bims-carter 2025-08-10 papers

Issue of 2025–08–10
eight papers selected by
Luca Bolliger, lxBio

Front Immunol. 2025 ;16 1615212

Tracing the development of CAR-T cell design: from concept to next-generation platforms.

Chimeric Antigen Receptor (CAR)-T cell therapy represents a transformative breakthrough in cancer immunotherapy by harnessing the adaptive immune system to selectively eradicate cancer cells. Pioneering advances in the treatment of hematological malignancies have led to the FDA approval of several CAR-T cell therapies, particularly for patients with relapsed or refractory disease. This success is a result of continuous refinements in CAR architecture, which have evolved from early prototypes with limited therapeutic efficacy to advanced next-generation receptors that incorporate co-stimulatory domains, cytokine signaling, safety switches, and precision control mechanisms. This review elucidates the fundamental rationale behind CAR-T cell development and addresses key biological challenges encountered. Advances in receptor engineering, metabolic reprogramming, and optimized immune signaling have markedly enhanced the persistence, antitumor activity, and safety profiles of CAR-T cells. Additionally, emerging genetic engineering tools, including CRISPR, base editing, prime editing, and RNA and epigenome editing, hold promise for reducing immunogenicity and minimizing the risk of graft-versus-host disease (GVHD). However, CAR-T cell therapy continues to face several challenges, including severe side effects such as cytokine release syndrome (CRS) and neurotoxicity, inconsistent therapeutic responses, and high production costs. To overcome these barriers, novel approaches are under development that include generating CAR-T cells in vivo, utilizing logic-gated CAR systems, and expanding CAR platforms to include other immune effector cells, such as natural killer cells (CAR-NK) and macrophages (CAR-M). The future of CAR-based therapies is expected to integrate synthetic biology, immune checkpoint modulation, and innovative delivery methods to enhance both therapeutic efficacy and safety. This review synthesizes current knowledge and emerging strategies to guide future advancements aimed at expanding the applicability of CAR therapy to various cancer types and potentially other diseases.

Keywords: CAR design; CAR-T cell therapy; T cell engineering; adoptive cell therapy; gene editing; immunotherapy; next-generation CAR; synthetic immunology

DOI: https://doi.org/10.3389/fimmu.2025.1615212

Cell. 2025 Aug 07. pii: S0092-8674(25)00796-2. [Epub ahead of print]188(16): 4173-4174

iPSC-derived CAR-NK cells: Off-the-shelf cellular therapy for systemic sclerosis.

May Daher, Katayoun Rezvani.

Chimeric antigen receptor (CAR) T cell therapy has opened new possibilities for patients with refractory autoimmune diseases such as systemic sclerosis, but personalized manufacturing and treatment-related toxicities limit its broader use. In this preview, we discuss the first clinical application of an off-the-shelf, iPSC-derived CAR-NK cell product in systemic sclerosis as reported by Wang et al. in this issue of Cell.

DOI: https://doi.org/10.1016/j.cell.2025.07.007

Clin Exp Med. 2025 Aug 04. 25(1): 274

Emerging CAR immunotherapies: broadening therapeutic horizons beyond cancer.

Natthaporn Sueangoen, Somsak Prasongtanakij.

Chimeric antigen receptor-based immunotherapy has transformed cancer treatment, especially for hematologic malignancies like acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Innovations in CAR design from first-generation constructs relying on CD3ζ signaling to next-generation CARs with co-stimulatory domains have enhanced T cell persistence and antitumor efficacy. Despite these successes, translating CAR-T therapy to solid tumors faces significant challenges, including antigen heterogeneity, immunosuppressive tumor microenvironments, and toxicities such as cytokine release syndrome and neurotoxicity. To overcome these hurdles, CAR therapies involving alternative immune cells are currently being developed, such as CAR-natural killer, CAR-T regulatory (Treg), CAR-macrophages (Ms), and others, each offering distinct biological advantages and potential for broader applications. Beyond oncology, CAR approaches are being explored for autoimmune diseases, infectious diseases, and fibrosis, expanding their therapeutic scope. Manufacturing complexities and safety concerns related to gene modification also highlight the need for scalable, safe production methods, including non-viral gene delivery systems. This review summarizes the evolution, current applications, and future prospects of CAR-based therapies, emphasizing the importance of ongoing innovation to enhance specificity, safety, and clinical efficacy across diverse disease contexts.

