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 "slug": "car-t-cell-therapy",
 "title": "CAR T-cell therapy",
 "updated": "2026-10-15",
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 "excerpt": "CAR T-cell therapy is an immunotherapy in which a patient's T cells are engineered with a chimeric antigen receptor to attack cancer cells, used mainly for blood cancers.",
 "snippet": "CAR T-cell therapy is an immunotherapy in which a patient's T cells are engineered with a chimeric antigen receptor to attack cancer cells, used mainly for blood cancers.",
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 "markdown": "# CAR T-cell therapy\n\nCAR T-cell therapy is an immunotherapy in which a patient's T cells are engineered ex vivo to express a chimeric antigen receptor (CAR), a synthetic receptor that redirects the cells against cancer cells carrying a chosen surface antigen, and is used clinically to treat hematologic malignancies.<sup>[1](https://www.ncbi.nlm.nih.gov/books/NBK537294/)</sup> Six CAR T-cell products held US approval as of 2023, four targeting CD19 and two targeting BCMA,<sup>[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC11514108/)</sup> and nearly 35,000 patients in the United States had received autologous CAR T cells for hematologic malignancies.<sup>[3](https://www.mdpi.com/2673-7523/4/3/17)</sup>\n\n| Key fact | Detail |\n|---|---|\n| Mechanism | Autologous T cells are transduced with a viral vector encoding a CAR: an antibody-derived scFv fused to costimulatory (CD28 or 4-1BB) and CD3ζ signaling domains, recognizing antigen independently of MHC<sup>[4](https://www.fda.gov/media/156896/download)</sup> |\n| Manufacturing time | Typically 3–6 weeks vein-to-vein; Kymriah manufacture and release usually takes about 3–4 weeks<sup>[5](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2824%2900273-4/fulltext)</sup><sup> • </sup><sup>[6](https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf)</sup> |\n| Efficacy (myeloma) | KarMMa: 73% response, median PFS 8.8 months (ide-cel); CARTITUDE-1: 97% response, 12-month PFS 77% (cilta-cel)<sup>[7](https://www.nejm.org/doi/full/10.1056/NEJMoa2024850)</sup><sup> • </sup><sup>[8](https://pubmed.ncbi.nlm.nih.gov/34175021/)</sup> |\n| CRS | Occurs in 50–90% of patients depending on construct and antigen; managed with tocilizumab, corticosteroids, and supportive care<sup>[9](https://www.mdpi.com/2072-6694/17/2/282)</sup><sup> • </sup><sup>[1](https://www.ncbi.nlm.nih.gov/books/NBK537294/)</sup> |\n| Neurotoxicity | ICANS occurs in 20–64% of patients, grade ≥3 in 10–28%<sup>[9](https://www.mdpi.com/2072-6694/17/2/282)</sup> |\n| Resistance | CD19 escape after axi-cel or tisa-cel in 9–25% of B-ALL and 27–35% of DLBCL relapses<sup>[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10965011/)</sup> |\n| Regulatory status | FDA classifies CAR T products as human gene therapy products<sup>[4](https://www.fda.gov/media/156896/download)</sup> |\n\n## How it works\n\nA chimeric antigen receptor fuses an antibody-derived antigen-recognition domain to T-cell signaling machinery, so the engineered [T cell](https://www.edgepedia.org/t-cell) kills target cells by antibody-like specificity without requiring MHC presentation.<sup>[4](https://www.fda.gov/media/156896/download)</sup> The extracellular recognition element is a single-chain variable fragment (scFv); the intracellular part combines a costimulatory domain with the CD3ζ chain, whose cytoplasmic domain alone is sufficient to couple to receptor-associated signal transduction pathways, the fact that made first-generation CAR signaling possible.<sup>[11](https://doi.org/10.1016/0092-8674%2891%2990314-o)</sup> Domains used in various combinations include CD3ζ, 4-1BB (CD137), CD28, and CD40.<sup>[4](https://www.fda.gov/media/156896/download)</sup>\n\nThe costimulatory domain shapes the therapeutic phenotype. CD28-co-stimulated CARs show better effector function, while 4-1BB-co-stimulated CARs tend to exhibit a memory-like phenotype.<sup>[12](https://www.cell.com/molecular-therapy-family/advances/fulltext/S2329-0501%2824%2900066-4)</sup> All approved products are second-generation CARs using CD28 or 4-1BB costimulation; CD28 CARs proliferate faster with higher CRS grades, while 4-1BB CARs persist longer with less toxicity.