Here, we integrated single chain variable fragment (scFv) development with CAR T cell generation based on a newly developed scFv phagemid library. High-throughput long-read PacBio sequencing identified 4.5 × 107 unique full-length scFv proteins within the generated library. As a proof of principle, we screened for scFvs targeting C-type lectin-like molecule-1 (CLL1) with subsequent cloning into a third generation retroviral CAR backbone. Functional assays revealed the specificity and potency of these CAR T cells in targeting CLL1-positive AML cells in vitro. In vivo studies reduced tumor burden and improved survival rates compared to controls. Taken together, screening for tumor-specific scFvs against CLL1 can rapidly generate AML-specific CAR T cells with effective tumor killing in vivo.
    Keywords:  CAR T cell therapy; CLL1; acute myeloid leukemia; phage display library; scFv
    DOI:  https://doi.org/10.1002/ijc.70146
  20. Clin Lymphoma Myeloma Leuk. 2025 Sep 10. pii: S2152-2650(25)03399-3. [Epub ahead of print]
    The Promise of Immunotherapies in T-Cell Lymphoma.
    Colin J Thomas, Stefan K Barta.
      T-cell non-Hodgkin lymphomas (NHL) are a heterogenous group of malignancies that represent a minority of all NHL cases world-wide. Outcomes with traditional chemotherapy-based regimens remain poor with notably dismal outcomes in the relapsed/refractory setting. The power of immunotherapy has revolutionized treatments and outcomes for hematologic malignancies and has already made significant strides in addressing the treatment needs in T-cell NHLs. Given the heterogeneity of T-cell lymphoma subtypes and biology, a wide variety of innovative immunotherapies have been evolving to treat these various malignancies. Here, we review the promising advancement of various immunotherapies in T-cell NHLs including antibody-based therapies targeting T-cell surface antigens and checkpoint signaling, as well as the expanding strategies for chimeric antigen receptor T-cell (CAR-T) therapy in this difficult to treat disease space.
    Keywords:  Antibody; CAR-T therapy; Cellular therapy; Checkpoint inhibitor; Lymphoid cancer
    DOI:  https://doi.org/10.1016/j.clml.2025.09.006
  21. EMBO Mol Med. 2025 Sep 29.
    Targeting mitochondrial Kv1.3 enables precise autoreactive T cell therapy for multiple sclerosis.
    Stefano Pluchino, Cory M Willis.
      
    DOI:  https://doi.org/10.1038/s44321-025-00306-3
  22. Curr Opin Oncol. 2025 Sep 04.
    Predictors of response to CD19 chimeric antigen receptor T-cell therapy in large B-cell lymphoma: a consolidated review.
    Ori Ben Valid, Roni Shouval.
       PURPOSE OF REVIEW: CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has transformed outcomes for relapsed/refractory large B-cell lymphoma (LBCL), yet nearly half of treated patients relapse, and toxicities remain frequent. A deeper understanding of response predictors is urgently needed to guide patient selection, treatment optimization, and development of rational combination strategies.
    RECENT FINDINGS: Emerging data reveal that response to CAR-T therapy is shaped by patient-specific, tumor-intrinsic, and treatment-related factors. Clinical variables such as age, performance status, inflammation, and microbiome composition influence efficacy. Tumor burden, disease distribution, histologic subtype, and genomic alterations correlate with resistance. Treatment factors, including bridging strategies, lymphodepletion regimen, and CAR-T product design, affect expansion, persistence, and clinical outcomes. Novel insights from immune profiling, radiomics, and single-cell transcriptomics offer further granularity and predictive potential.
    SUMMARY: Predictors of CAR-T response span diverse biological and clinical domains and are increasingly actionable. Integrating multimodal biomarkers into routine workflows can personalize care and improve outcomes. Prospective validation, real-time monitoring, and adaptive trial designs are essential next steps toward precision CAR-T therapy.
    Keywords:  chimeric antigen receptor T-cell therapy; immunotherapy; large B-cell lymphoma; predictive biomarkers; treatment outcomes
    DOI:  https://doi.org/10.1097/CCO.0000000000001188
  23. Anal Sci. 2025 Sep 30.
    Advances in microfluidic chip technology for cell analysis.
    Luxi Shu, Yan Zhang.