Keywords: Alternative CAR immune cells; CAR-T cell therapy; Immunosuppressive tumor microenvironment; Immunotherapy for non-cancer diseases; Solid tumors

DOI: https://doi.org/10.1007/s10238-025-01820-x

Discov Oncol. 2025 Aug 03. 16(1): 1461

Knowledge-map and bibliometric analysis of scientific research on FDA-approved Chimeric Antigen Receptor T cell products (2015-2024).

Moutaz W Sweileh.

BACKGROUND: Chimeric Antigen Receptor T cell (CAR-T) therapy is a groundbreaking, personalized immunotherapy that genetically engineers patient or donor-derived T cells to recognize and eliminate cancer cells. The U.S FDA has approved six CAR-T cell products in the past decade.
OBJECTIVE: Given their clinical success and scientific novelty, this study aimed to map the research landscape surrounding the FDA-approved CAR-T cell therapies using bibliometric and knowledge mapping analysis.
METHODS: A comprehensive title/abstract search was conducted in Scopus database for documents published between 2015 and 2024. The search terms included generic, trade, and abbreviated names of all FDA-approved CAR-T cell products. Bibliometric indicators including average annual growth rate, citation impact, key contributors, authorship pattern, and international collaboration were assessed. Visualization maps of co-authorship and keyword co-occurrence were generated using VOSviewer.
RESULTS: A total of 1163 documents were retrieved, with an average annual growth rate of 63.4%. Tisa-cel and axi-cel dominated the literature with 51.7% (n = 601) and 554 (47.6%) publications respectively. Ide-cel appeared in 152 (13.1%) publications, liso-cel in 125 (10.7%), and cilta-cel in 120 (10.3%). Brexu-cel was the least represented with 106 (9.1%) publications. The retrieved publications received 57,097 citations (mean = 49.1 citations per article; H-index = 103). Hematology and oncology-related journals were most prolific. The United States led global research output with 694 (59.7%) publications. Research output from European countries showed strong dependence on U.S.-based partnerships. Institutionally, the University of Texas MD Anderson Cancer Center, with 132 publications, was the leading institutions, followed by Moffitt Cancer Centre, and Memorial Sloan-Kettering Cancer Center. Authorship analysis revealed significant collaborative efforts, averaging 10.9 authors per article. Co-authorship map revealed academia-industry partnership. Temporal analysis of keywords revealed an evolution from CD19 target research (tisa-cel and axi-cel) to BCMA focused therapies (ide-cel and celta-cel). Thematic analysis showed four research themes: (1) molecular, therapeutic, and regulatory development of CAR-T constructs; (2) outcome of clinical trials; (3) economic and policy dimension of CAR-T therapy; and (4) treatment of relapsed and refractory multiple myeloma.
CONCLUSIONS: This study offers a translationally relevant perspective for clinicians, researchers, and policymakers, and underscores the evolving priorities in therapeutic development, access, and sustainability in precision oncology.

Keywords: Bibliometric; CAR-T cell therapy; Hematologic malignancies; Oncology; U.S. FDA

DOI: https://doi.org/10.1007/s12672-025-03360-y

Rinsho Ketsueki. 2025 ;66(7): 679-686

[Next-generation CAR gene-modified cell therapy: overcoming resistance and exploring novel applications].

Reona Leo Sakemura.

In recent years, chimeric antigen receptor (CAR)-engineered cellular therapy has brought remarkable advancements in cancer immunotherapy and autoimmune disease treatment. CAR T-cell therapy has demonstrated high efficacy in multiple myeloma (MM), but its durability is limited due to immune suppression within the tumor microenvironment (TME). This study elucidates how cancer-associated fibroblasts (CAFs) impair BCMA CAR T-cell function, and describes development of dual-specific CAR T-cells targeting CAFs. The results showed that CAFs promoted CAR T-cell exhaustion via TGF-β, PD-L1, IL-10, and the FAS/FASL pathway. BCMA-FAP and BCMA-CS1 CAR T cells exhibited enhanced cytotoxicity against MM cells and CAFs, overcoming TME-mediated suppression. E-cadherin-targeting CAR MSCs (Ecad CAR-MSCs) to address graft-versus-host disease (GvHD) were also developed for this study. These CAR MSCs significantly reduced GvHD by selectively accumulating in the intestinal epithelium, suppressing T-cell activation via IL-10 and galectin-9 while promoting Treg induction. These findings suggest that CAF-targeting dual-specific CAR T cells enhance the efficacy of MM immunotherapy, while Ecad CAR-MSCs offer a novel approach to treating GvHD. These approaches hold promise for clinical translation to improve outcomes in cellular therapy.

