bims-carter 2026-09-27 papers

bims-carter

Biomed News

on CAR-T Therapies

Issue of 2026–09–27
37 papers selected by
Luca Bolliger, lxBio

Beyond Oncology: Exploring the Expanding Role of CAR T Cell Therapy in Autoimmune and Infectious Diseases-A Systematic Review.
Predicting cytokine release syndrome after CAR T-cell therapy for autoimmune diseases.
In vivo CAR T-cell generation: delivery platforms, clinical progress, and translational barriers.
[In vivo CAR-T cells: When the patient becomes their own factory].
Beyond the Generic Tumor: Engineering Patient-Specific Immune Ecosystems for Cancer.
Regulatory Convergence in Cell and Gene Therapy: Harmonizing Quality, CMC, and Approval Pathways Across the FDA, EMA, PMDA, and Emerging Markets.
CAR-based therapies in systemic autoimmunity: from deep immune depletion toward durable immune reset.
Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.
Decentralized CAR-T production: clinical, economic, and regulatory perspectives. Worldwide Network for Blood & Marrow Transplantation (WBMT) special article.
Predicting prevalence and severity of cytokine release syndrome after CAR T-cell therapy in patients with autoimmune disease: a retrospective cohort study.
mRNA Therapeutics Beyond Infectious Diseases: Expanding Therapeutic Applications and Future Perspectives.
B-cell centrality dictates therapeutic efficacy across autoimmune diseases: a systematic review.
Harnessing tumor immune checkpoints for autoimmune disease therapeutics.
Manufacturing cost analysis and exploratory economic evaluation of natural killer cell immunotherapy for paediatric solid tumors.
From Delivery to Design: Site-Specific Genome Engineering for Next-Generation CAR T-Cell Therapy.
Integrating oral health and preventive dental care into CAR-T cell therapy.
Antibody-Based Therapeutics in Autoimmune Diseases: Mechanisms, Challenges, and Future Perspectives.
The Post-Authorisation Maze: Mapping of European Pharmaceutical Market Access Pathways in the Early JCA Era.
Programmable ternary polyplexes redirect systemic mRNA delivery to the spleen for in vivo CAR engineering.
Oncofetal antigens as emerging targets in chimeric antigen receptor (CAR)-T cell-based immunotherapies: opportunities and challenges.
In vivo CAR‑T cell therapy: mechanisms, clinical advances and optimization strategies.
Oncolytic virotherapy at the tumor microenvironment-CAR Therapy interface: Mechanisms, clinical translation, and future directions.
Expert assessment of the attributes of high-cost medications: a case study of CAR T-cell therapy in the gulf cooperation council.
Microfluidic-based rapid generation of chimeric antigen receptor T cells improves low-multiplicity-of-infection transduction efficiency while preserving functional activity.
Slow-cooked naive T cells make better effectors.
Genome-Wide Integration Site Profiling of Multi-Component CAR T-Cell Engineering Systems with ADA1/CD26 Co-Transduction.
CAR-T therapy for immune-mediated necrotizing myopathy: a review of mechanisms and emerging clinical evidence.
Nucleofection-Based CRISPR/Cas Delivery in Human T Cells for Immunotherapy Applications.
Spatial Treg niches and the therapeutic reprogramming of tumour tolerance in cancer.
Transduction efficiency in clinical CAR T cell products: A retrospective study at a single center.
B-cell targeting strategies for the treatment of multiple sclerosis: from non-cellular therapies to CAR-engineered cell therapies.
Beyond CAR-T: Preventing and Treating Relapse in B-Cell Haematological Malignancies.
Chimeric Antigen Receptor T-Cell Therapy Is Associated with Low Absolute Rates of Orofacial Adverse Events and Significantly Less When Compared to Hemopoietic Stem Cell Therapy.
Teclistamab in relapsed, multi-refractory acquired hemophilia A after failure of anti-CD19 CAR-T cell therapy.
Human-centric preclinical models for CAR T cell therapy in solid tumors: Where patient-derived organoids fit.
The role and potential of CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis.
A Phase I/II Trial of Anti-CD22/CD19 CAR-T Cell Therapy, CART2219.1, in Adult and Pediatric Relapsed/Refractory B-ALL.

Pathophysiology. 2026 Sep 19. pii: 70. [Epub ahead of print]33(3):

Beyond Oncology: Exploring the Expanding Role of CAR T Cell Therapy in Autoimmune and Infectious Diseases-A Systematic Review.

Kawther Zaher, Jehan Alrahimi.

  Background: Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of select hematologic malignancies and is increasingly being explored for non-oncological indications, including autoimmune diseases and persistent infectious diseases. This systematic review synthesized current evidence on CAR T cell and CAR-Treg approaches beyond oncology, with emphasis on therapeutic targets, translational and clinical outcomes, safety, and implementation barriers. Methods: The review followed PRISMA 2020 guidelines. PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, ClinicalTrials.gov, and major trial registries were searched for studies published from 1 January 2010 to 31 March 2026. Eligible studies included clinical, preclinical, and translational investigations of CAR T cell or CAR-Treg strategies in autoimmune or infectious diseases. Results: Because of heterogeneity in disease indications, CAR constructs, endpoints, and study designs, findings were synthesized descriptively. The strongest early clinical signals were observed with B cell-directed CAR T cell therapy for severe, refractory autoimmune diseases, particularly systemic lupus erythematosus, systemic sclerosis, and inflammatory myopathies. Infectious disease applications, mainly HIV and hepatitis B, showed preliminary safety, persistence, and partial antiviral activity, but durable pathogen eradication remains unproven. Conclusion: Overall, CAR T cell therapy beyond oncology is promising but remains preliminary, requiring standardized reporting, long-term safety monitoring, scalable manufacturing, and carefully defined risk-benefit thresholds. Human clinical evidence was interpreted separately from preclinical and mechanistic evidence, and clinical conclusions were based primarily on human studies.

Keywords:  CAR T cells; CAR-Treg; HIV; autoimmune disease; cellular therapy; chimeric antigen receptor; hepatitis B; immune reset; infectious disease; systemic lupus erythematosus

DOI:  https://doi.org/10.3390/pathophysiology33030070
Lancet Rheumatol. 2026 Sep 25. pii: S2665-9913(26)00279-1. [Epub ahead of print]

Predicting cytokine release syndrome after CAR T-cell therapy for autoimmune diseases.

Catherine Z Shen, Christoph T Ellebrecht.

DOI: https://doi.org/10.1016/S2665-9913(26)00279-1
Front Immunol. 2026 ;17 1927594

In vivo CAR T-cell generation: delivery platforms, clinical progress, and translational barriers.

Tianqun Huo, Hongping Yao, Ziyan Kong.

  Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of several hematological malignancies, but its broader application remains constrained by the complexity, cost, and time required for conventional ex vivo manufacturing. In vivo CAR T-cell therapy has emerged as a promising next-generation strategy that aims to generate CAR T cells directly within the patient through targeted delivery of CAR-encoding genetic information to endogenous T cells. This approach has the potential to simplify treatment workflows, shorten manufacturing timelines, reduce production costs, and improve the accessibility of CAR-based immunotherapy. In this review, we summarize the conceptual evolution from ex vivo to in vivo CAR T-cell therapy and discuss major delivery platforms for in vivo CAR T-cell generation, including engineered lentiviral vectors (LVs), adeno-associated viral vectors, lipid nanoparticles, polymeric nanoparticles, extracellular vesicles, and fusogenic nanovesicles. We further examine key translational challenges and corresponding optimization strategies, including approaches to improve T-cell targeting specificity and delivery controllability, reduce vector immunogenicity, enhance CAR expression persistence, mitigate safety concerns associated with ectopic transduction or genomic integration, and potentially overcome the physical, antigenic, and immunosuppressive barriers encountered in solid tumors. Finally, we summarize early clinical trial progress and discuss future directions for improving the safety, efficacy, and translational potential of in vivo CAR T-cell therapy. Overall, in vivo CAR T-cell therapy represents an important extension of adoptive cell therapy and may reshape the development and clinical implementation of cell-based immunotherapies.

Keywords:  clinical translation; gene delivery; in vivo CAR T-cell therapy; lentiviral vectors (LVs); lipid nanoparticles

DOI:  https://doi.org/10.3389/fimmu.2026.1927594
Bull Cancer. 2026 Sep 22. pii: S0007-4551(26)00396-6. [Epub ahead of print]

[In vivo CAR-T cells: When the patient becomes their own factory].

François Vilcot, Carole-Anne Brugère, Jaime Fuentealba, Roch Houot.

  Over the past decade, ex vivo autologous chimeric antigen receptor (CAR)-T cell therapies have profoundly reshaped the treatment of B-cell malignancies. Despite their remarkable clinical efficacy, their use remains limited by complex manufacturing processes, demanding logistics, long production times, and high costs. In vivo CAR-T approaches are emerging as a potential solution to overcome these obstacles by inducing CAR expression in T-cells directly within the patient's body. This overview provides a comprehensive look at the current development of these therapies. We describe the main delivery platforms under clinical investigation, focusing on lentiviral vectors (LVV) and lipid nanoparticles (LNP), and discuss their differences in terms of mechanisms of action, associated risks, and optimization strategies. We also summarize the key ongoing clinical trials evaluating in vivo CAR-T approaches in hematologic malignancies and autoimmune diseases. Finally, we highlight other in vivo CAR generation methods under development that may address remaining challenges.

