Systematic Review of CAR T-Cell Therapy for Cancer Treatment in Leukemia and Beyond: Applications, Limitations, and Promise
DOI:
https://doi.org/10.58445/rars.2767Keywords:
CAR T-cell therapy, immunotherapy, Leukemia, hematologic Cancer, solid malignancy, Therapeutic Development, treatment efficacy, clinical application, systematic reviewAbstract
Chimeric antigen receptor (CAR) T-cell therapy is a new and groundbreaking immunotherapy that has advanced treatment for hematologic cancers like leukemia and has the potential to shape the future of cancer research. CAR T-cell therapy involves the extraction of patients' T-cells, their genetical modification to include the chimeric antigen receptors recognizing the targeted cancer cells, their reproduction, and their reinjection into the patient. Applying this type of therapy has been especially impactful for leukemia, a prevalent and virulent cancer. A systematic literature review was conducted using targeted PubMed searches to synthesize peer-reviewed studies on CAR T-cell therapy, encompassing biological, translational, and clinical advances. This literature review explores the origins, molecular design, and mechanisms of action of CAR T-cells, detailing their evolution across multiple generations of engineering. The review also examines the therapy’s clinical efficacy on both solid and hematological malignancies, associated toxicities such as the cytokine release syndrome and the immune effector cell-associated neurotoxicity syndrome, and the current limitations of its solid tumor application. Additionally, considerations pertaining to cost, accessibility, and regulatory frameworks are discussed. Finally, this review highlights the future of CAR T-cell therapy, including allogeneic therapies and optimizations of autologous treatments. Although this therapy is primarily effective against blood cancers, it represents a consequential opportunity for improvement in varied cancer therapies. Further insights into this field will not only deepen our understanding of immunotherapy; they will also underscore the potential for innovative treatment developments to recognize and combat other types of lethal malignancies.
References
Global Burden of Disease Cancer Collaboration. The global burden of cancer 2013. JAMA Oncol. 1, 505–527 (2015).
Leukemia: symptoms, signs, causes, types & treatment. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/4365-leukemia (2022).
Whiteley, A. E., Price, T. T., Cantelli, G. & Sipkins, D. A. Leukaemia: a model metastatic disease. Nat. Rev. Cancer 21, 461–475 (2021).
Cancer stat facts: Leukemia. National Cancer Institute. https://seer.cancer.gov/statfacts/html/leuks.html (2023).
Huang, J. et al. Disease burden, risk factors, and trends of leukaemia: A global analysis. Front. Oncol. 12, 904292 (2022).
Leukemia - diagnosis and treatment. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/leukemia/diagnosis-treatment/drc-20374378 (2024).
Acute lymphoblastic leukemia treatment. National Cancer Institute. https://www.cancer.gov/types/leukemia/patient/adult-all-treatment-pdq (2025).
Chemotherapy. Mayo Clinic. https://www.mayoclinic.org/tests-procedures/chemotherapy/about/pac-20385033 (2024).
Chemotherapy to treat cancer. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/chemotherapy (2025).
Radiation therapy for cancer. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/radiation-therapy (2025).
Targeted therapy for cancer. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/targeted-therapies (2022).
Stem cell and bone marrow transplants for cancer. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/types/stem-cell-transplant (2023).
Cappell, K. M. & Kochenderfer, J. N. Long-term outcomes following CAR T cell therapy: what we know so far. Nat. Rev. Clin. Oncol. 20, 359–371 (2023).
Ahmad, U. et al. Chimeric antigen receptor T cell structure, its manufacturing, and related toxicities; A comprehensive review. Adv. Cancer Biol. - Metastasis 4, 100035 (2022).
Jensen, M. C. & Riddell, S. R. Designing chimeric antigen receptors to effectively and safely target tumors. Curr. Opin. Immunol. 33, 9–15 (2015).
Haslauer, T. et al. CAR T-cell therapy in hematological malignancies. Int. J. Mol. Sci. 22, 8996 (2021).
Khalil, D. N. et al. Chapter 1 - the new era of cancer immunotherapy: Manipulating T-cell activity to overcome malignancy. in Advances in Cancer Research (eds. Wang, X.-Y. & Fisher, P. B.) vol. 128 1–68 (Academic Press, 2015).
