bims-carter 2025-11-09 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2025–11–09
25 papers selected by
Luca Bolliger, lxBio

Chimeric antigen receptor natural killer (CAR-NK) cells: from preclinical promise to clinical reality in cancer immunotherapy.
Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-γδ T strategies in solid tumor immunotherapy.
CAR-T cell therapy: A therapeutic strategy for cancer treatment.
Universal CAR-T Cell Therapy for Cancer Treatment: Advances and Challenges.
Multiplex engineering and multifunction T cells for precise and effective immunotherapies.
CAR-T cells immunotherapy in the treatment of glioblastoma.
Modeling and addressing on-target/off-tumor toxicity of claudin 18.2 targeted immunotherapies.
CAR T cells for multiple sclerosis: Engineering T cells to disrupt chronic B cell-driven neuroinflammation.
CAR-T therapy for neuroendocrine neoplasms: a review of molecular targets and clinical translation.
CAR-T cell therapies in autoimmune rheumatic diseases: a brief report on the clinical trial landscape, current status, and future perspectives.
Tracing the Technological Trajectory of CAR-T Cell Therapy in Cancer Treatment through Patent Analysis.
CAR T-cell therapy in systemic sclerosis: the next frontier in immune modulation.
Incorporating mRNA therapeutics into biological treatments of hematologic malignancies.
Gene Therapies: Any Merit in Nephrology?
National Landscape of Logistical and Non-Medical Requirements for Transplantation and Cellular Therapy.
Umbilical cord blood: a comprehensive review of protective and restorative properties in clinical applications - a narrative review.
Incorporation of target safety review in drug discovery.
Reimagining drug regulation in the age of AI: a framework for the AI-enabled Ecosystem for Therapeutics.
Leveraging the heterogeneity of the NK cell repertoire for the development of immunotherapies for acute leukemia.
New advances on the interaction between internal and external factors in the tumor microenvironment of solid tumors.
Antibody-drug conjugates in cancer therapy: current landscape, challenges, and future directions.
Emerging Nucleic Acid Cargos for Next-Generation RNA Vaccines and Therapeutics.
Genetic Perturbation Modelling for Human Cell Therapy With BRNET.
mRNA Vaccines: Current Applications and Future Directions.
Mapping the frontiers: a bibliometric perspective on t cell-based immunotherapy in pancreatic cancer since the twenty-first century.

Immunotherapy. 2025 Nov 04. 1-13

Chimeric antigen receptor natural killer (CAR-NK) cells: from preclinical promise to clinical reality in cancer immunotherapy.

Hunter Cassidy Cochran, Kevin Ashkan Ghobadi, Armin Ghobadi.

  Chimeric antigen receptor (CAR) natural killer (NK) cell therapy represents an emerging frontier in cancer immunotherapy. CAR-NK cells offer the potential for "off-the-shelf" treatments with a favorable safety profile, due in part to their innate capacity for HLA-unrestricted tumor targeting and an absence of graft-versus-host disease. Landmark clinical studies using cord blood - derived CAR-NK cells and another employing iPSC-derived CAR-NK cells have reported impressive response rates, durable remissions, and minimal toxicity. Furthermore, a growing landscape of ongoing clinical trials is exploring innovative strategies to enhance persistence, overcome solid tumor challenges, and prevent antigen escape. These advances collectively underscore the potential of CAR-NK therapies to revolutionize cancer treatment while addressing limitations associated with current CAR-T cell approaches.

Keywords:  CAR‐NK cells; adoptive cell therapy; cancer immunotherapy; clinical trials; natural killer cells

DOI:  https://doi.org/10.1080/1750743X.2025.2582464
Front Immunol. 2025 ;16 1675807

Beyond CAR-T Cells: exploring CAR-NK, CAR-M, and CAR-γδ T strategies in solid tumor immunotherapy.

Yingjie Hou, Shihua Hu, Chong Liu, Xin Chen, Yuru Wang, Youzherui Li, Zihe Fu, Chunjing Feng, Yanhua Gong, Zichuan Liu, Shouchun Peng.

  Adoptive cell therapy (ACT) employing chimeric antigen receptor (CAR) engineering represents a transformative advancement in cancer immunotherapy. CAR-T cell therapies have demonstrated significant clinical success in hematological malignancies, yet their application to solid tumors faces persistent challenges. Key limitations include the paucity of tumor-specific antigens, poor intratumoral infiltration, immunosuppressive tumor microenvironment (TME), and treatment-related toxicities such as cytokine release syndrome (CRS) and neurotoxicity. In contrast, CAR natural killer (CAR-NK) cells show promise in solid tumors such as ovarian, pancreatic, and glioblastoma, with encouraging preclinical and early clinical evidence, although limited persistence and antigen heterogeneity remain major challenges. Unlike CAR-T cells, CAR-NK therapies mediate tumor clearance through both cytotoxic (e.g., granzyme/perforin release) and cytokine-mediated mechanisms while mitigating toxicity risks. Their lack of human leukocyte antigen (HLA) dependency enables "off-the-shelf" manufacturing from allogeneic donors, circumventing patient-specific production bottlenecks. CAR-macrophage (CAR-M) therapies further address solid tumor barriers by leveraging innate phagocytic clearance, antigen-presenting functions, and TME penetration. Macrophages inherently infiltrate hypoxic tumor regions and remodel stromal barriers, enabling CAR-Ms to synergize with adaptive immunity by cross-priming T cells. Preclinical models highlight CAR-M efficacy in depleting immunosuppressive tumor-associated macrophages (TAMs) and reversing TME-driven immune evasion. Emerging CAR- Gamma-Delta T (CAR-γδ T) cell therapies combine CAR-mediated antigen specificity with the intrinsic tumoricidal activity of γδ T cells, which recognize stress-induced ligands independently of major histocompatibility complex (MHC) presentation. This dual-targeting capability enhances tumor selectivity while reducing on-target/off-tumor toxicity. This review systematically examines cellular sources, mechanistic advantages and clinical progress. By evaluating these platforms' complementary strengths, we propose rational strategies for integrating CAR-NK, CAR-M, and CAR-γδ T cells into tailored therapeutic regimens for solid tumors.