Keywords:  Auto-immunité; Autoimmunity; Cellular therapy; Hémato-oncologie; Immunotherapy; Immunothérapie; Lentiviral vectors; Lipid nanoparticles; Nanoparticules lipidiques; Onco-hematology; Thérapie cellulaire; Vecteurs lentiviraux

DOI:  https://doi.org/10.1016/j.bulcan.2026.07.016
Crit Rev Oncol Hematol. 2026 Sep 20. pii: S1040-8428(26)00498-1. [Epub ahead of print] 105611

Beyond the Generic Tumor: Engineering Patient-Specific Immune Ecosystems for Cancer.

Samira Anvari, Jalal Naghinezhad, Reza Farokhi, Mahshid Akhavan Rahnama, Saghar Hoseinzadeh, Mohsen Nikbakht, Mohammad Ahmadvand.

  Cancer immunotherapy has transformed the treatment landscape of malignancies; however, durable clinical responses remain limited by interpatient heterogeneity, tumor evolution, antigen loss, and variability in immune recognition. Advances in genomic sequencing, neoantigen discovery, immunopeptidomics, mRNA-based therapeutics, and cellular engineering have expanded opportunities for developing individualized immunotherapeutic strategies based on patient-specific tumor and immune characteristics. This review examines the state of personalized cancer immunotherapy, with emphasis on individualized neoantigen-specific therapies (iNeST), neoantigen vaccines, mRNA-based antigen delivery platforms, engineered T-cell approaches, and computational methods for antigen prioritization and immune-response prediction. We summarize the biological rationale, preclinical and clinical evidence, and limitations of these approaches, while considering their translational potential and clinical feasibility. We examine the relationships among tumor mutational landscapes, neoantigen immunogenicity, antigen processing and presentation, HLA restriction, immune-cell engineering, and computational immunology. We further assess key barriers to clinical implementation, including limitations in neoantigen prediction and validation, intratumoral heterogeneity, antigen evolution and loss, manufacturing complexity, scalability, regulatory requirements, and the need for prospective clinical validation. Overall, current evidence supports personalized immunotherapy as a promising approach for improving the precision of cancer treatment, but its clinical application remains constrained by biological, technical, manufacturing, regulatory, and clinical challenges. Future progress will require more accurate and experimentally validated neoantigen identification, improved computational and immunologic modeling, robust manufacturing and quality-control processes, and prospective clinical studies demonstrating safety, feasibility, and therapeutic benefit. This review evaluates the current evidence, identifies knowledge gaps, and outlines priorities for the responsible clinical development of individualized cancer immunotherapy.

Keywords:  Neoantigens; Personalized Immunotherapy; Systems Immunology; T-Cell Therapy; Tumor Mutational Landscape; mRNA Vaccines

DOI:  https://doi.org/10.1016/j.critrevonc.2026.105611
BioTech (Basel). 2026 Sep 16. pii: 79. [Epub ahead of print]15(4):

Regulatory Convergence in Cell and Gene Therapy: Harmonizing Quality, CMC, and Approval Pathways Across the FDA, EMA, PMDA, and Emerging Markets.

Nagendra Verma, Swati Arora.

  Cell and gene therapies (CGTs) have progressed from proof of concept to an established commercial pipeline, yet global translation remains constrained by fragmented regulatory frameworks; heterogeneous Chemistry, Manufacturing, and Controls (CMC) requirements; and divergent approval pathways. This narrative review compares CGT quality, CMC, and approval-pathway regulation across the US Food and Drug Administration (FDA), European Medicines Agency (EMA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA), together with five emerging-market agencies: Brazil, Russia, India, China, and Mexico (BRIC-M), current to June 2026. Four convergence gaps recur across all eight jurisdictions: unstandardized potency assay validation, inconsistent post-change comparability expectations, uneven ICH guideline implementation, and divergent evidentiary thresholds for small-population trials. Convergence readiness varies sharply within the emerging-market group, from ICH Regulatory Membership and internationally benchmarked CMC guidance in China and Brazil to reference-country reliance in Mexico and observer status in Russia and India. On this basis, we propose the Global CGT Regulatory Convergence Framework (GCRC-F), a reference architecture of four independently adoptable pillars: (i) Unified CMC Standards, (ii) a Data Harmonization Layer for long-term follow-up and real-world evidence, (iii) an Adaptive Approval Layer linking accelerated designations across agencies, and (iv) a Manufacturing Standardization Layer that is built on existing regulatory precedents rather than novel instruments, with participation tiered by demonstrated regulatory-science maturity. The framework is offered as a structured proposal for discussion; it has not been evaluated by regulators or industry stakeholders, and its feasibility remains to be tested through the consultation and case-study methods identified.

Keywords:  BRIC-M; Chemistry, Manufacturing, and Controls (CMC); EMA; FDA; PMDA; advanced-therapy medicinal products (ATMPs); cell and gene therapy; convergence framework; potency assay; regulatory harmonization

DOI:  https://doi.org/10.3390/biotech15040079
Int Immunopharmacol. 2026 Sep 23. pii: S1567-5769(26)01308-1. [Epub ahead of print]189 117461

CAR-based therapies in systemic autoimmunity: from deep immune depletion toward durable immune reset.

Hongyu Zhang, Baixiu Wu, Hengquan Wan, Kaile Wu, Tao Si, Zheyi Zhou, Zheng Peng.

  Systemic autoimmune diseases are sustained by self-renewing networks of autoreactive B cells, antibody-secreting cells, pathogenic T-cell programs and tissue-resident inflammatory niches. Conventional immunosuppression and biologic therapy can reduce disease activity, but often fail to produce durable drug-free remission because the immune architecture that sustains autoreactivity is suppressed rather than dismantled. CAR-based therapies have introduced a different therapeutic concept: deep interruption of autoreactive immune circuits followed by immune reconstitution. Early clinical experience, particularly with CD19-directed CAR-T cells in refractory systemic lupus erythematosus, lupus nephritis, systemic sclerosis and idiopathic inflammatory myopathies, has shown profound B-cell depletion, rapid decline of disease-associated autoantibodies and clinical remission without immediate maintenance immunosuppression in selected patients. These findings support serological reset and provide early evidence for cellular reset, but they do not yet prove durable homeostatic reset. In this Review, we propose a three-tier framework for immune reset after CAR-based therapy: serological reset, cellular reset and homeostatic reset. We use this framework to examine the mechanistic and translational uncertainties now facing the field, including the long-lived plasma-cell kinetic paradox, the distinction between peripheral depletion and tissue eradication, the uncertainty of repertoire-based claims of immune renewal, persistence of autoreactive T-cell memory, the contribution of lymphodepleting conditioning and the trade-off between pathogenic depletion and protective humoral immunity. We argue that future progress will require tissue-validated, clonally resolved and functionally informed definitions of therapeutic success. Longitudinal B-cell and T-cell tracking, paired or protocol-defined tissue analyses, assessment of tertiary lymphoid structures and plasma-cell niches, and formal evaluation of vaccine responsiveness and immune competence are, in our view, important considerations for future studies. The success of CAR-based therapy in systemic autoimmunity should ultimately be judged not by depletion depth alone, but by whether it can rebuild a stable, nonpathogenic and immunologically competent immune system.

Keywords:  B-cell depletion; CAR-T cell therapy; CAR-based therapy; Immune reset; Plasma cells; Systemic autoimmunity

DOI:  https://doi.org/10.1016/j.intimp.2026.117461
Pharmaceuticals (Basel). 2026 Sep 12. pii: 1449. [Epub ahead of print]19(9):

Barriers and Blueprints: Next-Generation Engineering Strategies for CAR-T Cell Therapy in Gastrointestinal Tumors.

Mariam Ismail, Noran Al-Gizey, Zaid Alabed, Nour Mustafa, Ebtesam Al-Najjar, Yazan Hamdaneh, Nehal Eid, Abdullah Esmail.

  Gastrointestinal (GI) malignancies account for approximately one-quarter of new cancer diagnoses and more than one-third of cancer-related deaths worldwide, yet as of August 2026, only one CAR-T therapy has received regulatory approval for a solid tumor indication anywhere in the world. The recent CT041-ST-01 phase II trial of satricabtagene autoleucel, the first randomized CAR-T trial conducted in a solid tumor, demonstrated a significant improvement in progression-free survival for patients with advanced gastric cancer (median 3.25 vs. 1.77 months; hazard ratio (HR) 0.37, p < 0.001). While this landmark study established the clinical feasibility of CAR-T therapy in solid tumors, it also underscored the biological barriers that continue to limit durable responses. GI tumors are characterized by heterogeneous antigen expression, dense desmoplastic stroma, inefficient immune-cell trafficking, profoundly immunosuppressive tumor microenvironments, and progressive T-cell dysfunction, all of which are further compounded by the logistical and economic challenges of autologous cell manufacturing. In this narrative review, we organize these obstacles within a unified four-barrier engineering framework and critically examine the strategies being developed to overcome each of them. We discuss advances in multi-antigen and logic-gated CAR architectures, stromal remodeling through fibroblast activation protein (FAP)-targeted approaches and extracellular matrix-degrading enzymes, chemokine receptor engineering, regional delivery, hypoxia-responsive CARs, cytokine-armored and persistence-enhanced constructs, dominant-negative and switch receptors, metabolic reprogramming, and intrinsic checkpoint disruption. We also review emerging manufacturing platforms, including allogeneic CAR-T and CAR-natural killer (CAR-NK) cells, induced pluripotent stem cell-derived products, CAR-macrophages, and in vivo CAR generation, together with engineering strategies designed to improve safety and scalability. Rather than relying on a single technological advance, the future of CAR-based therapy for GI malignancies will likely depend on integrating multiple engineering approaches to address the diverse biological barriers within the tumor microenvironment. By synthesizing current preclinical and early clinical evidence, this review provides a translational framework for the next generation of CAR-based cellular therapies in gastrointestinal oncology.