CAR T cells: Engineering immune cells to treat cancer. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/research/car-t-cells (2025).
Maus, M. V. & June, C. H. Making better chimeric antigen receptors for adoptive T-cell therapy. Clin. Cancer Res. 22, 1875–1884 (2016).
Lemal, R. & Tournilhac, O. State-of-the-art for CAR T-cell therapy for chronic lymphocytic leukemia in 2019. J. Immunother. Cancer 7, 202 (2019).
Gargett, T. & Brown, M. P. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. Front. Pharmacol. 5, 235 (2014).
Carlsten, M. & Childs, R. W. Genetic manipulation of NK cells for cancer immunotherapy: Techniques and clinical implications. Front. Immunol. 6, 266 (2015).
Ren, J. & Zhao, Y. Advancing chimeric antigen receptor T cell therapy with CRISPR/Cas9. Protein Cell 8, 634–643 (2017).
Kagoya, Y. et al. A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects. Nat. Med. 24, 352–359 (2018).
Sterner, R. C. & Sterner, R. M. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J. 11, 1–11 (2021).
Zhang, G. et al. Anti-melanoma activity of T cells redirected with a TCR-like chimeric antigen receptor. Sci. Rep. 4, 3571 (2014).
Chailyan, A., Marcatili, P. & Tramontano, A. The association of heavy and light chain variable domains in antibodies: Implications for antigen specificity. FEBS J. 278, 2858–2866 (2011).
Hudecek, M. et al. The nonsignaling extracellular spacer domain of chimeric antigen receptors is decisive for in vivo antitumor activity. Cancer Immunol. Res. 3, 125–135 (2015).
Srivastava, S. & Riddell, S. R. Engineering CAR-T cells: Design concepts. Trends Immunol. 36, 494–502 (2015).
H. Almåsbak et al. Inclusion of an IgG1-Fc spacer abrogates efficacy of CD19 CAR T cells in a xenograft mouse model. Gene Ther. 22, 391–403 (2015).
Hombach, A., Hombach, A. A. & Abken, H. Adoptive immunotherapy with genetically engineered T cells: Modification of the IgG1 Fc ‘spacer’ domain in the extracellular moiety of chimeric antigen receptors avoids ‘off-target’ activation and unintended initiation of an innate immune response. Gene Ther. 17, 1206–1213 (2010).
Bridgeman, J. S. et al. The optimal antigen response of chimeric antigen receptors harboring the CD3ζ transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex. J. Immunol. 184, 6938–6949 (2010).
Dotti, G., Gottschalk, S., Savoldo, B. & Brenner, M. K. Design and development of therapies using chimeric antigen receptor-expressing T cells. Immunol. Rev. 257, 107–126 (2014).
Alabanza, L. et al. Function of novel anti-CD19 chimeric antigen receptors with human variable regions is affected by hinge and transmembrane domains. Mol. Ther. 25, 2452–2465 (2017).
Tokarew, N., Ogonek, J., Endres, S., von Bergwelt-Baildon, M. & Kobold, S. Teaching an old dog new tricks: Next-generation CAR T cells. Br. J. Cancer 120, 26–37 (2019).
Brocker, T. & Karjalainen, K. Signals through T cell receptor-zeta chain alone are insufficient to prime resting T lymphocytes. J. Exp. Med. 181, 1653–1659 (1995).
Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016).
Pulè, M. A. et al. A chimeric T cell antigen receptor that augments cytokine release and supports clonal expansion of primary human T cells. Mol. Ther. 12, 933–941 (2005).
Martínez-Lostao, L., Anel, A. & Pardo, J. How do cytotoxic lymphocytes kill cancer cells? Clin. Cancer Res. 21, 5047–5056 (2015).
Chen, K. H. et al. A compound chimeric antigen receptor strategy for targeting multiple myeloma. Leukemia 32, 402–412 (2018).
Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat. Biotechnol. 31, 71–75 (2013).
Lim, W. A. & June, C. H. The principles of engineering immune cells to treat cancer. Cell 168, 724–740 (2017).
CAR T-cell therapy and its side effects. American Cancer Society. https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/car-t-cell1.html (2024).