Keywords:  NK cells; chimeric antigen receptor; macrophage cells; solid tumor; γδT cells

DOI:  https://doi.org/10.3389/fimmu.2025.1675807
Semin Oncol. 2025 Nov 03. pii: S0093-7754(25)00122-8. [Epub ahead of print]52(6): 152430

CAR-T cell therapy: A therapeutic strategy for cancer treatment.

Shabana Sharif, Upma Sharma, Ashok Kumar Yadav.

  In the twenty-first century, chimeric antigen receptor (CAR)-T cell therapy has transformed cancer immunotherapy by offering novel approaches and life-saving treatments for illnesses that were previously incurable. This method is currently being used in clinical trials for solid tumors like prostate cancer and glioblastoma, as well as viral and autoimmune illnesses. It has demonstrated impressive efficacy in treating a variety of hematological malignancies. Harvesting a patient's T cells, genetically modifying them using viral vectors to express CARs that target specific antigens, and then reintroducing the altered cells into the patient is the process of CAR-T cell therapy. These CAR-T cells detect and destroy target cells specifically, regardless of the presence of the major histocompatibility complex (MHC) antigen. The major turning points in the development of CAR-T cells, from their creation to their use in medicine, are highlighted in this overview. It describes how CAR-T cells were developed historically, highlights the significant advancements that have made them a ground-breaking treatment, and talks about the obstacles that still need to be overcome, such as the high cost of production, restricted availability, and toxicity problems like cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. The review also looks at the field's future developments with the goals of increasing therapeutic uses, minimizing toxicity, and maximizing efficacy. With safer and more efficient CAR T cell therapies being developed, we are optimistic that a larger group of cancer patients may soon benefit from this innovative treatment.

Keywords:  Cancer; Chimeric antigen receptor (CAR-T); Cytokine release syndrome; Immunotherapy; Tumor

DOI:  https://doi.org/10.1016/j.seminoncol.2025.152430
Oncol Res. 2025 ;33(11): 3347-3373

Universal CAR-T Cell Therapy for Cancer Treatment: Advances and Challenges.

Jianan Lei, Zhuona Ni, Ruidi Zhang.

  This review aims to explore the development, challenges, and future directions of UCAR cell therapy as a scalable alternative to autologous CAR-T for cancer treatment. Consequently, limitations of autologous CAR-T, including long production, variable quality, and cost, drive off-the-shelf UCAR development to standardize manufacturing and improve access. Current UCAR-T cell strategies focus on mitigating the risks of graft-vs.-host disease and host-vs.-graft rejection through advanced gene editing technologies, including clustered regularly interspaced short palindromic repeat-associated system Cas9-mediated knockout of the T cell receptor, human leukocyte antigen, and cluster of differentiation 52 (CD52). Beyond conventional T cells, cell types such as double-negative T cells, γδT cells, and virus-specific T cells are being engineered with CARs to improve tumor targeting and minimize off-tumor toxicity. UCAR-T therapy is frequently used for hematologic malignancies, including acute lymphoblastic leukemia, non-Hodgkin lymphoma, and multiple myeloma, with efficacy and safety supported by numerous clinical studies. Although trials for solid tumors (e.g., CYAD-101, CTX130) show modest responses, challenges such as tumor heterogeneity and T cell exhaustion remain. Future research should focus on optimizing gene editing precision, integrating combination therapies, and advancing scalable manufacturing platforms. With expanded targets and cell types, UCAR therapies show promise for both hematologic and solid tumors, reshaping cancer treatment and patient outcomes.

Keywords:  Chimeric antigen receptor; cancer; hematological malignancies; solid tumor; universal cell therapy

DOI:  https://doi.org/10.32604/or.2025.067445
Front Immunol. 2025 ;16 1680410

Multiplex engineering and multifunction T cells for precise and effective immunotherapies.

Leila Jafarzadeh, Ali Smaani, Jean-Sébastien Delisle.

  Adoptive T cell transfer has emerged as a pillar of modern cancer immunotherapy. Propelled by viral and non-viral-based technologies, such as CRISPR-Cas9, genetic engineering offers novel opportunities for both emerging cellular therapies and the improvement of more established approaches such as chimeric antigen receptor (CAR) modified T cells. First-generation genetically modified T-cell therapeutics remain limited by the intrinsic constraints imposed by T-cell biology, such as T-cell exhaustion, poor trafficking into hostile tumor beds, toxicity, and challenges associated with tumor antigenic escape. Several of such limitations can be addressed by further engineering, expanding significantly the potential of cell therapy. This review focuses on the promise of using currently available cellular engineering technologies to genetically engineer single T cells at multiple different loci and/or confer several novel functions to circumvent the shortcomings of adoptive immunotherapy to treat cancer. Various methodologies and rationales for the design of these advanced engineered cellular products are described, along with emerging clinical data supporting the use of multiplex-engineered T cells. The limitations of advanced cell engineering and the remaining gaps that need to be filled to optimize the efficacy of adoptive T-cell immunotherapies are also discussed.

Keywords:  CRISPR-Cas9; T cells; Transgenic TCR; adoptive immunotherapy; cancer immunotherapy; chimeric antigen receptor; genetic engineering

DOI:  https://doi.org/10.3389/fimmu.2025.1680410
Cancer Immunol Immunother. 2025 Nov 06. 74(12): 363

CAR-T cells immunotherapy in the treatment of glioblastoma.

Aleksandra Królikowska, Maciej Tarnowski.