Keywords:  CAR-NK cells; CAR-T cell therapy; adoptive cell therapy; gastrointestinal cancers; genetic engineering; immunotherapy; precision oncology; solid tumors; synthetic biology; tumor microenvironment

DOI:  https://doi.org/10.3390/ph19091449
Bone Marrow Transplant. 2026 Sep 24.

Decentralized CAR-T production: clinical, economic, and regulatory perspectives. Worldwide Network for Blood & Marrow Transplantation (WBMT) special article.

Abdulrahman Nasiri, Riad El Fakih, Christian Chabannon, Laurent Garderet, Jurgen Kuball, Ali Bazarbachi, Anna Sureda, Marcos De Lima, Muhammad Bilal Abid, Farhatullah Syed, Ibrahim N Muhsen, Daniel Weisdorf, Hildegard T Greinix, Anna Ossami Saidy, Mohammad Alhomoud, Abdulwahab Albabtain, Helen Baldomero, Shahrukh Hashmi, Lorenz Thurner, Nina Worel, Adrian Seber, Sebastian Galeano, Usama Gergis, Raheel Iftikhar, Yoshihisa Kodera, Marcelo Pasquini, Yoshiko Atsuta, Syed Osman Ahmed, Damiano Rondelli, Mohamad Mohty, John A Snowden, Ibrahim Yakoub Agha, Mohamed Kharfan-Dabaja, Dietger Niederwieser, Mickey Koh, Mahmoud Aljurf.

Chimeric antigen receptor T-cell therapy transformed the treatment of hematologic malignancies and is rapidly expanding into solid tumors and autoimmune diseases. However, its full clinical potential remains constrained by centralized manufacturing, production costs, logistical complexity, prolonged vein-to-vein times, limited global accessibility, and regulatory frameworks that hinder rapid implementation of manufacturing innovations. Decentralized point-of-care manufacturing, pioneered by academic and clinical centers, offers a promising alternative to address these limitations and broaden patient access. This review summarizes the current landscape of POC CAR T-cell manufacturing, emphasizing clinical outcomes, economic sustainability, and regulatory considerations. Program experience across North America, Europe, Asia, and other regions demonstrates manufacturing innovations that reduce production times from several weeks to as few as 6-8 days. Early clinical studies report safety and efficacy comparable to commercially manufactured products while substantially lowering costs, with some models targeting production expenses of approximately USD 40,000 per treatment (excluding building and maintaining the production facility). We also examine supportive policy initiatives and regulatory pathways, including hospital exemption models, together with implementation challenges such as manufacturing heterogeneity, quality assurance, and workforce development. Finally, we discuss emerging technologies, including allogeneic CAR T-cell platforms, artificial intelligence-driven manufacturing, and in vivo gene editing, that may democratize global access.

DOI: https://doi.org/10.1038/s41409-026-03044-3
Lancet Rheumatol. 2026 Sep 25. pii: S2665-9913(26)00230-4. [Epub ahead of print]

Predicting prevalence and severity of cytokine release syndrome after CAR T-cell therapy in patients with autoimmune disease: a retrospective cohort study.

Shirley Chiu Wai Chan, Koray Tascilar, Andreas Wirsching, Soraya Kharboutli, Fabian Müller, H Huang, Jingjing Feng, Huji Xu, Ann-Christin Pecher, Jörg Henes, Ioanna Minopoulou, David Simon, Gerhard Krönke, Denise Walther, Dimitrios Mougiakakos, Christina Düsing, Jörg H W Distler, Isabell Haase, Martin Krusche, Tobias Krickau, Markus Metzler, Laura Bucci, Simon Völkl, Tobias Rothe, Jule Bachl, Andreas Mackensen, Ricardo Grieshaber-Bouyer, Georg Schett, Melanie Hagen.

BACKGROUND: Chimeric antigen receptor (CAR) T cells are highly effective in depleting B cells and are therefore being tested for their safety and efficacy in autoimmune diseases. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are potential toxic effects of CAR T-cell therapy. We aimed to identify biomarkers predicting incidence and severity of CRS in CAR T-cell treated patients with autoimmune diseases.
METHODS: This retrospective cohort study included patients with autoimmune diseases treated with autologous CAR T-cell therapy from six centres in Germany and one centre in China. Demographic and disease-specific characteristics were recorded. Patients from Germany were treated with CD19 targeting CAR T cells. Patients from China were treated with either dual target CD19-BCMA CAR T cells or co-infused with CD19 CAR T cells and BCMA CAR T cells. Baseline biomarkers (B-cell counts and concentrations of IL-6, C-reactive protein [CRP], and ferritin) were recorded at the eligibility assessment visit before study entry or named patient programme use. IL-6 was measured by ELISA. The primary outcomes were the occurrence of CRS and ICANS. The severity of CRS and ICANS was classified using the American Society for Transplantation and Cellular Therapy criteria. Multivariable logistic regression was used to define factors associated with CRS occurrence. There was no involvement of people with lived experience in study design.
FINDINGS: Between March 1, 2021, and July 1, 2025, we included 108 patients with autoimmune diseases who received autologous CAR T-cell therapy. The median age at administration was 34 years (IQR 27-44). 76 (70%) of 108 patients were women and 32 (30%) were men. 86 (80%) of 108 patients developed CRS after CAR T-cell therapy (grade one in 71 [66%] patients, grade two in 14 [13%] patients, and grade three in one [1%] patient). ICANS occurred in three (3%) patients (grade one in two [2%] patients and grade two in one [1%] patient). Patients who developed CRS had significantly higher baseline B-cell counts (43 cells per μL [IQR 10-108] vs 6 cells per μL [0-18]; p=0·0002), IL-6 concentrations (10 pg/ml [IQR 4-62] vs 3 pg/ml [2-6]; p=0·0003), and CRP concentrations (5 mg/L [IQR 2-14] vs 3mg/L [1-5]; p=0·042) compared with patients without CRS. Multivariable logistic regression confirmed the association between CRS, B-cell counts (OR 1·31 [95% CI 1·06-1·67]; p=0·012) and IL-6 concentrations (OR 2·28 [95% CI 1·30-4·65]; p=0·0001).
INTERPRETATION: Higher baseline B-cell counts and systemic inflammation are associated with the development of CRS after CAR T-cell therapy in patients with autoimmune diseases. These data might help to identify patients with autoimmune disease that are at higher risk of developing CRS after CAR T-cell therapy.
FUNDING: Deutsche Forschungsgemeinschaft, Collaborative Research Centers, Clinician Scientist Program NOTICE.

DOI: https://doi.org/10.1016/S2665-9913(26)00230-4
Immun Inflamm Dis. 2026 Sep;14(9): e70511

mRNA Therapeutics Beyond Infectious Diseases: Expanding Therapeutic Applications and Future Perspectives.

Gedion Mengistu Dejen.

   BACKGROUND: Messenger RNA (mRNA) therapeutics have rapidly evolved from experimental nucleic acid constructs into a clinically validated therapeutic platform. Their successful application during the COVID-19 pandemic accelerated interest in broader therapeutic uses beyond infectious diseases.
AIMS: This review summarizes the expanding therapeutic applications of mRNA technologies, recent technological advances, translational progress, current challenges, and future prospects across diverse medical fields.
MATERIALS AND METHODS: A comprehensive review of the published literature was conducted, synthesizing evidence from preclinical investigations, clinical studies, and recent advances in mRNA engineering, delivery systems, and translational research.
RESULTS: Advances in mRNA design, nucleoside modification, codon optimization, and delivery platforms, particularly lipid nanoparticles and emerging organ-targeted carriers, have expanded applications to cancer immunotherapy, personalized vaccines, autoimmune and inflammatory diseases, protein replacement therapy, cardiovascular regeneration, neurological disorders, and rare genetic diseases. Emerging technologies, including self-amplifying and circular RNA systems, further enhance therapeutic potential.
DISCUSSION: Despite significant progress, challenges remain, including optimization of targeted delivery, long-term safety, repeat-dose tolerability, manufacturing complexity, cold-chain requirements, production costs, and equitable global access. Continued technological innovation and regulatory harmonization are critical for successful clinical translation.
CONCLUSION: mRNA therapeutics are transitioning from a vaccine-centered technology to a versatile platform for precision medicine. Advances in delivery systems, scalable manufacturing, and artificial intelligence-assisted sequence design are expected to accelerate their integration into the treatment of chronic, genetic, and regenerative diseases.

Keywords:  cancer immunotherapy; lipid nanoparticles; mRNA therapeutics; messenger RNA; personalized medicine; precision medicine; regenerative medicine; translational medicine

DOI:  https://doi.org/10.1002/iid3.70511
Front Immunol. 2026 ;17 1906254

B-cell centrality dictates therapeutic efficacy across autoimmune diseases: a systematic review.

Vishakha Hooda, Harsh Goel, Taruna Madan, Alpana Sharma.