<sup>[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC11514108/)</sup> In the landmark CLL case, a lentiviral construct coupling an anti-CD19 scFv to 4-1BB and CD3ζ produced in vivo expansion with a doubling time of about 1.2 days and an elimination half-life of 31 days.<sup>[13](https://www.nejm.org/doi/full/10.1056/NEJMoa1103849)</sup>\n\n## How it is done\n\nAutologous manufacturing starts with unstimulated leukapheresis (procedure filtering blood to collect white blood cells) to collect peripheral blood mononuclear cells, T-cell enrichment by magnetic beads or density-based methods, activation and transduction with a lentiviral or retroviral vector encoding the CAR cassette, and expansion until therapeutic doses are reached.<sup>[12](https://www.cell.com/molecular-therapy-family/advances/fulltext/S2329-0501%2824%2900066-4)</sup> Kymriah, for example, is made from leukapheresis-derived cells enriched for T cells, activated with anti-CD3/CD28 antibody-coated beads, and transduced with a lentiviral vector encoding an anti-CD19 CAR with 4-1BB and CD3ζ domains.<sup>[14](https://www.fda.gov/media/107296/download?attachment=)</sup> Retroviruses and lentiviruses are used with all currently approved CAR-T cell therapies.<sup>[15](https://doi.org/10.1016/j.ymthe.2025.03.005)</sup>\n\nThe whole process typically takes 3–6 weeks: leukapheresis, cell selection, activation, CAR engineering, 1–3 weeks of ex vivo expansion, formulation, cryopreservation, and quality control.<sup>[5](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2824%2900273-4/fulltext)</sup> Anti-CD3/CD28 bead activation is the dominant method, and the most common production combination is bead activation, viral transduction, and expansion in the G-Rex bioreactor.<sup>[16](https://discovery.ucl.ac.uk/id/eprint/10050033/1/Veraitch_20180109_CAR%20T%20cell%20manufacturing%20Review%20-%20Revision.pdf)</sup> The cellular starting material is a major source of lot-to-lot variability.<sup>[4](https://www.fda.gov/media/156896/download)</sup>\n\n## Origin\n\nIn 1989, G. Gross, T. Waks, and Z. Eshhar described the \"T-body\" in the [Proceedings of the National Academy of Sciences](https://www.edgepedia.org/proceedings-of-the-national-academy-of-sciences), redirecting T-cell specificity in an MHC-independent manner.<sup>[17](https://doi.org/10.1073/pnas.86.24.10024)</sup> Irving and Weiss's 1991 demonstration in Cell that the CD3ζ cytoplasmic chain alone can trigger activation supplied the signaling basis.<sup>[11](https://doi.org/10.1016/0092-8674%2891%2990314-o)</sup>\n\nThe clinical era opened with Porter and colleagues' 2011 NEJM report of a refractory CLL patient in whom a low dose of about \\( 1.5 \\times 10^{5} \\) anti-CD19 CAR T cells per kilogram expanded more than 1000-fold and produced complete remission.<sup>[13](https://www.nejm.org/doi/full/10.1056/NEJMoa1103849)</sup> Grupp and colleagues reported the first pediatric relapsed/refractory ALL treatments in 2013 in the NEJM and introduced tocilizumab for CRS,<sup>[18](https://doi.org/10.1056/nejmoa1215134)</sup> and Maude and colleagues showed sustained remissions in 2014 in the NEJM, leading to the ELIANA trial and the first FDA approval.<sup>[19](https://doi.org/10.1056/nejmoa1407222)</sup> [Tisagenlecleucel](https://www.edgepedia.org/tisagenlecleucel) was the first FDA-approved CAR-T treatment, in August 2017, for patients up to 25 years with refractory B-cell precursor ALL; axicabtagene ciloleucel followed in October 2017 for relapsed/refractory large [B-cell lymphoma](https://www.edgepedia.org/b-cell-lymphoma).<sup>[1](https://www.ncbi.nlm.nih.gov/books/NBK537294/)</sup>\n\n## Variants\n\nBeyond the approved second-generation autologous products, several engineered variants exist. Fourth-generation \"TRUCK\" or armored CAR-T cells carry regulated suicide genes or cytokine secretion.<sup>[15](https://doi.org/10.1016/j.ymthe.2025.03.005)</sup> Universal CAR-T (UCAR-T) cells use gene editing with ZFN, TALEN, or CRISPR-Cas9 to knock out endogenous TCRs and HLA class I in donor cells; allogeneic UCAR-T products can be made in large batches, cryopreserved, and given on demand.