  Glioblastoma multiforme (GBM) is highly lethal brain tumor with limited benefit from standard treatment, such as surgery, radiotherapy, and chemotherapy. Its location within the central nervous system, together with the blood-brain barrier, and immunosuppressive niche restricts access and efficacy of therapies. This review examines the current progress of the chimeric antigen receptor (CAR) T cell therapy in GBM, emphasizing therapeutically significant target antigens, delivery strategy and innovations designed to improve safety and persistence. Evidence from preclinical research and early phase clinical trials was assessed to identify key antigen, evaluate routes of administration, and summarize next-generation engineering concepts. Clinical experiences demonstrate that locoregional delivery can enhance tumor penetration compared with systemic infusion. Moreover, CAR-T cells engineered to recognize epidermal growth factor receptor variant III, interleukin-13 receptor subunit alpha-2, human epidermal growth factor receptor 2, or disialoganglioside have shown biological activity in GBM. Emerging platforms, such as dual-target CARs, synNotch, and cytokine-releasing "armored" T cells, develop specificity and overcome barriers posed by tumor heterogeneity and immune suppression. CAR-T therapy in GBM has moved beyond proof-of-concept, with encouraging but preliminary signals of efficacy. Future success will require multi-target approaches, integration with modulators of tumor microenvironment, and optimized delivery systems to achieve durable clinical benefit.

Keywords:  CAR-T cells; Cell therapy; GBM; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-025-04222-w
Nat Commun. 2025 Nov 01. 16(1): 9651

Modeling and addressing on-target/off-tumor toxicity of claudin 18.2 targeted immunotherapies.

Elizabeth J Carstens, Kazuki Takahashi, Naoya Sakamoto, Martina De Vizio, Micaela Morgado, Shahryar Khoshtinat Nikkhoi, Abhishek Mangipudi, Canh Hiep Nguyen, Tate Weltzin, Izuma Nakayama, Qiang Lv, Jue Zeng, Cui Nie, Changjing Deng, Xiaoxiao Wang, Lile Liu, Samuel J Klempner, Anusuya Ramasubramanian, Jonathan A Nowak, Andrew J Aguirre, Kohei Shitara, Eric L Smith.

Successfully extending immunotherapies to solid tumors involves addressing several key challenges, importantly the "antigen dilemma", the expression of a solid tumor target antigen on the normal tissue of tumor origin. Claudin 18.2 (CLDN18.2) has emerged as an important target for upper gastrointestinal (GI) cancer therapies (such as Zolbetuximab, a naked antibody, recently approved; or CT041, a second-generation chimeric antigen receptor (CAR) T cell therapy with promising clinical data). However, GI toxicities are reported from clinical use of both Zolbetuximab and CT041. Here, we describe clinical Zolbetuximab treatment associated cases of gastric erosive lesions. We also demonstrate and characterize on-target/off-tumor gastric toxicity targeting CLDN18.2 in a preclinical mouse model of CT041-scFv derived CAR T cell therapy. By developing CLDN18.2 fully-human VH-only single domain CARs, we demonstrate that on-target/off-tumor toxicity inversely correlates with affinity of the binder, and that a lower affinity CAR may widen the therapeutic window for CLDN18.2 by decreasing on-target/off-tumor toxicity while preserving efficacy.

DOI: https://doi.org/10.1038/s41467-025-65148-6
Mult Scler Relat Disord. 2025 Oct 26. pii: S2211-0348(25)00554-1. [Epub ahead of print]104 106812

CAR T cells for multiple sclerosis: Engineering T cells to disrupt chronic B cell-driven neuroinflammation.

Daniel Ortuño-Sahagún, Cristina Hermosillo-Abundis, María Paulina Reyes-Mata, Óscar Arias Carrión.

  Chimeric antigen receptor (CAR) T-cell therapy is emerging as a promising approach to overcome the limitations of current B-cell-targeted treatments for multiple sclerosis (MS), particularly in progressive forms where disease-modifying therapies (DMTs) often fail to halt neuroinflammation and disability progression. By penetrating both lymphoid tissues and the central nervous system (CNS), anti-CD19 CAR T cells enable deeper and more durable depletion of autoreactive B cells than monoclonal antibodies. Preclinical studies, including experimental autoimmune encephalomyelitis (EAE) models, support their capacity to induce immune tolerance, suppress demyelinating inflammation, and modulate microglial activation. Experience from the early clinical phase -which currently includes six ongoing trials-demonstrates encouraging safety profiles, CNS trafficking of CAR T cells and evidence of pathogenic B-cell depletion in progressive MS, neuromyelitis optica spectrum disorder (NMOSD), and refractory non-relapsing phenotypes. These include the first-in-human trial CT103A (BCMA-targeted CAR T) in progressive MS and NMOSD (NCT04561557), the detection of CAR T cells in the CNS without ICANS in Anti-CD19 CAR T therapy (NCT06138132), the favorable safety in the multicenter study BMS986353 (NCT06220201), and the confirmed CNS penetration in the UCSF's KYV-101, a CD19 CAR T Cell Therapy study (NCT06451159). Next-generation CAR platforms-including regulatory CAR T cells, brain-targeted safety switches, and antigen-specific modulators-may enhance precision and mitigate neurotoxicity, a critical concern in patients with neurologically vulnerable conditions. However, key challenges remain: the absence of validated CNS-specific antigens, risks such as ICANS, delayed parkinsonian-like syndromes, or progressive multifocal leukoencephalopathy (PML), immune exhaustion within the inflamed CNS, and the logistical demands of autologous cell manufacture. This mini-review synthesizes preclinical and early clinical evidence, outlines translational barriers, and discusses strategies to optimize safety, targeting, and scalability.

Keywords:  Autoreactive B cells; CAR T-cell therapy; CNS targeting; Immune tolerance; Multiple sclerosis; Neuroinflammation; Progressive MS

DOI:  https://doi.org/10.1016/j.msard.2025.106812
Front Immunol. 2025 ;16 1695716

CAR-T therapy for neuroendocrine neoplasms: a review of molecular targets and clinical translation.