   Background: B cells play a critical role in autoimmunity through autoantibody production, plasma cell differentiation, antigen presentation, cytokine secretion, and germinal center responses. The clinical efficacy, durability, and safety profiles vary across autoimmune diseases. Therefore, the objective is to assess B-cell therapeutic responses and their correlation with disease pathology in autoimmunity.
Methods: Embase, Web of Science, and PubMed were systematically screened for clinical trials published between 2020 and July 2025. A total of 24 clinical trials across five autoimmune conditions-pemphigus vulgaris, myasthenia gravis, rheumatoid arthritis, systemic sclerosis, and Sjögren's syndrome-were evaluated for B-cell-targeted therapy. Interventions included B-cell depletion therapy, CAR-T cell therapy, BTK inhibition, rituximab and its biosimilars, and combination strategies.
Results: Across 24 clinical trials, more than 3,500 participants were included. We observed that autoantibody-mediated diseases pemphigus vulgaris and myasthenia gravis had the most superior and durable immune response to B-cell depletion by rituximab and inebilizumab, respectively. BTK inhibition showed rapid but non-durable responses. Immune complex diseases like rheumatoid arthritis and systemic sclerosis showed improvement in activity scores and partial response, and no clinical remission after treatment with rituximab and its biosimilars. The next-generation approach BCMA-directed CAR T-cell therapy showed promising results with potential durability in myasthenia gravis. Combination therapy using belimumab and rituximab resulted in a significantly better clinical outcome than monotherapy in Sjögren's syndrome. Overall, B-cell therapy safety profiles showed no severe adversity and were well tolerated.
Conclusions: The success of B-cell therapeutics appears to align with B-cell contribution, disease biology, and the depth of B-cell targeting in autoimmune conditions. Precision targeting is needed to effectively combat autoimmune diseases.

Keywords:  B cell therapy; BTK inhibition; CAR T; autoimmunity; combinatorial therapy; myasthenia gravis; pemphigus; rheumatoid arthritis

DOI:  https://doi.org/10.3389/fimmu.2026.1906254
Front Immunol. 2026 ;17 1725372

Harnessing tumor immune checkpoints for autoimmune disease therapeutics.

Hanmei Yang, Ping Zhang, Yi Wu, Na Xie, Guobo Shen.

  Immune checkpoint (IC) pathways, originally identified in T-cell exhaustion in cancer, are increasingly recognized as key modulators of immune tolerance in autoimmune diseases (ADs). In ADs, these molecules function more accurately as inhibitory receptors (IRs) that fine-tune, rather than inducing classical exhaustion phenotypes, autoreactive immune cells. Unlike oncology, where checkpoint blockade enhances immunity, AD therapy aims to restore tolerance through IC agonism or immune reset approaches (e.g., CAR-T cells). This review synthesizes recent advances in targeting CTLA-4, PD-1, LAG-3, TIM-3, and TIGIT. Clinical success with CTLA-4-Ig (abatacept) and emerging efficacy of PD-1 agonists (e.g., peresolimab) provide proof-of-concept that augmenting inhibitory signaling can ameliorate autoimmunity. However, outcomes remain context-dependent, reflecting interplay between effector and regulatory subsets and tissue-specific environments. Mechanistic challenges, including multivalent receptor engagement, ligand complexity, and signaling heterogeneity (e.g., ITIM/ITSM phosphorylation), limit current approaches. Insights from immune-related adverse events (irAEs) highlight shared pathways of dysregulation and inform risk-benefit considerations. A major translational gap persists between acute transplant models and chronic autoimmunity, and validated predictive biomarkers are lacking. Beyond T cells, B cells, dendritic cells, and innate populations expand therapeutic opportunities. Future progress will require multi-omics profiling, biomarker-driven stratification, and next-generation agonist design. IC-targeted strategies hold promises but demand context-aware, mechanistically informed development for broad clinical impact in ADs.

Keywords:  autoimmune diseases; immune checkpoints; immune tolerance; immunoregulation; inhibitory receptors; targeted therapy

DOI:  https://doi.org/10.3389/fimmu.2026.1725372
Clin Transl Immunology. 2026 ;15(9): e70122

Manufacturing cost analysis and exploratory economic evaluation of natural killer cell immunotherapy for paediatric solid tumors.

Sabera Tabassum Wahid, Melissa Elliott, Yufan Wang, Wayne Nicholls, Natacha Omer, Fernando Souza-Fonseca-Guimaraes, Haitham Tuffaha.

   Objectives: Natural killer (NK) cell therapy is a promising allogeneic, off-the-shelf immunotherapy for solid tumors, yet economic evidence to guide its clinical translation is absent. This study aimed to conduct a micro-costing analysis of their manufacturing and perform an exploratory economic evaluation of NK cell therapy for paediatric solid tumors from an Australian health system perspective.
Methods: A micro-costing analysis was conducted using primary laboratory production data across six manufacturing steps and categories. Hospitalisation costs were estimated by expert opinion. Effectiveness estimates were drawn from chimeric antigen receptor (CAR)-T cell therapy economic evaluations. Analyses included incremental cost-effectiveness ratios (ICERs), headroom analysis, net monetary benefit (NMB) and probabilistic sensitivity analysis.
Results: Manufacturing cost was AUD 58 681 (USD 38 143) per batch (AUD 9780; USD 6357 per dose). Eighty-eight per cent of costs were concentrated in three steps: NK cell expansion (50.8%), mRNA transfection (25.1%) and T-cell depletion (11.7%), with consumables/reagents comprising 85% of the total production cost. Combining manufacturing (AUD 58 681) and hospitalisation (AUD 75 000; USD 48 750) costs, the total NK cell therapy cost was AUD 133 681 (USD 86 893) per patient, yielding an illustrative ICER of AUD 35 167 (USD 22 859) per QALY gained, based on a proxy effectiveness estimate. Economic headroom was AUD 56 386 (USD 36 651) per patient. Probabilistic analysis showed 51.7% probability of cost-effectiveness at AUD 50 000/QALY, with a minimum of 2.67 QALYs required.
Conclusion: NK cell therapy shows indicative early economic signals warranting further clinical and economic investigation. Micro-costing identifies actionable manufacturing cost drivers to inform process optimisation, and these exploratory estimates provide a foundation for iterative economic evaluation as clinical evidence develops.

Keywords:  cell therapy manufacturing; cost‐effectiveness analysis; early economic evaluation; micro‐costing; natural killer cell therapy; paediatric solid tumors

DOI:  https://doi.org/10.1002/cti2.70122
Biomedicines. 2026 Aug 27. pii: 1925. [Epub ahead of print]14(9):

From Delivery to Design: Site-Specific Genome Engineering for Next-Generation CAR T-Cell Therapy.

Hala Aldahshan, Abeer Al-Hubaysh, Dimah K Alrabiah, Meshael Alturki, Reem R Alkharji, Salwa Lin, Mohammed S Aldughaim, Raef Albugami.

  Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of haematological malignancies, but conventional viral transduction results in semi-random genomic integration, contributing to heterogeneous CAR expression and potential insertional effects. Site-specific genome engineering offers an alternative by directing CAR insertion to defined genomic loci, allowing greater control over transgene expression and cellular function. This narrative review evaluates advances in site-specific CAR T-cell engineering, focusing on integration mechanisms, donor platforms, genomic loci, safety, and translational readiness. Homology-directed repair (HDR) and homology-independent targeted integration (HITI) are critically compared alongside viral and non-viral donor systems. Candidate loci are evaluated according to their functional consequences and level of evidence, with TRAC representing the most extensively characterised target, while PDCD1, CD7, CD247, and other loci offer distinct functional opportunities but remain supported by varying levels of preclinical and translational evidence. The review also examines genomic risks associated with targeted editing, including structural rearrangements and chromosome-scale abnormalities, and considers emerging applications in allogeneic, solid-tumour, and in vivo CAR T-cell engineering. Overall, site-specific integration provides a framework for linking CAR placement to therapeutic function, but no single locus or integration strategy is universally optimal. Clinical evidence remains limited relative to the expanding preclinical landscape, and genomic safety, scalable manufacturing, and clinical validation remain major priorities for translation.

Keywords:  CAR-T cell therapy; CRISPR/Cas9; HITI; TRAC locus; genomic safe harbour; homology-directed repair; immune cell engineering; non-viral manufacturing; site-specific genome engineering; targeted CAR integration

DOI:  https://doi.org/10.3390/biomedicines14091925
Support Care Cancer. 2026 Sep 24. pii: 1012. [Epub ahead of print]34(10):

Integrating oral health and preventive dental care into CAR-T cell therapy.

Pasquale Niscola, Maria Ilaria Del Principe.



Keywords:  CAR-T cell therapy; Hematologic malignancies; Immunotherapy; Oral complications; Supportive oral care

DOI:  https://doi.org/10.1007/s00520-026-11268-8
Int J Mol Sci. 2026 Sep 09. pii: 8030. [Epub ahead of print]27(18):

Antibody-Based Therapeutics in Autoimmune Diseases: Mechanisms, Challenges, and Future Perspectives.

Naim Mahroum.

  Autoimmune diseases encompass nearly 100 distinct conditions characterized by dysregulated immune responses against self-antigens, resulting in tissue damage, chronic inflammation, and substantial morbidity. Over recent decades, the global burden of autoimmune diseases has increased, while their therapeutic management has undergone a paradigm shift from broad, nonspecific immunosuppression toward targeted biologic therapies. Among these, antibody-based therapeutics, including monoclonal antibodies targeting cytokines, cell-surface molecules, and co-stimulatory pathways, have transformed the treatment of numerous systemic and organ-specific autoimmune disorders. Nevertheless, important challenges remain, including primary non-response, secondary loss of efficacy related to immunogenicity or disease adaptation, increased susceptibility to infections, and mechanistic redundancy among therapeutic targets. This review provides a comprehensive overview of the cellular and molecular mechanisms underlying antibody-based therapies, summarizes major therapeutic target classes across autoimmune diseases, and examines their clinical and mechanistic limitations. Emerging therapeutic platforms, including bispecific antibodies, antibody-drug conjugates (ADCs), novel Fc-engineering, and cellular approaches such as CD19-targeted chimeric antigen receptor (CAR)-T therapy, are also discussed. Finally, antigen-specific immunotherapies designed to restore antigen-specific immune tolerance while preserving systemic host defense are explored. These approaches may represent an important next frontier in the treatment of autoimmune diseases, moving beyond broad systemic immune modulation toward more selective and durable immune control.