<sup>[20](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1519671/full)</sup><sup> • </sup><sup>[21](https://link.springer.com/article/10.1186/s13045-025-01737-8)</sup> Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumor rejection in preclinical models,<sup>[22](https://doi.org/10.1038/nature21405)</sup> and c-Jun overexpression induces exhaustion resistance in CAR T cells.<sup>[23](https://doi.org/10.1038/s41586-019-1805-z)</sup> Faster manufacturing has also arrived: [Kite Pharma](https://www.edgepedia.org/kite-pharma) received FDA approval of a 5-day manufacturing protocol for axicabtagene ciloleucel, reducing vein-to-vein time to as little as 14 days, and reduced-duration culture from 9 days to 3–5 days improves CAR T-cell memory phenotype and function.<sup>[5](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2824%2900273-4/fulltext)</sup><sup> • </sup><sup>[24](https://doi.org/10.1038/s41551-021-00842-6)</sup>\n\n## Applications\n\nIn relapsed/refractory B-cell ALL, the ELIANA trial of tisagenlecleucel produced an overall response rate of 70.3% among infused patients, with 67.2% MRD-negative complete responses and median overall survival of 29.9 months.<sup>[6](https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf)</sup> In ZUMA-1, axi-cel produced an ORR of 82% and complete response rate of 54% in 111 heavily pretreated large B-cell lymphoma patients, with 18-month overall survival of 52%.<sup>[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC11514108/)</sup>\n\nIn multiple myeloma, KarMMa (ide-cel) treated 128 patients with 73% response and median PFS 8.8 months,<sup>[7](https://www.nejm.org/doi/full/10.1056/NEJMoa2024850)</sup> while CARTITUDE-1 (cilta-cel) treated 97 patients with a median of six prior therapies, achieving 97% ORR, a 12-month PFS rate of 77%, and long-term remissions of at least 5 years.<sup>[8](https://pubmed.ncbi.nlm.nih.gov/34175021/)</sup><sup> • </sup><sup>[25](https://www.nature.com/articles/s41577-026-01322-1)</sup> Decade-long leukemia remissions with persistent CD4+ CAR T cells have also been documented.<sup>[25](https://www.nature.com/articles/s41577-026-01322-1)</sup>\n\nToxicity management is integral to use. CRS occurred in 77% of ELIANA patients, with 51% of CRS patients receiving tocilizumab,<sup>[14](https://www.fda.gov/media/107296/download?attachment=)</sup><sup> • </sup><sup>[26](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=aad3ba54-dfd3-4cb3-9e2b-c5ef89559189)</sup> and with Yescarta, CRS occurred in 90% of NHL patients but ≥grade 3 in only 9%.<sup>[27](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9b70606e-b99c-4272-a0f1-b5523cce0c59)</sup> CAR-related encephalopathy syndrome typically occurs within the first 5 days, managed by grade using the CARTOX-10 neurological assessment with supportive care, corticosteroids, and IL-6 antagonists.<sup>[1](https://www.ncbi.nlm.nih.gov/books/NBK537294/)</sup>\n\n## Limitations and alternatives\n\nManufacturing failure excludes some patients: 8% of ELIANA enrollees could not be manufactured,<sup>[6](https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf)</sup> and 33% of LBCL patients who undergo leukapheresis do not reach infusion.<sup>[5](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2824%2900273-4/fulltext)</sup> Poor expansion predicts failure: in Yescarta LBCL patients, responders' median peak CAR T-cell levels were 205% higher than nonresponders.<sup>[27](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9b70606e-b99c-4272-a0f1-b5523cce0c59)</sup>\n\nAntigen escape is a relapse mechanism. CD19 escape occurred in 9–25% of B-ALL and 27–35% of DLBCL cases after axi-cel or tisa-cel; in one tisagenlecleucel analysis, 12 of 17 relapsed patients had CD19-negative disease with frameshift mutations in exons 2–5 of CD19 predicting a truncated protein lacking membrane anchorage.<sup>[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10965011/)</sup> Loss of SPPL3 causes CD19 hyperglycosylation that suppresses CAR-T effector function, and lineage switching has also been documented, with two of seven KMT2A-rearranged B-ALL patients relapsing as acute myeloid leukemia.