Olga Golounina, Ildar Minniakhmetov, Rita Khusainova, Marina Loguinova, Ramil Salakhov, Hui Fan, Natalia Mokrysheva.

  Neuroendocrine neoplasms (NENs) represent a heterogeneous group of malignancies. In metastatic and progressive forms, standard therapies are often ineffective. CAR-T therapy, which has demonstrated remarkable efficacy in hematologic malignancies, is considered a promising approach for NEN treatment, despite significant barriers inherent to solid tumors. This review aims to comprehensively analyze and systematize current scientific data on the development of CAR-T therapy for NENs of various origins. It focuses on relevant molecular targets, preclinical findings demonstrating the efficacy and safety profiles of CAR-T cells directed against potential targets, and the current status of early-phase (I/II) clinical trials for CAR-T therapy in NENs. The review examines major barriers to CAR-T therapy in solid tumors, including NENs, and presents innovative strategies to overcome them. Further research and clinical trials focusing on therapy personalization, enhanced safety and efficacy, and the development of combination approaches are essential for the successful integration of CAR-T therapy into clinical practice and for improving outcomes in patients with treatment-refractory NENs.

Keywords:  CAR-T therapy; DLL3; chimeric antigen receptor(CAR); immunotherapy; neuroendocrine neoplasms (NENs); personalized therapy; solid tumors; somatostatin receptors (SSTR)

DOI:  https://doi.org/10.3389/fimmu.2025.1695716
Front Immunol. 2025 ;16 1630569

CAR-T cell therapies in autoimmune rheumatic diseases: a brief report on the clinical trial landscape, current status, and future perspectives.

Xiao Xu, Su-Hua Su.

  Autoimmune rheumatic diseases (ARDs) are chronic inflammatory disorders where B cells play a key role. Traditional B-cell-targeted therapies have limitations, whereas CAR-T-cell therapy, which aims for a broader reset of the B-cell compartment by targeting B-cell surface markers such as CD19 or B-cell maturation antigen (BCMA), has unique advantages. Currently, most CAR-T cell trials for ARDs are in the early stages, with 64.29% (36/56 trials) of studies being phase I trials and only 7.14% (4/56 trials) progressing to phase II trials, primarily focusing on conditions, such as systemic lupus erythematosus (SLE) and lupus nephritis (LN). Geographically, clinical research is predominantly led by China (48% of trials [27/56 trials]) and the United States (34% of trials [19/56 trials]), although large-scale global collaborations remain limited, with only 3.6% (2/56 trials) of projects involving both U.S. and Chinese teams. Funding for these studies is driven primarily by non-leading pharmaceutical firms (75% [42/56 trials] of sponsors). Despite promising efficacy, e.g., CD19-targeted CAR-T cell therapy has induced significant clinical remission in refractory SLE patients, challenges remain, including high costs, complex production, and safety risks. Future progress requires expanding trials, optimizing CAR constructs, enhancing collaboration, and establishing safety monitoring networks, to promote the application of CAR-T cell therapy in ARDs and advance precision medicine.

Keywords:  CAR-T; CAR-T therapy; autoimmune rheumatic diseases; cell therapy; clinical trial landscape

DOI:  https://doi.org/10.3389/fimmu.2025.1630569
Recent Pat Anticancer Drug Discov. 2025 Oct 31.

Tracing the Technological Trajectory of CAR-T Cell Therapy in Cancer Treatment through Patent Analysis.

Yilan Guan, Yunting Liu, Yuxuan Sun, Baijun Liu, Hongmei Yuan.

   INTRODUCTION: CAR-T technology represents a state-of-the-art approach in cancer treatment. This study constructs a multi-dimensional framework for analyzing the technological trajectory to comprehensively clarify the evolution trend of CAR-T technology in cancer treatment.
METHODS: Based on relevant patent data, three methodologies were applied: MPA (to identify dominant technological pathways), Word2Vec (to convert textual content into semantic vectors), and PCA-Kmeans (for dimensionality reduction and clustering). These methods facilitated the construction of one comprehensive technological trajectory and three supplementary trajectories.
RESULTS: The comprehensive technological trajectory exhibits a linear evolutionary trend. In its early stages, the focus was primarily on optimizing the CAR signal transduction domain. Recently, patent technologies have predominantly focused on T-cell modification and expansion, as well as the identification of multiple target antigens. Future research is expected to emphasize the co-expression of antigen targets with immune checkpoint inhibitors. Additionally, the supplementary technology trajectories suggest that refining the CAR-T regulatory mechanism, coexpressing GPX4 to enhance cellular anti-apoptotic capabilities, and expanding investigations into NKG2D targets may represent critical strategies for addressing the high costs and limited long-term persistence associated with CAR-T technology.
DISCUSSION: Systematic guidance is provided for formulating CAR-T technology patent strategies, and limitations in the current multi-dimensional analysis framework-such as data sources, indication analysis, and modeling methods-are highlighted, necessitating further optimization through integration with clinical data and advanced algorithms.
CONCLUSION: A systematic technical synthesis is provided for both academic investigations and enterprise R&D, revealing the intrinsic patterns and potential advancements in the technological evolution of the field.

Keywords:  CAR-T; PCA-Kmeans.; cancer treatment; main path analysis; patent analysis; technological trajectory; word2vec

DOI:  https://doi.org/10.2174/0115748928406285251014064259
Curr Opin Rheumatol. 2025 Oct 31.

CAR T-cell therapy in systemic sclerosis: the next frontier in immune modulation.

Panagiotis Garantziotis, Janina Auth, Georg Schett, Christina Bergmann.