Keywords:  antibody-based treatment; autoimmunity; immunomodulation; immunosuppressants; monoclonal antibodies

DOI:  https://doi.org/10.3390/ijms27188030
J Mark Access Health Policy. 2026 Sep 17. pii: 55. [Epub ahead of print]14(3):

The Post-Authorisation Maze: Mapping of European Pharmaceutical Market Access Pathways in the Early JCA Era.

Lisa-Maria Hagemann, Karolin Eberle, Jana Maurer, Alexandra Carls, Andreas D Meid, Eva-Maria Reuter.

  The Regulation (EU) 2021/2282 on health technology assessment (HTAR) harmonises clinical evidence assessment across Europe. However, national appraisal, pricing, and reimbursement processes remain divergent and could affect the efficiency of decision-making and patient access. Here we mapped the sequencing of national assessment, pricing, and reimbursement steps across 30 European countries. National pathways from marketing authorisation to reimbursed access were systematically identified and coded as categorical process sequences. Inpatient and outpatient pathways were analysed separately. Pathway dissimilarities were calculated using Optimal Matching and grouped by hierarchical clustering. We further explored whether clusters differed with regard to country-level indicators, including medicine availability, average time to access, gross domestic product, and healthcare expenditure. We found substantial procedural heterogeneity across countries in both inpatient and outpatient settings. Nevertheless, recurring pathway structures were identified. Across settings, the dominant distinction was between assessment-led pathways, in which evidence assessment precedes pricing and reimbursement steps, and pricing-led pathways, in which price formation occurs prior to assessment and reimbursement-related steps. Cluster membership was not associated with any country-level indicators. Our findings provide policymakers, agencies, and industry with a baseline for understanding national procedural heterogeneity and for evaluating how market access pathways evolve as the JCA is implemented.

Keywords:  EU HTA regulation; EU big four; European access environment; European economic area; access timelines; health technology assessment; innovative health technologies; joint clinical assessment (JCA); market access; oncology

DOI:  https://doi.org/10.3390/jmahp14030055
J Control Release. 2026 Sep 21. pii: S0168-3659(26)00792-3. [Epub ahead of print]399(Pt B): 115388

Programmable ternary polyplexes redirect systemic mRNA delivery to the spleen for in vivo CAR engineering.

Sung Been Lim, SeonJeong Kim, Jun Su An, Hye Won Jang, Hyun Jin Kim.

  In vivo engineering of chimeric antigen receptor (CAR) immune cells has emerged as a promising alternative to ex vivo cell manufacturing, but its clinical translation remains limited by the lack of delivery systems capable of selective programming immune cells within lymphoid organs. Here we report a rationally engineered ternary polyplex that redirects intravenously-administered CAR mRNA from the lungs to the spleen through programmable surface-charge modulation while maintaining nanoparticle stability. The polyplex consists of amphiphilic polyaspartamide/mRNA secondary complexes coated with a pH-responsive charge-conversion polymer, enabling efficient systemic delivery and endosomal release of mRNA. Systemic optimization of polymer architecture, hydrophobicity, and surface charge identifies design principles governing spleen-selective delivery, resulting in luminescence intensities that are over 250-fold higher in the spleen than in the liver and over 330-fold higher than in the lungs following intravenous administration. The optimized formulation preferentially transfects splenic dendritic cells, macrophages, and natural killer cells, enabling transient in vivo expression of anti-CD19 CAR. This immune cell programming promotes macrophage activation, enhances CAR-mediated phagocytic activity, and induces antigen-specific depletion of peripheral B cells for several days. Transcriptomic profiling further reveals coordinated activation of innate immune pathways associated with macrophage polarization, dendritic cell activation, and natural killer cell responses. These findings establish programmable ternary polyplexes as a platform for spleen-selective mRNA delivery and provide a nonviral strategy for in vivo CAR immune cell engineering.

Keywords:  CD19 CAR; Chimeric antigen receptor; In vivo cell engineering; Polyplex; Spleen

DOI:  https://doi.org/10.1016/j.jconrel.2026.115388
Front Cell Dev Biol. 2026 ;14 1910208

Oncofetal antigens as emerging targets in chimeric antigen receptor (CAR)-T cell-based immunotherapies: opportunities and challenges.

Sam Sebastian Smith, Astero Klampatsa.

  Oncofetal antigens are emerging targets for chimeric antigen receptor (CAR)-based immunotherapies due to their developmentally restricted expression and frequent re-emergence in malignant cells. These antigens are tightly linked to cellular plasticity, stem-like programs, immune evasion, and resistance to cytotoxic therapies, making them biologically compelling targets. Multiple oncofetal antigens have entered early-phase clinical trials as CAR-T cell targets with promising results in several cancers including neuroblastoma and diffuse midline gliomas. However, antitumor efficacy in most solid malignancies has thus far been modest. This reflects shared obstacles, including low-level expression in normal tissues, intratumoral antigen heterogeneity, immune suppression within the tumor microenvironment, CAR-T cell exhaustion, and limited persistence. In this Mini-Review, we discuss the biological foundations of oncofetal antigen expression, synthesize clinical and pre-clinical experience targeting these antigens with CAR-T cell therapies, and highlight emerging engineering and combination strategies designed to overcome current limitations. We propose that integrating principles from developmental biology, tumor evolution, and immuno-engineering will be essential to unlocking the therapeutic potential of oncofetal antigen-directed CAR-T therapies in solid tumors.

Keywords:  CAR; CAR (chimeric antigen receptor); CAR-T therapy; oncofetal; oncofetal antigen

DOI:  https://doi.org/10.3389/fcell.2026.1910208
Biochem Pharmacol. 2026 Sep 19. pii: S0006-2952(26)00833-6. [Epub ahead of print] 118491

In vivo CAR‑T cell therapy: mechanisms, clinical advances and optimization strategies.

Yikun Li, Fengling Wang, Jiaqian Li, Haozhan Gao, Dan Li, Wei Wang.

  In vivo CAR-T cell therapy is an innovative strategy that directly delivers CAR-encoding transgenes to endogenous T cells, reprogramming them in situ. It offers advantages of streamlined production and reduced costs. Published clinical trials have shown encouraging therapeutic outcomes for in vivo CAR-T. Nevertheless, multiple key obstacles still remain to be addressed. These obstacles include insufficient targeting specificity of delivery vehicles, vector-mediated immune clearance, manufacturing bottlenecks and safety concerns. The delivery system is a critical component of in vivo CAR-T therapy and can be classified into viral and non-viral vectors. Currently, optimizing delivery systems to support their robust implementation in preparation for in vivo CAR-T has become a critical factor in advancing in vivo CAR-T therapy. In this review, we first summarize the mechanisms, current clinical landscape, and major challenges of in vivo CAR-T cell therapy. Subsequently, in response to these challenges, we systematically outline existing optimization strategies applicable to this therapy. Additionally, we provide perspectives for researchers on the optimization of in vivo CAR-T cell therapy.

Keywords:  Cell therapy; Delivery system; In vivo CAR-T; Lentiviral vector; Lipid nanoparticle

DOI:  https://doi.org/10.1016/j.bcp.2026.118491
Cancer Treat Res Commun. 2026 Sep 19. pii: S2468-2942(26)00359-X. [Epub ahead of print]49 101449

Oncolytic virotherapy at the tumor microenvironment-CAR Therapy interface: Mechanisms, clinical translation, and future directions.

Ali M Atoom, Jasur Rizaev, Djamila Polatova, Pareshkumar N Patel, K V Jamuna, Laxmidhar Maharana, Neeraj Bainsal, Divya Singhal.

  Oncolytic virotherapy has evolved from a tumor-selective cytolytic strategy into a programmable immunotherapeutic platform that reshapes the tumor microenvironment (TME). Oncolytic viruses (OVs) selectively infect malignant cells, induce immunogenic cell death, release tumor antigens, and activate innate and adaptive immunity, potentially converting cold tumors into inflamed states. However, clinical translation remains limited by antiviral clearance, heterogeneous delivery, stromal barriers, immunosuppressive cells, and incomplete integration with cellular immunotherapy. This review synthesizes these mechanisms, platforms, and translational challenges. This review emphasizes platform-specific interactions between oncolytic viruses (OVs) and CAR-T, CAR-NK, and tumor-infiltrating lymphocyte (TIL) therapies. OVs may enhance CAR-T trafficking, antigen availability, local immune activation, and resistance to suppressive tumor microenvironmental signals. In CAR-NK therapy, OV-mediated cytokine support and TME remodeling may improve recruitment and activity, although antiviral NK responses can limit viral persistence. TIL therapy is considered separately because it relies on endogenous tumor-antigen recognition rather than engineered CAR targeting. Overall, direct OV-CAR evidence remains largely preclinical and platform-specific, while early clinical experience is more established for OV combinations with TILs and other immunotherapies in human studies. However, these mechanisms are supported predominantly by preclinical and early translational evidence, and direct clinical validation of OV-CAR combinations remains limited. Antiviral clearance, heterogeneous intratumoral infection, neutralizing immunity, delivery constraints, and potentially overlapping inflammatory toxicities may also restrict therapeutic synergy. Finally, we propose biomarker-driven trial designs that incorporate viral pharmacology, TME conversion, antigen-presentation competence, cellular-product persistence, and response assessment in injected and non-injected lesions.