<sup>[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10965011/)</sup> Impaired death-receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T-cell dysfunction.<sup>[28](https://doi.org/10.1158/2159-8290.cd-19-0813)</sup> Salvage options include CD22-directed CAR-T, which achieved 70% complete remission in a phase I trial of 58 patients after CD19 CAR-T failure.<sup>[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC10965011/)</sup>\n\nLate effects include persistent cytopenias beyond 3 months in 20–40% of patients<sup>[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC11514108/)</sup> and secondary T-cell malignancies: Kymriah's boxed warning was updated in June 2025 to state that mature T-cell malignancies, including CAR-positive tumors, have occurred after BCMA- and CD19-directed CAR T therapies and may present as soon as weeks after infusion with fatal outcomes.<sup>[26](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=aad3ba54-dfd3-4cb3-9e2b-c5ef89559189)</sup>\n\nCompared with alternatives, randomized trials favor CAR T over standard care: in ZUMA-7, axi-cel gave median event-free survival of 8.3 months versus 2.0 months; in TRANSFORM, liso-cel gave 10.1 versus 2.3 months; in KarMMa-3, ide-cel gave 71% versus 42% response and median PFS 13.3 versus 4.4 months.<sup>[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC11514108/)</sup> Bispecific antibodies are off-the-shelf alternatives with lower response rates: blinatumomab achieved 44% CR in relapsed/refractory adult B-ALL, and teclistamab achieved 63% ORR in heavily pretreated myeloma versus response rates exceeding 80% for BCMA CAR-Ts.<sup>[9](https://www.mdpi.com/2072-6694/17/2/282)</sup> In vivo CAR engineering removes ex vivo manufacturing entirely: [Interius BioTherapeutics](https://www.edgepedia.org/interius-biotherapeutics)' INT2104 was approved in Australia in July 2024, the first in vivo CAR gene therapy to enter clinical trials worldwide, and in a phase 1 study, EsoBiotec's ESO-T01, an immune-shielded lentiviral vector encoding an anti-BCMA CAR, was given as a single intravenous infusion without leukapheresis, ex vivo manufacturing, or lymphodepletion, with four of five patients responding.<sup>[29](https://link.springer.com/article/10.1186/s12951-026-04232-5)</sup><sup> • </sup><sup>[30](https://www.nature.com/articles/s41591-026-04244-6)</sup> As of the end of 2025, 12 CAR-T therapies have been approved worldwide.<sup>[29](https://link.springer.com/article/10.1186/s12951-026-04232-5)</sup>\n\n## References\n\n1. [Chimeric Antigen Receptor T-Cell Therapy (StatPearls, NCBI Bookshelf)](https://www.ncbi.nlm.nih.gov/books/NBK537294/)\n2. [Overview of approved CAR-T products and utility in clinical practice](https://pmc.ncbi.nlm.nih.gov/articles/PMC11514108/)\n3. [State of the Art on CAR T-Cell Therapies for Onco-Haematological Disorders and Other Conditions (Oncologie, MDPI)](https://www.mdpi.com/2673-7523/4/3/17)\n4. [Considerations for the Development of Chimeric Antigen Receptor T Cell Products; Guidance for Industry (FDA)](https://www.fda.gov/media/156896/download)\n5. [fulltext (thelancet.com)](https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026%2824%2900273-4/fulltext)\n6. [Kymriah EPAR Product Information (EMA)](https://www.ema.europa.eu/en/documents/product-information/kymriah-epar-product-information_en.pdf)\n7. [Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma (KarMMa, NEJM)](https://www.nejm.org/doi/full/10.1056/NEJMoa2024850)\n8. [Ciltacabtagene autoleucel (CARTITUDE-1): a phase 1b/2 open-label study](https://pubmed.ncbi.nlm.nih.gov/34175021/)\n9. [Comprehensive Review of Early and Late Toxicities in CAR T-Cell Therapy and Bispecific Antibody Treatments for Hematologic Malignancies (Cancers)](https://www.mdpi.com/2072-6694/17/2/282)\n10. [Mechanisms of resistance to chimeric antigen receptor-T cells in haematological malignancies (PMC copy of the Nature Reviews Drug Discovery review)](https://pmc.ncbi.nlm.nih.gov/articles/PMC10965011/)\n11. [The