   PURPOSE OF REVIEW: Cellular therapies such as CD19-targeting CAR T cells are a rapidly evolving field in an area of unmet clinical needs: autoimmune diseases including systemic sclerosis (SSc). The aim of this review is to summarize the available data on safety and efficacy of CAR T-cell therapy in SSc and to discuss upcoming developments and challenges for the near future.
RECENT FINDINGS: Several case reports and series recently described the treatment of SSc patients with CD19-targeting CAR T cells, which resulted in profound B-cell depletion and downregulation of autoimmunity. Encouraging results on efficacy in several disease manifestations were reported including skin and organ fibrosis. Also, vascular phenomena including digital ulcerations improved. The safety profile showed mostly mild-to-moderate cytokine release syndrome (CRS) and low rates of neurotoxicity. Infectious complications ranged from mild upper airway infections to pneumonia. However, a case of herpes simplex reactivation with secondary lethal haemophagocytosis was also described.
SUMMARY: Current evidence suggests very promising effects of CD19-CAR T-cell therapy on several SSc manifestations. Additional larger trials are needed. Current frontiers are patient selection, refining lymphodepletion protocols, and expanding target antigens beyond CD19.

Keywords:  B-cell depletion; CD19-targeting CAR T-cell therapy; systemic sclerosis

DOI:  https://doi.org/10.1097/BOR.0000000000001133
Front Immunol. 2025 ;16 1680071

Incorporating mRNA therapeutics into biological treatments of hematologic malignancies.

Jaromir Hunia, Jaromir Tomasik, Natalia Czerwik, Parmida Sadat Pezeshki, Dominika Nowis.

  The recent advancement of mRNA technology has opened new therapeutic avenues for treating hematologic malignancies, offering innovative approaches to enhance existing immunotherapies. This review examines the expanding role of in vitro transcribed (IVT)-mRNA-based platforms in hemato-oncology, focusing on key areas: monoclonal antibody production, bispecific antibody development, and CAR-T cell engineering. Unlike conventional biologics, mRNA allows for in vivo expression of therapeutic proteins, reducing manufacturing complexity and expanding access through scalable, cell-free synthesis. IVT-mRNA-encoded monoclonal and bispecific antibodies can overcome limitations such as short half-life and the need for continuous infusion, while enabling innovations like Fc silencing, protease-activated masking, and combinatorial immunotherapies. In CAR-T cell therapy, IVT-mRNA provides transient, safer alternatives to viral vector-based approaches and facilitates emerging strategies such as in vivo CAR programming and IVT-mRNA vaccine-like boosters. Despite these advantages, challenges remain, including delivery precision, durability of therapeutic effects, and limited clinical trial success. Beyond therapeutic mechanisms, the integration of bioinformatics and AI in IVT-mRNA design is accelerating the development of personalized and efficient cancer treatments. Overall, mRNA technology is redefining immunotherapy in hematology and holds the potential to broaden access to advanced treatments globally.

Keywords:  CAR-T cells; artificial intelligence in hematology; bispecific antibodies; hematologic malignancies; mRNA technology; monoclonal antibodies

DOI:  https://doi.org/10.3389/fimmu.2025.1680071
G Ital Nefrol. 2025 Oct 24. pii: 2025-vol5. [Epub ahead of print]42(5):

Gene Therapies: Any Merit in Nephrology?

Emre Leventoğlu, Sevcan A Bakkaloğlu, Fatih Süheyl Ezgü.

  Gene therapy is an innovative medical approach that involves altering or replacing defective genetic material to treat or potentially cure genetic disorders. This technique primarily uses viral or non-viral vectors to deliver genetic material into cells, aiming to restore normal gene function. The therapy has the potential to address a wide range of diseases, including genetic, cardiovascular, and neurodegenerative disorders. In this review, the focus will be on gene therapies related to kidney diseases. Topics to be covered include the use of messenger ribonucleic acid (mRNA) therapies for conditions such as hypertension and kidney cancer, as well as targeted gene therapies using small interfering RNA (siRNA) and adeno-associated viruses to treat glomerular diseases and prevent kidney damage. The application of gene therapies in treating well-known genetic conditions, such as Alport syndrome and cystinosis, will also be discussed. Additionally, the review will explore the progress of RNA interference (RNAi) therapies in acute kidney injury (AKI) and chronic kidney disease (CKD). Finally, the challenges and risks associated with gene therapy, including immune responses, insertional mutagenesis, and the high costs of treatment, will be examined.

Keywords:  Gene Therapy; Kidney Diseases; Molecular Nephrology; Nephrogenetics

DOI:  https://doi.org/10.69097/42-05-2025-06
Transplant Cell Ther. 2025 Nov 03. pii: S2666-6367(25)01543-X. [Epub ahead of print]

National Landscape of Logistical and Non-Medical Requirements for Transplantation and Cellular Therapy.

Hannah R Abrams, Helene Starks, Lindsey Bandini, Terry Harrington, Mary-Elizabeth M Percival, Roland B Walter, Kathryn Russell, Raya Mawad, Jacob Appelbaum, Mohamed L Sorror, Anna B Halpern.