Keywords:  Adoptive cellular therapy; Car-nk therapy; Car-t therapy; Oncolytic virus; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.ctarc.2026.101449
Front Pharmacol. 2026 ;17 1812612

Expert assessment of the attributes of high-cost medications: a case study of CAR T-cell therapy in the gulf cooperation council.

Yazed AlRuthia, Sara Al Dallal, Anas Hamad, Mohamed Ebrahim Al Khalifa, Sultana Al-Sabahi, Said Wani, Abdullah Alibrahim, Ibtisam Alharbi, Abdulaziz Alhenaidi, Mohammad Almari, Abdulrahman Aloumi, Mariam Aljalahma.

   Background: The influx of high-cost advanced therapies, particularly CAR T-cell therapies, poses profound economic and operational challenges for healthcare systems in the Gulf Cooperation Council (GCC). As the region transitions from volume-based procurement to Value-Based Healthcare (VBHC), decision-makers must balance the urgent need for innovative curative treatments with fiscal sustainability and limited local health economics data.
Methods: This study utilized a quantitative expert preference rating approach, using a rating-based Conjoint Analysis to assess the utility and relative importance of key value drivers for CAR T-cell therapies. Eighteen Key Opinion Leaders (KOLs) evaluated four hypothetical CAR T-cell product profiles. Individual ratings for sequentially presented attributes were collected from participants and subsequently analyzed using an ordinary least squares (OLS) transformation regression model based on Multi-Attribute Utility Theory (MAUT) to estimate part-worth utilities.
Results: The analysis identified labeled indications and outcome-based agreements as the dominant drivers of decision-making utility, with markedly higher estimated utility values than upfront price and individual efficacy or safety metrics. Specifically, a cohort-level Outcome-Based Agreements model, where reimbursement is conditional on the response rate of a treated patient population, generated the single highest utility value (U = 24.07). In terms of structural attributes, experts demonstrated a statistically significant preference for comprehensive Patient Support Programs (PSPs) and Technology Transfer commitments (local manufacturing) over simple scientific guidance or basic discounts.
Conclusion: Decision-makers in the GCC prioritize risk-sharing mechanisms and broad therapeutic indications over traditional cost-containment strategies when evaluating high-cost CAR T-cell therapies. These findings suggest that to ensure equitable and sustainable patient access, policymakers must establish unified regulatory frameworks that facilitate performance-linked reimbursement models and incentivize the localization of advanced therapy infrastructure.

Keywords:  CAR T-cell therapy; conjoint analysis; gulf cooperation council (GCC); health policy; high-cost medications; managed entry agreements; market access; value-based healthcare

DOI:  https://doi.org/10.3389/fphar.2026.1812612
J Transl Med. 2026 Sep 05. pii: 1207. [Epub ahead of print]24(1):

Microfluidic-based rapid generation of chimeric antigen receptor T cells improves low-multiplicity-of-infection transduction efficiency while preserving functional activity.

Ying Jiang, Guidong Zhu, Haiyan Zhang, Dongqi Tang.

   BACKGROUND: Conventional chimeric antigen receptor T-cell (CAR-T) manufacturing requires prolonged ex vivo processing and substantial viral input. We investigated whether brief T-cell activation combined with closed-loop microfluidic recirculation could improve low-multiplicity-of-infection (MOI) lentiviral transduction while generating functional CD19 CAR-T cells within a 24-h core process.
METHODS: Primary human T cells were activated with CD3/CD28 beads for 4 h and transduced with CD19 CAR/green fluorescent protein reporter (CAR/GFP) lentivirus at MOI 0.5 or 1.0 in donor-matched microfluidic-chip and static-plate comparisons. Unless otherwise stated, microfluidic rapid-manufactured CAR-T (MF-rmCAR-T) products were generated at MOI 1.0 by 20 h closed-loop recirculation. Conventionally manufactured CAR-T (cmCAR-T) products served as the product-level comparator. Day 7 CAR/GFP positivity, bulk-product vector copy number (VCN), viability, expansion, and phenotype were assessed, followed by in vitro functional testing and exploratory evaluation in a systemic Raji-Luc xenograft model. Donor-matched data were analyzed using paired t-tests or two-way repeated-measures ANOVA with Šídák correction, as appropriate.
RESULTS: Microfluidic processing increased Day 7 CAR/GFP positivity versus matched static transduction at MOI 0.5 (14.6% ± 1.7% vs. 7.3% ± 1.2%; p < 0.001) and MOI 1.0 (22.1% ± 1.5% vs. 13.9% ± 1.7%; p < 0.001) without reducing viability. MF-rmCAR-T and cmCAR-T products showed comparable CAR/GFP positivity, viability, viable-cell recovery, and Day 7 expansion, whereas MF-rmCAR-T products had lower bulk-product VCN (1.2 ± 0.2 vs. 2.8 ± 0.4 copies/cell; p < 0.01), greater central-memory representation, and lower TIM-3 and LAG-3 expression. MF-rmCAR-T cells showed numerically higher bulk Raji-Luc killing and greater lysis after normalization to equivalent CAR/GFP-positive effector numbers, together with higher IFN-γ release and lower post-co-culture PD-1 expression. Both CAR-T products reduced tumor burden and prolonged survival versus untransduced T-cell controls, with no significant difference between the CAR-T groups.
CONCLUSIONS: Closed-loop microfluidic recirculation enabled a 24-h CD19 CAR-T manufacturing workflow with improved low-MOI transduction, lower bulk-product VCN, and preserved antitumor activity. These findings support evaluation in larger preclinical studies and scalable closed manufacturing systems.

Keywords:  CAR-T cell therapy; Cell therapy manufacturing; Low-MOI transduction; Microfluidic recirculation; Rapid manufacturing

DOI:  https://doi.org/10.1186/s12967-026-08928-y
J Exp Med. 2026 Oct 05. pii: e20261490. [Epub ahead of print]223(10):

Slow-cooked naive T cells make better effectors.

Hee Yeun Won, Jung-Hyun Park.

While the TCR diversity of naive T cells is well established, the extent of their functional heterogeneity remains largely uncharted. In this issue of JEM, Sajiki et al. (https://doi.org/10.1084/jem.20252076) demonstrate that long-lived naive CD8 T cells accrue tonic TCR signaling during homeostasis, driving their differentiation into functionally superior effectors.

DOI: https://doi.org/10.1084/jem.20261490
Biomedicines. 2026 Aug 29. pii: 1941. [Epub ahead of print]14(9):

Genome-Wide Integration Site Profiling of Multi-Component CAR T-Cell Engineering Systems with ADA1/CD26 Co-Transduction.

Kevin Song, Yue Hu, Xiaotong Song.

  Background: Retroviral vectors remain widely used for CAR T-cell manufacturing, including emerging multi-component engineering strategies that incorporate additional functional modules to enhance therapeutic performance. However, genome-wide profiling of integration patterns in CAR T cells subjected to multiplex retroviral engineering has not previously been reported. Methods: We performed genome-wide profiling of retroviral integration sites in CAR T-cell products derived from two targeting platforms (IL15-GPC3 and HER2). Each platform was evaluated under conditions with or without co-transduction of a retroviral vector encoding ADA1 and CD26. Experiments were conducted using cells obtained from a single donor with three technical replicates. Vector copy number (VCN), chromosomal distribution, genomic feature annotation, and integration hotspot analyses were conducted. Results: VCN levels were comparable across all CAR T-cell products and were not significantly affected by ADA1/CD26 co-expression. Integration events were broadly distributed across the genome with enrichment in gene-dense chromosomal regions. Chromosome 19 showed a prominent integration preference, with a secondary enrichment observed on chromosome 17. The majority of integration sites were located within intronic regions, with no enrichment observed in promoter regions. Recurrent integration hotspots were identified; however, no evidence of dominant clonal expansion was observed across conditions. Comparative analyses between ADA1/CD26 and control groups showed minimal differences in integration patterns. Conclusions: To our knowledge, this study provides the first comprehensive, genome-wide characterization of retroviral integration site profiles in CAR T-cell products manufactured by multi-vector co-transduction with an ADA1/CD26 module. By employing harmonized comparison with external reference datasets, we offer a directly benchmarked integration site characterization of multi-component CAR T-cell manufacturing. These findings establish a reference framework for integration site monitoring in next-generation CAR T-cell engineering systems and inform risk evaluation for emerging combinatorial vector strategies.

Keywords:  CAR T-cell; genome-wide profiling; retroviral vector; viral integration

DOI:  https://doi.org/10.3390/biomedicines14091941
Clin Rheumatol. 2026 Sep 24.

CAR-T therapy for immune-mediated necrotizing myopathy: a review of mechanisms and emerging clinical evidence.

Yingchao Sun, Cheng Xu, Ci Lu, Mingli Ouyang, Ning Shen, Yiyun Wang, Xin Li, Yongmei Han.