cytoplasmic domain of the T cell receptor ζ chain is sufficient to couple to receptor-associated signal transduction pathways (Cell, 1991)](https://doi.org/10.1016/0092-8674%2891%2990314-o)\n12. [CAR-T cell manufacturing landscape, Lessons from the past decade and considerations for early clinical development (Molecular Therapy Methods & Clinical Development)](https://www.cell.com/molecular-therapy-family/advances/fulltext/S2329-0501%2824%2900066-4)\n13. [Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia (Porter, Levine, Kalos, Bagg, June; NEJM 2011)](https://www.nejm.org/doi/full/10.1056/NEJMoa1103849)\n14. [KYMRIAH (tisagenlecleucel) Package Insert](https://www.fda.gov/media/107296/download?attachment=)\n15. [From concept to cure: The evolution of CAR-T cell therapy (Molecular Therapy, 2025)](https://doi.org/10.1016/j.ymthe.2025.03.005)\n16. [A guide to manufacturing CAR T (Current Opinion in Biotechnology, Vormittag et al., via UCL Discovery)](https://discovery.ucl.ac.uk/id/eprint/10050033/1/Veraitch_20180109_CAR%20T%20cell%20manufacturing%20Review%20-%20Revision.pdf)\n17. [G Gross, T Waks, Z Eshhar (1989). Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity.. Proceedings of the National Academy of Sciences.](https://doi.org/10.1073/pnas.86.24.10024)\n18. [Stephan A. Grupp and colleagues (2013). Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia. New England Journal of Medicine.](https://doi.org/10.1056/nejmoa1215134)\n19. [Shannon L. Maude and colleagues (2014). Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia. New England Journal of Medicine.](https://doi.org/10.1056/nejmoa1407222)\n20. [CAR-T cell therapy: developments, challenges and expanded applications from cancer to autoimmunity (Frontiers in Immunology)](https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1519671/full)\n21. [Recent advances in universal chimeric antigen receptor T cell therapy (Journal of Hematology & Oncology)](https://link.springer.com/article/10.1186/s13045-025-01737-8)\n22. [Justin Eyquem and colleagues (2017). Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature.](https://doi.org/10.1038/nature21405)\n23. [Rachel C. Lynn and colleagues (2019). c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature.](https://doi.org/10.1038/s41586-019-1805-z)\n24. [Saba Ghassemi and colleagues (2022). Rapid manufacturing of non-activated potent CAR T cells. Nature Biomedical Engineering.](https://doi.org/10.1038/s41551-021-00842-6)\n25. [A guide to CAR T cell therapies: development, current status and future prospects (Nature Reviews Immunology)](https://www.nature.com/articles/s41577-026-01322-1)\n26. [KYMRIAH Package Insert (DailyMed, revised 12/2025)](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=aad3ba54-dfd3-4cb3-9e2b-c5ef89559189)\n27. [YESCARTA (axicabtagene ciloleucel) Package Insert](https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=9b70606e-b99c-4272-a0f1-b5523cce0c59)\n28. [Nathan Singh and colleagues (2020). Impaired Death Receptor Signaling in Leukemia Causes Antigen-Independent Resistance by Inducing CAR T-cell Dysfunction. Cancer Discovery.](https://doi.org/10.1158/2159-8290.cd-19-0813)\n29. [In vivo CAR-T therapy: from molecular design to precision delivery (Journal of Nanobiotechnology)](https://link.springer.com/article/10.1186/s12951-026-04232-5)\n30. [In vivo generation of anti-BCMA CAR-T cells in relapsed or refractory multiple myeloma: a phase 1 study (Nature Medicine)](https://www.nature.com/articles/s41591-026-04244-6)\n\n---\n*Topic: Encyclopedia › Life and health › Human health and medicine › Medicines and therapeutics › Biologics, monoclonal antibodies, and biosimilars*\n\n*Initially written Sep 29, 2026 · Edited: Oct 15, 2026*\n\n*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*\n\nLicense: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license\n",
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 "speakable": "CAR T-cell therapy is an immunotherapy in which a patient's T cells are engineered with a chimeric antigen receptor to attack cancer cells, used mainly for blood cancers."
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