   BACKGROUND: New disease indications and supportive care advances have expanded the populations who may benefit from cellular therapies, including autologous or allogeneic hematopoietic cell transplant (HCT) and/or chimeric antigen receptor T-cell therapy (CAR T). However, non-medical requirements for these therapies, such as caregiver and housing availability, may limit access. We sought a detailed national assessment of non-medical requirements for HCT and CAR T-cell therapy to describe and quantify barriers.
OBJECTIVE: Describe the national landscape and implementation of logistical and non-medical requirements for HCT and CAR T-cell therapy.
STUDY DESIGN: We developed a web-based survey of HCT/CAR T-cell therapy requirements and obtained pilot feedback from three centers that regularly perform HCT/CAR T-cell therapy. We distributed the survey via the NCCN Best Practices Committee, which is composed of physician, nursing, and administrative leaders from 34 member institutions. We requested survey completion by an institutional content area expert.
RESULTS: The response rate was 91% (31/34). >80% of centers required a caregiver, local housing, and local transportation, but the number of days required, institutional supports, and acceptable distances varied widely. A subset of centers offered 'all-outpatient' procedures and required more stringent logistical criteria, including autologous HCT by 13/19 centers (68%), allogeneic HCT by 4/8 centers (50%), and CAR T-cell therapy by 10/16 centers (63%). Many centers excluded patients with a history of medication nonadherence, substance use, or psychiatric comorbidity, but most did not employ formal adjudication or definition of patient eligibility. Institutions noted "soft" contraindications or case-by-case review for these patients and those experiencing homelessness, lack of insurance, or without citizenship. Overall, caregiving, housing, cost, and insurance coverage emerged as the top non-medical barriers to HCT and CAR T-cell therapy.
CONCLUSIONS: Significant variability exists in non-medical requirements for HCT and CAR T-cell therapy, with a lack of standard policies across institutions. We recommend that centers formally track reasons for non-eligibility to identify non-medical barriers to HCT and CAR T-cell therapy and develop targeted interventions to reduce the number of patients who are excluded for non-medical reasons.

Keywords:  Administrative Burden; Caregivers; Chimeric Antigen Receptor T-Cells; Logistics; access to care; hematopoietic cell transplant

DOI:  https://doi.org/10.1016/j.jtct.2025.10.031
Ann Med Surg (Lond). 2025 Oct;87(10): 6618-6625

Umbilical cord blood: a comprehensive review of protective and restorative properties in clinical applications - a narrative review.

Emmanuel Ifeanyi Obeagu.

  Umbilical cord blood has emerged as a valuable biological resource rich in hematopoietic stem and progenitor cells, offering promising therapeutic potential in regenerative medicine, hematologic disorders, and immune modulation. Compared to bone marrow and peripheral blood stem cells, UCB demonstrates several clinical advantages, including lower risk of graft-versus-host disease (GVHD), increased tolerance for human leukocyte antigen (HLA) mismatch, and rapid availability. Transplantation success rates with UCB have improved significantly, with recent studies reporting overall survival rates of 60-70% in pediatric hematopoietic stem cell transplant recipients and 55-65% in adult recipients, particularly in malignant conditions. The incidence of acute GVHD following UCB transplantation ranges from 20% to 40%, while chronic GVHD occurs in approximately 10-20% of cases - lower than rates observed with other stem cell sources. Moreover, UCB-derived stem cells are being investigated for their regenerative and immunomodulatory capabilities in conditions such as cerebral palsy, type 1 diabetes, and ischemic injury, with early-phase trials showing encouraging safety and efficacy profiles. Despite these advancements, disparities in cost-effectiveness and accessibility remain pressing issues. Public cord blood banks offer greater equity in access and have facilitated most unrelated transplants, whereas private banks, often costly, primarily serve families for autologous use with limited clinical indication. This review provides a comprehensive analysis of the biological underpinnings, clinical applications, and outcomes associated with UCB-based therapies, while highlighting ongoing challenges in global access, standardization, and therapeutic scalability.

Keywords:  immunomodulation; neuroprotection; regenerative medicine; stem cell therapy; umbilical cord blood

DOI:  https://doi.org/10.1097/MS9.0000000000003823
J Toxicol Sci. 2025 ;50(11): 593-599

Incorporation of target safety review in drug discovery.

Yuichiro Amano, Brandon Jeffy, Hisashi Anayama, Jodi Goodwin.

  Ensuring the safety of new pharmaceuticals and therapies is paramount in drug discovery. Takeda's Discovery Toxicology plays a crucial role in reducing safety-related risks by focusing on the quality of drug discovery targets. This involves identifying potential toxicities early in the development phase, enabling the mitigation of risks before they impact later stages of drug development. The Target Safety Review (TSR) initiates the Target Safety Assessment (TSA) process, providing a strategic assessment of safety concerns arising from target modulation. The TSR types range from comprehensive evaluations to simplified versions, assessing on-target and off-target effects, project background, biological information, and chemistry. Importantly, the TSR includes risk ranking and de-risking plans. Risks are ranked based on their probability and impact, enabling informed decision-making throughout the drug development process. This minireview discusses several case studies at Takeda, illustrating the importance of early risk identification. Of course, challenges remain, such as the appropriate timing of TSR creation, limited human on-target information, the need for effective risk assessment methods, incorporation of safety indicators into pharmacological studies, and addressing specific background risks in patient populations. Nonetheless, utilizing the TSR and TSA processes ensures a streamlined and safer drug development journey and provides a comprehensive approach to effectively address potential safety risks.

Keywords:  Discovery toxicology; Probability and impact; Risk mitigation; Target safety review

DOI:  https://doi.org/10.2131/jts.50.593
Front Med (Lausanne). 2025 ;12 1679611

Reimagining drug regulation in the age of AI: a framework for the AI-enabled Ecosystem for Therapeutics.

Rominder Singh, Karen Zhou, Jared R Auclair.

  Artificial intelligence (AI) is increasingly integrated into drug development and regulatory decision-making; however, the regulatory landscape governing these technologies remains fragmented. While agencies such as the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) have begun issuing guidance on AI applications in human therapeutics, these frameworks differ substantially in scope, terminology, and application. This lack of alignment complicates regulatory interpretation, creates barriers to regulatory coordination, and impedes equitable access to AI-enabled therapies. In this article, we introduce the AI-enabled Ecosystem for Therapeutics (AI2ET) framework, a conceptual and policy-oriented model designed to support the federation of regulatory knowledge and promote regulatory alignment. The AI2ET shifts regulatory focus from individual AI-generated products to the broader AI-enabled systems, platforms, and processes that underpin drug development. This approach addresses current regulatory gaps in AI oversight by articulating clear definitions of the components that constitute the ecosystem, establishing risk-based decision-making pathways, and finally offering regulatory guidance to navigate the ecosystem. The article offers six key policy recommendations that include strengthening international cooperation, establishing shared regulatory definitions, and investing in regulatory capacity building. By laying down a conceptual foundation for regulatory science-based oversight of AI in therapeutic development, the AI2ET framework offers a path forward for inclusive, effective, and equitable oversight of AI in regulating human therapeutics.