  Among the heterogeneous group of idiopathic inflammatory myopathies (IIMs), immune-mediated necrotizing myopathy (IMNM) stands out for its hallmark of severe muscle necrosis accompanied by only sparse inflammation. The condition is strongly driven by myositis-specific autoantibodies (MSAs), chiefly anti-HMGCR and anti-SRP, which are central to its pathophysiology. Despite advances in immunosuppressive therapies, many patients remain refractory to conventional treatments. Recent developments in cellular therapies, especially chimeric antigen receptor T cell (CAR-T) therapy, have shown transformative potential in autoimmune diseases. This review aims to synthesize current knowledge on IMNM pathophysiology, elucidate the mechanistic rationale for CAR-T therapy, summarize emerging clinical evidence, and explore the feasibility of CAR-Treg-based approaches for IMNM. Key Points • This review summarizes the unique pathophysiological features and current therapeutic challenges of immune-mediated necrotizing myopathy (IMNM). • The role of anti-HMGCR and anti-SRP autoantibodies in IMNM pathogenesis and their implications for targeted immunotherapy are highlighted. • The mechanistic rationale and emerging clinical evidence supporting CAR-T therapy in IMNM are systematically reviewed. • CAR-Treg-based strategies are explored as a potential precision immunotherapy approach for refractory IMNM.

Keywords:  CAR-T therapy; CAR-Treg therapy; HMGCR; Immune-mediated necrotizing myopathy; SRP

DOI:  https://doi.org/10.1007/s10067-026-08426-y
Methods Mol Biol. 2027 ;3075 389-409

Nucleofection-Based CRISPR/Cas Delivery in Human T Cells for Immunotherapy Applications.

María Ortiz-Bueno, Alejandro Millán-López, Kornel Labun, Karim Benabdellah.

  Electroporation-based delivery of CRISPR/Cas systems has emerged as a powerful and versatile approach for gene editing in primary human T cells, enabling efficient, transient, and nonviral modification while minimizing genomic integration risks. This chapter focuses on the principles and practical implementation of electroporation (nucleofection) for the delivery of Cas9 ribonucleoprotein (RNP) complexes into human T cells, highlighting critical parameters that influence editing efficiency, cell viability, and scalability for research and clinical applications. We provide a comprehensive protocol for multiplex gene editing in primary human T cells using Cas9 RNP electroporation, including optimization of cell activation status, buffer composition, electroporation settings, and post-electroporation recovery. Particular emphasis is placed on strategies to achieve high-efficiency disruption of target loci such as TRAC and B2M, enabling the generation of edited T cell products with defined functional properties. As a representative application, we describe how this delivery platform can be integrated with chimeric antigen receptor (CAR) engineering to produce edited CAR-T cells, including universal "off-the-shelf" designs with reduced risks of graft-versus-host disease and immune rejection. Downstream evaluation methods, including multiparameter flow cytometry for assessing editing efficiency and immunophenotype, are also outlined.

Keywords:  CRISPR/Cas9; Electroporation; Gene editing; Nonviral delivery; Nucleofection; Primary cells; RNP delivery; T cells

DOI:  https://doi.org/10.1007/978-1-0716-5547-4_20
Front Cell Dev Biol. 2026 ;14 1921036

Spatial Treg niches and the therapeutic reprogramming of tumour tolerance in cancer.

Jhommara Bautista, Miranda Di Capua Delgado, Juliana Viteri-Recalde, Melanie Benítez-Núñez, David Ramírez-Sánchez, Andrés López-Cortés.

  Regulatory T cells (Tregs) maintain immune homeostasis, but in cancer the same FOXP3-dependent programme can be co-opted to protect malignant tissue from immune elimination. This review critically synthesizes spatially resolved, single-cell and mechanistic evidence to determine when tumour-associated Tregs constitute active components of suppressive multicellular niches rather than merely correlates of immune exclusion. We integrate tumour-adapted regulatory states with anatomical positioning, neighbouring malignant and non-malignant cells, candidate suppressive mechanisms and upstream tumour-intrinsic, stromal and myeloid programmes. This framework distinguishes Treg-dominant suppressive niches from Treg-associated architectures in which regulatory-cell accumulation is secondary to other resistance mechanisms. We examine tumour nests, invasive margins, dendritic-cell and lymphoid aggregates, stromal and perivascular barriers, and hypoxic or metabolically constrained regions, assessing the strength of evidence linking each context to local immune restraint. We further consider how these niches emerge during tumour progression, change under therapeutic pressure, and persist, relocate or re-form during resistance. We evaluate selective depletion strategies targeting CCR8, CD25 and CTLA-4, together with functional reprogramming of TGF-β, adenosine, kynurenine, lactate, hypoxia and IL-2 pathways. Finally, we propose a tiered biomarker framework integrating Treg phenotype, transcriptional state, spatiotemporal topology, functional immune competence and longitudinal pharmacodynamic validation. The contribution of this Review is therefore not the niche concept itself, but its Treg-centred mechanistic and translational operationalization for identifying tumour-specific regulatory dependencies while preserving systemic self-tolerance.

Keywords:  biomarker-guided Treg targeting; immunotherapy resistance; regulatory T cells; spatial immune niches; tumour microenvironment

DOI:  https://doi.org/10.3389/fcell.2026.1921036
Mol Ther Adv. 2026 Dec 10. 34(4): 201839

Transduction efficiency in clinical CAR T cell products: A retrospective study at a single center.

Lipei Shao, Michaela Prochazkova, Yihua Cai, Kyu Lee Han, Kathryn Martin, Rongye Shi, Ruyan Yang, Jinxia Ma, Yanyan Zheng, Pamela Garces, Sue-Ellen Frodigh, Victoria Pham, Nan Zhang, Robert P Somerville, David F Stroncek, Ping Jin.

  Transduction efficiency (TE) is a key measure of CAR T cell manufacturing quality; however, its variability and relationship to the final product phenotype remain incompletely understood. In this retrospective study, we evaluated TE across 204 GMP-manufactured CAR T cell products, integrating manufacturing parameters, starting material composition, and immunophenotypic and transcriptomic profiles of final products. Multivariable linear regression and protocol-specific correlation analyses were performed to account for manufacturing-related confounding. TE variability was primarily associated with integrated manufacturing workflows and starting material composition. The CD4CD8-Prodigy-TransAct workflow was associated with higher TE compared with the CD4CD8-Bag-Dynabeads workflow, although contribution of individual manufacturing parameters could not be independently determined due to protocol-specific interdependencies. Within PBMC-based manufacturing, monocyte abundance was negatively associated with TE, suggesting protocol-dependent contributions of starting material composition. Higher TE was associated with a less differentiated T cell phenotype, including lower effector memory T cell (TEM) frequencies, particularly within CD4+CAR+ compartment. Transcriptomic analyses further identified associations between TE and proliferation- and oxidative phosphorylation-associated gene-expression signatures; however, these findings were exploratory and may reflect protocol-related differences. Collectively, TE variability was associated primarily with integrated manufacturing workflows, providing a real-world framework for understanding CAR T cell manufacturing performance.

Keywords:  CAR T cell; GMP manufacturing; cellular therapy; manufacturing optimization; retrospective analysis; transduction efficiency

DOI:  https://doi.org/10.1016/j.omta.2026.201839
Neurol Sci. 2026 Sep 24. pii: 806. [Epub ahead of print]47(10):

B-cell targeting strategies for the treatment of multiple sclerosis: from non-cellular therapies to CAR-engineered cell therapies.

Nilufar Salomova, Lusine G Khachatryan, Aminjon Amonov, Murodjon Normatov, Nasiba Khalmatova, Anvarjon Rashidov, Bekzod Babamuratov.

   BACKGROUND: Accumulating evidence indicates that B-cell lineages play a central role in the pathogenesis of multiple sclerosis (MS). This understanding has reshaped the therapeutic landscape of MS, particularly following the success of anti-CD20 monoclonal antibodies (mAbs), which have become a cornerstone of MS treatment. Despite their efficacy in reducing relapse rates and slowing disability accumulation, current B-cell-depleting therapies have important limitations, including incomplete control of compartmentalized immune responses within the central nervous system (CNS).
METHODS: This review summarizes the progress and limitations of current and emerging B-cell-targeting strategies for MS. We discuss established non-cellular approaches, including monoclonal antibodies, Bruton's tyrosine kinase (BTK) inhibitors, and B-cell activating factor (BAFF) inhibitors, and examine the rationale, potential advantages, and challenges of emerging chimeric antigen receptor (CAR)-engineered cell therapies.
RESULTS: Anti-CD20 mAbs have demonstrated significant clinical efficacy; however, their limited CNS penetration and broad depletion of B-cell populations highlight the need for more targeted approaches. BTK inhibitors represent an emerging strategy to modulate B-cell and myeloid-cell signaling, while BAFF-targeting therapies have provided important insights into the complex role of B-cell survival pathways in MS. CAR-engineered cell therapies have emerged as a promising cellular approach capable of inducing profound and potentially durable depletion of pathogenic B-cell populations, including CNS-resident B-cell subsets.
CONCLUSIONS: B-cell-targeting therapies continue to expand the therapeutic landscape of MS. Although current non-cellular approaches have improved disease control, their limitations emphasize the need for next-generation strategies. CAR-engineered cell therapies represent a promising frontier with the potential to achieve more sustained immune modulation and address some unmet therapeutic challenges in MS.

Keywords:  B-cells; BAFF inhibitors; BTK inhibitors; CAR-T cell therapy; Monoclonal antibodies; Multiple sclerosis

DOI:  https://doi.org/10.1007/s10072-026-09421-6
Cells. 2026 Sep 14. pii: 1660. [Epub ahead of print]15(18):

Beyond CAR-T: Preventing and Treating Relapse in B-Cell Haematological Malignancies.

Martina Canichella, Elisabetta Abruzzese, Mariagiovanna Cefalo, Valentina Gianfelici, Carla Mazzone, Gentiana Elena Trotta, Roberta Laureana, Luca Cupelli, Maria Ilaria Del Principe.

  Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL), non-Hodgkin lymphoma (NHL), and multiple myeloma (MM); however, a substantial proportion of patients eventually experience disease relapse despite an initial response. This review provides a brief overview of CAR-T cell therapy, including its manufacturing process and associated toxicities, before examining the biological mechanisms underlying post-CAR-T relapse in B-ALL, NHL-particularly large B-cell lymphoma (LBCL)-and MM. We critically review current and emerging strategies to prevent and manage relapse. Strategies for relapse prevention primarily include consolidation approaches, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT), maintenance with targeted agents (e.g., tyrosine kinase inhibitors in Philadelphia chromosome-positive B-ALL), and CAR-T cell reinfusion, whereas relapse management is disease-specific and increasingly incorporates novel therapeutic agents, including bispecific antibodies (BsAbs) and other targeted therapies. However, current evidence remains largely preliminary and is limited by the paucity of randomized prospective trials.

Keywords:  CAR-T cell therapy; acute lymphoblastic leukemia; allogeneic stem cell transplantation; consolidation therapy; large B-cell lymphoma; multiple myeloma; post-CAR-T relapse

DOI:  https://doi.org/10.3390/cells15181660
Dent J (Basel). 2026 Sep 01. pii: 549. [Epub ahead of print]14(9):

Chimeric Antigen Receptor T-Cell Therapy Is Associated with Low Absolute Rates of Orofacial Adverse Events and Significantly Less When Compared to Hemopoietic Stem Cell Therapy.

Stella O Oyewole, Emma Butler, Sagun D Goyal, Adepitan A Owosho.

  Background/Objectives: Chimeric antigen receptor T-cell (CAR-T) therapy has been approved for the management of relapsed and refractory hematologic malignancies, transforming the oncologic landscape and producing durable remissions in patient populations with limited alternatives. The systemic adverse events of CAR-T are well characterized; however, the orofacial adverse events have not been well described. The objective of this study is to leverage a large, de-identified, real-world dataset to (1) estimate the prevalence of orofacial adverse events following CAR-T, (2) compare event rates with the general population, and (3) directly contrast the orofacial toxicity burden of CAR-T with that observed after hemopoietic stem cell transplant (HSCT). Methods: We performed a retrospective cohort study using de-identified electronic health record data from TriNetX. CAR-T and HSCT cohorts were identified via RxNorm and procedure codes; a non-exposed control cohort was included. Patients with prior orofacial conditions or confounding therapies were excluded. New adverse orofacial events within one year were identified by International Classification of Diseases, 10th Revision (ICD-10) codes. Cohorts were 1:1 propensity-matched by age and sex; associations were estimated as odds ratios with two-sided 95% CIs. Results: In 1142 CAR-T recipients (mean age of 62), gastroesophageal reflux disease (GERD) was most frequent (5.18%). Oral mucosal events included stomatitis in 1.52%, mucositis in 1.31%, and lichenoid reactions in 1.03%. Dysphagia occurred in 1.8% and oral candidiasis in 1.6%. Several severe oral conditions were absent. Compared with the general population (CART vs. general population): mucositis-[12/995 vs. 0/1112] (OR 28.3)-and stomatitis-[16/987 vs. 0/1119] (OR 38)-risks were significantly increased, while CAR-T patients had significant lower risks of mucosal complications than HSCT recipients in this analysis (CART vs. HSCT): mucositis-[1.21% vs. 3.72%] (OR 0.316) and stomatitis-[1.42% vs. 3.91%] (OR 0.354). Conclusions: CAR-T therapy carries a distinct and generally lower orofacial toxicity burden than HSCT, but targeted dental assessment and prospective surveillance remain important to optimize supportive care for cellular therapy recipients.

Keywords:  CAR T-cell therapy; oral adverse events; oral mucositis; stomatitis; treatment-related adverse events

DOI:  https://doi.org/10.3390/dj14090549
J Thromb Haemost. 2026 Sep 24. pii: S1538-7836(26)00617-3. [Epub ahead of print]

Teclistamab in relapsed, multi-refractory acquired hemophilia A after failure of anti-CD19 CAR-T cell therapy.

Christiane E Dobbelstein, Kalin Stoyanov, Krasimira Aleksandrova, Lubomir Arseniev, Jana Leise, Stephan Klöß, Felicitas R Thol, Florian H Heidel, Andreas Tiede, Christian R Schultze-Florey.

  A patient with relapsed acquired hemophilia A (AHA), who previously failed multiple lines of immunosuppressive therapy (IST) including autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy received teclistamab, a bispecific monoclonal antibody engaging autologous CD3-positive T cells with the B cell maturation antigen (BCMA) on plasma cells and mature B cells. Teclistamab was well tolerated without clinically significant adverse events, except for hypogammaglobulinemia. Prompt and durable remission was observed that lasted for more than one year post treatment. This is the first case of refractory AHA successfully treated with teclistamab, providing a proof-of-concept of plasma cell-directed bispecific antibodies, supporting its further evaluation.

Keywords:  Acquired hemophilia; Bispecific monoclonal antibody; Bleeding; CAR-T; Cell therapy; Inhibitor; Teclistamab

DOI:  https://doi.org/10.1016/j.jtha.2026.09.027
Cancer Cell. 2026 Sep 24. pii: S1535-6108(26)00388-0. [Epub ahead of print]

Human-centric preclinical models for CAR T cell therapy in solid tumors: Where patient-derived organoids fit.

Xiujian Ma, Julio Inocencio, Darya Alizadeh, Mohsen Basiri, Christine E Brown.

Chimeric antigen receptor (CAR) T cell therapy has shown promising activity in solid tumors, yet translational progress remains limited by preclinical models that incompletely capture human tumor biology. Patient-derived organoids (PDOs) preserve key features of human tumors, including cellular heterogeneity and tissue architecture, thereby enabling functional evaluation of CAR T cell targets, next-generation approaches, resistance mechanisms, and selected safety considerations. We discuss how PDOs complement existing preclinical platforms to support CAR T cell development for solid tumors.

DOI: https://doi.org/10.1016/j.ccell.2026.08.011
Reumatologia. 2026 ;64(4): 322-331

The role and potential of CD19-targeted chimeric antigen receptor T-cell therapy in systemic sclerosis.

Krzysztof Michalak, Gabriela Chlebowska, Oliwia Sędziak, Dariusz Woszczyk.

   Introduction: Systemic sclerosis (SSc) remains a challenge due to high mortality and resistance to treatment. Chimeric antigen receptor T-cell (CAR-T) technology (anti-CD19) may offer an opportunity for an immune system reset and long-term disease remission, eliminating the need for lifelong medication.
Material and methods: This narrative review is based on a literature search in the PubMed and Scopus databases from 2023 to 2026. The main search phrases were: "CAR-T in systemic sclerosis", "CAR-T scleroderma", and "CAR-T SSc."
Results: CD19-targeted CAR-T therapy led to significant clinical improvement across analyzed cases. The median modified Rodnan skin score decreased by 8-13 points within 3-6 months. Disease activity, measured by the European Scleroderma Trials and Research Group Activity Index (EUSTAR-AI), showed a mean improvement ranging from 2.1 to 4.2 points. Pulmonary function remained stable or improved, with forced vital capacity increasing by up to 7% in responders. The safety profile was manageable, primarily consisting of grade 1 cytokine release syndrome in approximately 75-80% of patients.
Conclusions: CD19-targeted CAR-T therapy is a promising investigational option for patients with refractory SSc. Limitations include small study groups and a lack of randomized controlled trials, warranting further validation in ongoing clinical studies.

Keywords:  immunotherapy; scleroderma; systemic sclerosis

DOI:  https://doi.org/10.5114/reum/224664
Blood Cancer Discov. 2026 Sep 21.

A Phase I/II Trial of Anti-CD22/CD19 CAR-T Cell Therapy, CART2219.1, in Adult and Pediatric Relapsed/Refractory B-ALL.

Michaela Su-Fern Seng, Zexi Guo, Kai Soon Ng, Shui Yen Soh, Francesca Wei Inng Lim, Liang Piu Koh, William Yk Hwang, Aloysius Yl Ho, Yeh Ching Linn, Esther Hian Li Chan, Michelle L M Poon, Lip Kun Tan, Mickey Bc Koh, Tun Kiat Ko, Jia Yu, King Pan Ng, Teck Guan Soh, Jason Yongsheng Chan, Joe Poh Sheng Yeong, Rimas J Orentas, Wing Leung.

Durable remissions after anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy in relapsed/refractory B-lineage acute lymphoblastic leukaemia are limited by antigen escape and T-cell dysfunction. The tandem CAR22-19/LTG2737 construct links human-derived anti-CD22 and anti-CD19 scFvs to CD8 hinge/transmembrane, 4-1BB, and CD3ζ domains. In a multicentre phase I/II trial, all patients (n=11; 7 children, 4 adults) achieved complete remission by Day 28 (91% minimal residual disease-negative). At a 34-month median follow-up, median overall survival (OS) and leukaemia-free survival (LFS) were not reached. The 12-month OS was 82% (95%CI: 45%-95%) and LFS was 64% (95%CI: 30%-85%) without consolidative transplantation. Immune-effector cell-associated toxicities included cytokine release syndrome, haematotoxicity, and haemophagocytic lymphohistiocytosis-like syndrome. De novo CD19 escape caused one relapse. Exploratory multi-omic profiling linked durable response to higher CD22 antigen density on blasts; pre-infusion CD4 CAR-T cells expressing IL7Rα, LEF1, BACH2, and TCF7 but lower FOXP3; post-infusion NK-like effector CAR-T expansion; and central-memory CAR-T pool maintenance.

DOI: https://doi.org/10.1158/2643-3230.BCD-26-0115