      Microfluidic chips play a crucial role in the field of cell analysis. These miniature chips integrate seamlessly across key cell analysis stages, including sample preparation, cell culture, sorting, lysis, and detection. They possess many advantages such as miniaturization, integration, automation, and portability. The size of their microchannels is comparable to that of cells, thus enabling research to be conducted at the single-cell or even subcellular organelle level. They can also simulate the physiological conditions in vivo, conduct non-destructive or minimally destructive detections, and meet the requirements of high-throughput cell analysis, which is beneficial for parallel operations and continuous analysis. This article reviews the technological progress of microfluidic chips, focusing on three major directions: cell sorting and enrichment, single-cell analysis, and dynamic microenvironment simulation. The article also analyzes the challenges faced by this technology, such as cell damage control, handling of multicellular heterogeneity, data interpretation, etc., and proposes coping strategies such as the development of new biomaterials, multimodal integration technology, and artificial intelligence assistance. By combining cutting-edge technologies such as nanotechnology, 3D printing, and organoid culture, the functions of microfluidic chips can be further expanded to enable the simulation and analysis of more complex biological systems and provide important technical support for cell biology research and clinical translation.
    Keywords:  Cell analysis and detection; Cell sorting and enrichment; Dynamic microenvironment simulation; Microfluidic chip; Single-cell analysis
    DOI:  https://doi.org/10.1007/s44211-025-00851-4
  24. Expert Rev Precis Med Drug Dev. 2025 ;10(1): 16-33
    Immunotherapy for precision medicine in colorectal cancer.
    Miao Cao, Michael Xu, Zinah Bairmani, Babar Bashir, Scott A Waldman, Adam E Snook.
       Introduction: Colorectal cancer (CRC) is the fourth most common cancer and second leading cause of cancer-related death in the United States. The implementation of CRC screening has decreased CRC incidence in adults older than 65 years. However, among young adults who experience more aggressive disease progression, CRC incidence has been increasing for decades. Immunotherapy represents a collection of innovative and promising approaches with greater efficacy and safety. In this review, we discuss modalities and selected targets of immunotherapies for CRCs that are guided by precision medicine.
    Areas covered: The following review focuses on immunological approaches for CRCs, including therapeutic monoclonal antibodies, immune checkpoint blockade, cancer vaccines, and adoptive cell therapies.
    Expert opinion: Metastatic and refractory CRCs are significant causes of cancer-related mortality and remain difficult to treat with current standard therapies. Following multiple FDA approvals for hematologic malignancies, research into solid tumor immunotherapies has substantially increased. Several chimeric antigen receptor (CAR)-expressing T cell therapies are showing promise in CRC. Moreover, immune checkpoint blocking antibodies are transforming care for a subset of CRC patients. With advances in our understanding of oncogenic mechanisms and development of novel treatment approaches, personalized immunotherapies are poised to dramatically change the landscape of CRC treatment.
    Keywords:  Colorectal cancer; cancer vaccine; checkpoint blockade therapy; chimeric antigen receptor-T cell therapy; immunotherapy
    DOI:  https://doi.org/10.1080/23808993.2025.2560303
  25. Transl Oncol. 2025 Oct 01. pii: S1936-5233(25)00269-4. [Epub ahead of print]62 102538
    HDAC inhibitor (SAHA) enhances B7-H3-specific CAR T cell cytotoxic efficacy against chondrosarcoma cells and prolongs survival in an orthotopic mouse model.
    David O Osei-Hwedieh, Lile He, Kun Wang, Song Fan, Soldano Ferrone, Xinhui Wang, Joseph H Schwab.
      High-grade Chondrosarcoma (Grades II, III, and dedifferentiated) is an aggressive primary malignant bone tumor characterized by hyaline cartilaginous neoplastic tissue without any effective systemic therapy. Localized disease is treated with a complete surgical resection with negative margins. However, high-grade chondrosarcoma often spreads systemically, leading to low overall survival rates of 29 %. These clinical findings emphasize the urgent need for improved systemic therapies. Among them is chimeric antigen receptor (CAR) T cell therapy. In this study, tumor-associated antigen B7-H3, which is highly expressed in chondrosarcoma cells but has a restricted expression in normal tissues, is targeted with B7-H3-specific CAR T cells. Our results show that these CAR T cells are effective in killing chondrosarcoma cells in vitro and retard chondrosarcoma tumor growth in immunodeficient mice, which resulted in prolonged survival of tumor-bearing mice. To enhance the antitumor activity of B7-H3 CAR T cells, tumor cells or CAR T cells were treated ex-vivo with a low dose of vorinostat (SAHA), a histone deacetylase (HDAC) inhibitor that upregulates B7-H3 transcription and expression in several types of solid cancer cells as well as the chimeric antigen receptor. Our results demonstrate that treatment of B7-H3 CAR T cells or chondrosarcoma cells with SAHA enhances CAR T cell antitumor cytotoxic activity in vitro and in vivo.