Keywords:  artificial intelligence; drug development; drug regulations; human therapeutics; medicines; policy; regulatory harmonization

DOI:  https://doi.org/10.3389/fmed.2025.1679611
J Transl Med. 2025 Nov 04. 23(1): 1218

Leveraging the heterogeneity of the NK cell repertoire for the development of immunotherapies for acute leukemia.

Enora Ferron, Maxime Jullien, Katia Gagne, Christelle Retière.

  Acute leukemia represents a significant therapeutic challenge, necessitating the development of innovative approaches to improve the clinical outcomes of patients. Immunotherapies have become a mainstay in the treatment of acute leukemia. Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a well-established and efficacious procedure. Over time, a number of therapeutic approaches have emerged as promising strategies for achieving durable remission and have transformed the treatment of leukemia. Among the efficient immune cells engaged against leukemia, natural killer (NK) cells are innate cytotoxic cells that do not require antigenic specificity to exert their cytotoxic function. The potential of NK cells as a treatment for leukemic patients is emerging as a promising approach. They are capable of distinguishing between healthy and leukemic cells in a natural manner because of the sophisticated equilibrium between their numerous inhibitory and activating receptors. In recent years, NK cells have been found to be far more complex than expected. Indeed, the NK repertoire exhibits a remarkably high degree of phenotypic diversity, which is closely linked to the extensive polymorphism of immunogenetic KIR and HLA class I markers. It has been demonstrated that not all NK cells possess the same functional profile and that they respond to functional education mediated by these KIR-HLA molecular interactions. This review offers insights into the knowledge of NK cell diversity, with the goal of leveraging NK cell heterogeneity for the development of NK cell-based immunotherapies for acute leukemia.

Keywords:  Immunotherapies; Leukemia; NK cells; Repertoire

DOI:  https://doi.org/10.1186/s12967-025-07093-y
Expert Rev Clin Immunol. 2025 Nov 05. 1-14

New advances on the interaction between internal and external factors in the tumor microenvironment of solid tumors.

Cong Zhang, Qian Sun.

   INTRODUCTION: The tumor microenvironment is a dynamic and balanced internal environment that accompanies the whole process of tumor development, invasion, and metastasis. Immune checkpoint therapy, chimeric antigen receptor cell therapy, oncolytic virus therapy, and bispecific antibody therapy are the most anticipated immunotherapy methods. These therapies break the microenvironment conducive to tumor growth by regulating anti-tumor immunity. The underlying characteristics of the tumor immune microenvironment are the key scientific issues to break the bottleneck of solid tumor immunotherapy. With the rapid development and application of single-cell sequencing technology and spatial oncology technology, scientists have gradually recognized more complex details of cell-cell interaction in the tumor microenvironment.
AREAS COVERED: We review the latest research progress in tumor immune escape, tumor metabolic reprogramming, and neuroimmunity [PubMed database published between 2000 and 21 May 2025]. We analyze the effects of these biological processes on anti-tumor immunity, to seek breakthroughs for the design of combined immune therapy. We also summarize the latest research on major immunotherapies mentioned above.
EXPERT OPINION: Through the integration of frontier and hot basic scientific issues and the design of clinical trials, we hope to identify the potential combination treatment plan for immunotherapy to overcome the tumor microenvironment of solid tumors.

Keywords:  CAR-NK; immune checkpoint inhibitor; immune escape; oncolytic virus; tumor microenvironment

DOI:  https://doi.org/10.1080/1744666X.2025.2585349
Mol Cancer. 2025 Nov 03. 24(1): 279

Antibody-drug conjugates in cancer therapy: current landscape, challenges, and future directions.

Bonan Chen, Xiaohong Zheng, Jialin Wu, Guoming Chen, Jun Yu, Yi Xu, William K K Wu, Gary M K Tse, Ka Fai To, Wei Kang.

  Antibody-drug conjugates (ADCs) have emerged as a transformative modality in oncology by combining the target specificity of antibodies with the high potency of diverse cytotoxic payloads. This review provides an integrative overview of ADCs, spanning from molecular design to clinical translation. We dissect the structural components, antibodies, linkers, and payloads, and elucidate their impact on pharmacokinetics, tumor selectivity, and therapeutic index. Mechanistic pathways, including antigen recognition, receptor-mediated internalization, payload release, and immunogenic cell death (ICD), are highlighted to provide context for ADC function. Clinically, ADCs have demonstrated efficacy across hematologic and solid malignancies, with 15 Food and Drug Administration (FDA) approvals and an expanding investigational pipeline. However, challenges persist, including antigen heterogeneity, resistance mechanisms, systemic toxicities, and manufacturing complexities. Emerging innovations such as bispecific ADCs, immune-stimulatory payloads, AI-guided design, and nanotechnology-enhanced delivery are reshaping the ADC landscape. Finally, we emphasize the necessity of diagnostic precision and rational combination strategies, while highlighting emerging innovations that collectively shape the future direction of next-generation ADC therapeutics.

Keywords:  Antibody-drug conjugate; Drug resistance; Nanotechnology; Payload design; Targeted cancer therapy

DOI:  https://doi.org/10.1186/s12943-025-02489-2
Bioconjug Chem. 2025 Nov 04.

Emerging Nucleic Acid Cargos for Next-Generation RNA Vaccines and Therapeutics.

Hannah C Safford, Rohan Palanki, Melgious Ang, Michael J Mitchell.

