ArticleJournal for immunotherapy of cancer2023
CD4 CAR-T cells targeting CD19 play a key role in exacerbating cytokine release syndrome, while maintaining long-term responses.
Article in Journal for immunotherapy of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 49 citations in OpenAlex.
- Why CD4+ T cells matter in adoptive cell therapy for solid cancers.Immuno-oncology technology · 2026Review
- Harnessing Natural Killer Cells: From Neuroimmunology to Novel Therapies for Central Nervous System Diseases.MedComm · 2026Review
- Depletion of CD8Molecular therapy : the journal of the American Society of Gene Therapy · 2026Article
- αvβ3 CAR-T Cells Simultaneously Targeting Tumor and Metastases Produce Highly Effective Control in Preclinical Models of Melanoma and Triple-Negative Breast Cancer.Molecular cancer therapeutics · 2026Article
- Article
- Enhancing persistence while managing cytokine release syndrome to embrace next-generation CAR-T cell therapy.Journal of translational medicine · 2026Review
- Adaptive-like CAR-iPSC-CD4⁺ T cells outperform CD8⁺ counterparts in sustained ALL control.Inflammation and regeneration · 2026Article
- The transformative potential of lipid nanoparticles tailored for acute myeloid leukemia immunotherapy.Frontiers in immunology · 2026Review
- Data-driven computational modeling of CAR-T cell function.Frontiers in immunology · 2026Article
- Clinical implementation of a one-step no-wash flow cytometry method allows for real-time monitoring of patients treated with autologous CAR-T cells.Frontiers in oncology · 2026Article
- Immune effector cell-associated neurotoxicity syndrome following CAR T-cell therapy: a review of recent advances.Journal of translational medicine · 2025Review
- EomesoderminImmunity · 2025Article
- CD28 signaling complexes are correlated with patient outcomes in anti-CD19 41BB-costimulation CAR T cell therapy.Journal for immunotherapy of cancer · 2025Article
- CAR-T cells targeting CD155 reduce tumor burden in preclinical models of leukemia and solid tumors.The Journal of clinical investigation · 2025Article
- Characterization and comparative analysis of multifunctional natural killer cell engagers during antitumor responses.Cell reports. Medicine · 2025Article
- CD22 TCR-engineered T cells exert antileukemia cytotoxicity without causing inflammatory responses.Science advances · 2025Article
- Restoration of LAT activity improves CAR T cell sensitivity and persistence in response to antigen-low acute lymphoblastic leukemia.Cancer cell · 2025Article
- Article
- Vaccine-induced T cell receptor T cell therapy targeting a glioblastoma stemness antigen.Nature communications · 2025Article
- The Evolving Applications of Bispecific Antibodies: Reaping the Harvest of Early Sowing and Planting New Seeds.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2025Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTo date, T cells redirected with CD19-specific chimeric antigen receptors (CAR) have gained impressive success in B-cell malignancies. However, treatment failures are common and the occurrence of severe toxicities, such as cytokine release syndrome (CRS), still limits the full exploitation of this approach. Therefore, the development of cell products with improved therapeutic indexes is highly demanded.
methodsIn this project, we investigated how CD4 and CD8 populations cooperate during CD19 CAR-T cell responses and what is their specific role in CRS development. To this aim, we took advantage of immunodeficient mice reconstituted with a human immune system (HuSGM3) and engrafted with the B-cell acute lymphoblastic leukemia cell line NALM-6, a model that allows to thoroughly study efficacy and toxicity profiles of CD19 CAR-T cell products.
resultsCD4 CAR-T cells showed superior proliferation and activation potential, which translated into stronger stimulation of myeloid cells, the main triggers of adverse events. Accordingly, toxicity assessment in HuSGM3 mice identified CD4 CAR-T cells as key contributors to CRS development, revealing a safer profile when they harbor CARs embedded with 4-1BB, rather than CD28. By comparing differentially co-stimulated CD4:CD8 1:1 CAR-T cell formulations, we observed that CD4 cells shape the overall expansion kinetics of the infused product and are crucial for maintaining long-term responses. Interestingly, the combination of CD4.BBz with CD8.28z CAR-T cells resulted in the lowest toxicity, without impacting antitumor efficacy.
conclusionsTaken together, these data point out that the rational design of improved adoptive T-cell therapies should consider the biological features of CD4 CAR-T cells, which emerged as crucial for maintaining long-term responses but also endowed by a higher toxic potential.
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