    Keywords:  Chimeric antigen receptor (CAR) T cell therapy; Chondrosarcoma; SAHA; epigenetics
    DOI:  https://doi.org/10.1016/j.tranon.2025.102538
  26. Med. 2025 Sep 30. pii: S2666-6340(25)00276-4. [Epub ahead of print] 100849
    Antibody-drug conjugates: Current challenges and innovative solutions for precision cancer therapy.
    Xingyu Zhou, Yanjie Han, Yuan Fang, Peiwen Ma, Jiawei Zhou, Yale Jiang, Shujun Xing, Qiyu Tang, Yiru Hou, Shuhang Wang, Ning Li.
      Antibody-drug conjugates (ADCs) have advanced cancer therapy by combining antibody specificity with cytotoxic potency. However, clinical experience has revealed challenges limiting their efficacy and safety. This review addresses key questions in ADC development and corresponding optimization strategies. It discusses the relationship between target antigen expression and clinical response and the role of antibodies beyond targeting. Enhancing ADC distribution via bispecific targeting and probody masking is summarized. Traditional assumptions in linker design, such as favoring maximum stability, are re-evaluated to improve clinical outcomes. Innovations in linker chemistry encompass tumor microenvironment-responsive release mechanisms and bioorthogonal reactions. Emerging payload strategies like immune-stimulating ADCs (ISACs) and degrader-antibody conjugates (DACs) expand therapeutic possibilities but introduce new safety challenges. Ultimately, merely increasing ADC structural complexity is insufficient. Understanding tumor delivery barriers and bridging preclinical-clinical gaps will be vital to fully realize the potential of ADCs in precision oncology.
    Keywords:  ADC; ISAC; antibody-drug conjugate; immune-stimulating antibody conjugate; linker stability; solid tumor; targeted cancer therapy
    DOI:  https://doi.org/10.1016/j.medj.2025.100849
  27. Br J Haematol. 2025 Sep 30.
    Optimizing activation and culture conditions for the production of cord blood-derived CAR-T and natural killer cells.
    Naokazu Nakamura, Jiyuan Liao, Yasushi Soda, Mizuho Takahashi, Hiroto Kodera, Yukage Kobari, Yukihiko Hirai, Akifumi Takaori-Kondo, Takashi Okada.
      Cord blood (CB) is gaining attention as a source of chimeric antigen receptor (CAR) T/NK cells. Many studies have focused on the therapeutic effects, but the methods of activating and culturing T/NK cells without excessive exhaustion during the initial stages of the production of CB-derived CAR-T/NK cells are yet to be established. The activation and culture conditions developed for peripheral blood (PB) CAR-T/NK cells have been used for CB-CAR-T/NK cells, but there are differences in the composition and maturity of PB and CB lymphocytes. Thus, this study aims to optimize activation and culture conditions for the production of CB-CAR-T/NK cells. We compared different doses of various cytokines and found that the balance between activation and exhaustion was best with stimulation with a CD3/CD28 agonist followed by 40 U/mL interleukin (IL)-7+ 40 U/mL IL-15 for PB-T cells; 40 U/mL IL-2+ 40 U/mL IL-7+ 40 U/mL IL-15 for CB-T cells; 40 U/mL IL-2+ 40 U/mL IL-15 for PB-NK cells; and 40 U/mL IL-2+ 200 U/mL IL-15 for CB-NK cells. Using killing assays, we confirmed that these cytokine protocols improved the anti-tumour effects. These results will be useful for the development of CB-CAR-T/NK-cell therapies and suggest the potential of these modalities.
    Keywords:  activation; chimeric antigen receptor T‐cell therapy; culture; cytokines; immunotherapy
    DOI:  https://doi.org/10.1111/bjh.70139
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒05 at 10:30.