Messenger RNA (mRNA) lipid nanoparticles (LNPs) have emerged as a transformative technology with broad applications in vaccines, protein replacement therapy, and gene editing. However, the transient nature of mRNA expression often necessitates high or repeated dosing regimens, limiting its therapeutic potential. Thus, there is a critical need for innovation at the interface of RNA biology and drug delivery that prolong the duration of RNA translation. In this Viewpoint, we provide an overview of emerging nucleic acid cargos that address these challenges, specifically self-amplifying RNA (saRNA) and circular RNA (circRNA), and provide a framework for how these nucleic acid cargos can enable the next generation of vaccines and therapeutics for diverse clinical applications.

DOI: https://doi.org/10.1021/acs.bioconjchem.5c00476
IEEE J Biomed Health Inform. 2025 Nov 06. PP

Genetic Perturbation Modelling for Human Cell Therapy With BRNET.

Luyang Cai, Jixang Yu, Qiuzhen Lin, Lichen Liu, Xiangtao Li, Ka-Chun Wong.

Cellular responses to genetic perturbations are prevalent in wide contexts from the fundamental understandings on pathology to the development of clinical therapies and the discovery of novel drug targets. Nonetheless, the substantial amount of possible perturbation combinations renders wet-lab experiments prohibitively expensive and time-consuming. To address it, the BRNET model is proposed for predicting non-linear transcriptional outcomes where multiple perturbations exist. BRNET integrates prior knowledge with advanced embeddings into a non-stacked neural structure to predict transcriptional responses to both individual and multiple genetic perturbations. For unseen scenarios, BRNET also generalizes well under the corresponding perturbations. Experimental results highlight the capabilities of BRNET, demonstrating promising performance as compared to established deep learning models.

DOI: https://doi.org/10.1109/JBHI.2025.3629554
MedComm (2020). 2025 Nov;6(11): e70434

mRNA Vaccines: Current Applications and Future Directions.

Jianmei Li, Yixin Liu, Jie Dai, Li Yang, Feng Xiong, Jing Xia, Jing Jin, Yangping Wu, Xingchen Peng.

  Messenger RNA (mRNA) vaccines, as a novel class of biotherapeutics, leverage mRNA technology to instruct cells to produce specific antigens, thereby inducing an immune response. In recent years, significant progress has been made in applying these vaccines to infectious disease prevention and cancer treatment. Compared with traditional vaccines, mRNA vaccines offer high programmability, as well as greatly enhanced stability and immunogenicity, achieved through nucleotide modifications and advanced delivery systems such as lipid nanoparticles. However, many challenges remain in the design and delivery of mRNA vaccines, particularly for complex conditions like cancer. This review explores the latest advances and future prospects of mRNA vaccines in both infectious disease prevention and cancer therapy. It discusses the mechanisms of tumor immune escape and examines the potential of mRNA vaccines to overcome tumor immune resistance. The review also analyzes strategies for tumor vaccine design and the development of novel delivery systems, projecting the future role of mRNA vaccines in cancer therapy. By providing theoretical guidance and technical insights, this review aims to expand the development of mRNA vaccines across broader disease areas. It offers both a theoretical framework and a practical reference for researchers focused on infectious disease control and precision cancer immunotherapy. Ultimately, these insights will help advance the clinical application of next-generation mRNA therapeutics.

Keywords:  immune escape; mRNA vaccines; personalized vaccines; sequence optimization; targeted mRNA vaccines; vector optimization

DOI:  https://doi.org/10.1002/mco2.70434
J Cancer Res Clin Oncol. 2025 Nov 04. 151(12): 315

Mapping the frontiers: a bibliometric perspective on t cell-based immunotherapy in pancreatic cancer since the twenty-first century.

Ziniu Tang, Chen Wang, Zhenyu Ma, Peng Shang, Qipeng Yuan, Jinbo Yue.

   PURPOSE: T-cell immunotherapy is reshaping cancer care and offers a targeted strategy for pancreatic carcinoma (PC), yet a comprehensive map of its research trajectory is lacking. We aimed to chart the evolution of the field, identify leading contributors, and clarify the thematic shifts that are shaping clinical translation.
METHODS: We systematically analyzed articles and reviews indexed in the Science Citation Index Expanded of the Web of Science Core Collection from January 2000 to December 2024. Bibliographic metadata were aggregated for descriptive trend analyses and science-mapping of co-authorship, co-citation, and keyword co-occurrence networks. Temporal trend profiling was used to highlight emerging topics.
RESULTS: Global output on T-cell immunotherapy for PC has expanded markedly over the past two decades but remains unevenly distributed across regions. The United States leads in academic influence and translational impact, with China closely following in publication volume and contributions from high-impact institutions. Research has converged at the interface of immunotherapy, tumor-microenvironment modulation, and cellular engineering. Dominant themes include engineered T-cell approaches, immune-checkpoint modulation, and strategies leveraging tumor-infiltrating lymphocytes. Emerging fronts encompass AI-enabled target/drug discovery, biomarker-guided patient stratification, and individualized treatment designs. Persisting barriers include limited efficacy in the desmoplastic and immunosuppressive PC microenvironment, primary and acquired immune resistance, safety concerns, and regulatory and trial-design complexities.
CONCLUSIONS: T-cell immunotherapy for PC is a rapidly advancing, interdisciplinary domain led by the United States with rising contributions from China. Accelerating clinical translation will require: integrated T-cell engineering with microenvironment remodeling; rational combinations with checkpoint and stroma-targeted agents; robust predictive biomarkers with standardized endpoints; safety-engineering and risk-mitigation frameworks; and coordinated, multicenter collaboration. This bibliometric synthesis delineates the field's structure and priorities to improve outcomes for patients with PC.

Keywords:  Bibliometric analysis; Pancreatic carcinoma; T-cell immunotherapy; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00432-025-06356-x