Keywords: CAR T-cell therapy; CAR-MSC; GvHD; Tumor microenvironment

DOI: https://doi.org/10.11406/rinketsu.66.679

Curr Opin Immunol. 2025 Aug 05. pii: S0952-7915(25)00086-X. [Epub ahead of print]96 102610

Can we cure antiphospholipid syndrome?

Pier Luigi Meroni, Enrico Capobianco, Francesco Tedesco.

Antiphospholipid antibody syndrome (APS) is a vasculopathy with recurrent thrombosis and/or miscarriages mediated by autoantibodies against PL-binding proteins (aPL), mainly beta2glycoprotein I (β2GPI). While clotting is the key in vascular APS, thrombosis is not critical for placenta pathology. Despite that, anticoagulant/antiplatelet drugs are the leading treatments, but this is not a 'one-size-fits-all' therapy, and recurrences are reported. Additional therapies (e.g. antimalarials, statins) and a better characterization of the individual risk profile may improve the outcome. Nevertheless, we are still unable to 'cure' APS. The ideal target would be aPL suppression. However, immunosuppression or even B-cell therapies are not effective. Targeting CD38 on antibody-producing cells or anti-CD19 CAR-T cell therapy are promising alternatives, as well as the chimeric autoantigen receptor T cell therapy, due to the identification of β2GPI as an APS autoantigen. Further therapies aimed at improving clot lysis or affecting β2GPI/anti-β2GPI tissue complex formation are appealing preclinical perspectives.

DOI: https://doi.org/10.1016/j.coi.2025.102610

BMJ Oncol. 2025 ;4(1): e000566

Tumour-infiltrating lymphocyte therapy landscape: prospects and challenges.

Ruqin Chen, Jeffrey Johnson, Ali Rezazadeh, Arkadiusz Z Dudek.

Tumour-infiltrating lymphocyte (TIL) therapy has emerged as a promising adoptive cell transfer strategy for solid tumours. The recent accelerated approval of lifileucel by the Food and Drug Administration marks a significant milestone in the clinical application of TIL therapy. This review comprehensively examines the historical development, biology, clinical efficacy, safety and limitations of TIL therapy. We explore advancements in TIL manufacturing, including novel culture techniques, genetic modifications and automation, to enhance scalability and effectiveness. Despite promising results, TIL therapy faces challenges such as high-dose interleukin-2 toxicity, complex manufacturing processes and immune evasion mechanisms. Emerging strategies, including checkpoint inhibitor combinations, engineered TIL constructs and metabolic reprogramming, aim to improve TIL therapeutic efficacy. This review provides insights into the evolving landscape of TIL therapy and its potential to enhance current cancer immunotherapy.

Keywords: Cell engineering; Cell therapy; Immunotherapy; Melanoma; Solid tumour

DOI: https://doi.org/10.1136/bmjonc-2024-000566

Cell Rep Med. 2025 Aug 05. pii: S2666-3791(25)00355-6. [Epub ahead of print] 102282

Multiplexed iPSC platform for advanced NK cell immunotherapies.

Akhilesh Kumar, Colin Fischer, Frank Cichocki, Jeffrey S Miller.

Human pluripotent stem cell (PSC) derivation advances have revealed enormous potential for improved cancer immunotherapy and clinical-scale blood cell production. PSCs can self-renew indefinitely and be differentiated into specialized cells, making them promising candidates for producing cytotoxic lymphocytes. Deriving natural killer (NK) cells from PSCs unlocks new possibilities for studying developmental hematopoiesis and investigating potential immunotherapy treatments. Cellular therapies, combined with genetic engineering, are potent tools for combating cancer and viral infections. While NK cells directly lyse tumor cells, genetic modifications, such as chimeric antigen receptor (CAR) engineering or the deletion of checkpoint molecules, can enhance their functional capacity. Here, we discuss recent advances in induced PSC (iPSC) editing and guided differentiation, focusing on developing NK cell immunotherapeutic products and optimizing iPSCs as an NK cell source to broaden therapeutic options and address diverse patient needs. This comprehensive review evaluates iPSC-derived NK cell-based therapies, recent advances, and future genome-editing strategies.

Keywords: chimeric antigen receptor; gene editing; genetic engineering; immunotherapy; induced pluripotent stem cells; natural killer cells

DOI: https://doi.org/10.1016/j.xcrm.2025.102282