CAR T-cell therapy infographic. National Cancer Institute. https://www.cancer.gov/about-cancer/treatment/research/car-t-cell-therapy-infographic (2025).
Sadelain, M., Brentjens, R. & Rivière, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).
Carpenito, C. et al. Control of large, established tumor xenografts with genetically retargeted human T cells containing CD28 and CD137 domains. PNAS 106, 3360–3365 (2009).
Yu, S. et al. Chimeric antigen receptor T cells: A novel therapy for solid tumors. J. Hematol. Oncol. 10, 78 (2017).
Zhou, G. & Levitsky, H. Towards curative cancer immunotherapy: Overcoming posttherapy tumor escape. Immunol. Res. 2012, 124187 (2012).
Eskilsson, E. et al. EGFRvIII mutations can emerge as late and heterogenous events in glioblastoma development and promote angiogenesis through Src activation. Neuro-Oncol. 18, 1644–1655 (2016).
Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).
Dolcet, X., Llobet, D., Pallares, J. & Matias-Guiu, X. NF-kB in development and progression of human cancer. Virchows Arch. 446, 475–482 (2005).
Song, D., Lian, Y. & Zhang, L. The potential of activator protein 1 (AP-1) in cancer targeted therapy. Front. Immunol. 14, (2023).
Yasukawa, M. et al. Granule exocytosis, and not the Fas/Fas ligand system, is the main pathway of cytotoxicity mediated by alloantigen-specific CD4+ as well as CD8+ cytotoxic T lymphocytes in humans. Blood 95, 2352–2355 (2000).
Hombach, A., Köhler, H., Rappl, G. & Abken, H. Human CD4+ T cells lyse target cells via granzyme/perforin upon circumvention of MHC class II restriction by an antibody-like immunoreceptor. J. Immunol. 177, 5668–5675 (2006).
Henkart, P. A. Lymphocyte-mediated cytotoxicity: Two pathways and multiple effector molecules. Immunity 1, 343–346 (1994).
Ai, K. et al. Optimizing CAR-T cell therapy for solid tumors: Current challenges and potential strategies. J. Hematol. Oncol. 17, 105 (2024).
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348, 124–128 (2015).
Luo, F. et al. Bifunctional αHER2/CD3 RNA-engineered CART-like human T cells specifically eliminate HER2+ gastric cancer. Cell Res. 26, 850–853 (2016).
Li, W. et al. Redirecting T cells to glypican-3 with 4-1BB zeta chimeric antigen receptors results in Th1 polarization and potent antitumor activity. Hum. Gene Ther. 28, 437–448 (2017).
Wang, S. et al. Perspectives of tumor-infiltrating lymphocyte treatment in solid tumors. BMC Med. 19, 140 (2021).
Ho, W. Y., Blattman, J. N., Dossett, M. L., Yee, C. & Greenberg, P. D. Adoptive immunotherapy: Engineering T cell responses as biologic weapons for tumor mass destruction. Cancer Cell 3, 431–437 (2003).
Lee, D. W. et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. 25, 625–638 (2019).
Frey, N. V. & Porter, D. L. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Hematology 2016, 567–572 (2016).
Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).
Santomasso, B., Shpall, E. J., Rezvani, K., Westin, J. & Bachier, C. The other side of CAR T-cell therapy: Cytokine release syndrome, neurologic toxicity, and financial burden. Am. Soc. Clin. Oncol. Educ. Book 39, 433–444 (2019).
Shimabukuro-Vornhagen, A. et al. Cytokine release syndrome. J. Immunother. Cancer 6, 56 (2018).
Smith, L. & Venella, K. Cytokine release syndrome: Inpatient care for side effects of CAR T-cell therapy. Clin. J. Oncol. Nurs. 21, 29–34 (2017).
Tedesco, V. E. & Mohan, C. Biomarkers for predicting cytokine release syndrome following CD19-targeted CAR T cell therapy. J. Immunol. 206, 1561–1568 (2021).
Abboud, R. et al. Severe cytokine-release syndrome after T cell–replete peripheral blood haploidentical donor transplantation is associated with poor survival and anti–IL-6 therapy is safe and well tolerated. Biol. Blood Marrow Transplant. 22, 1851–1860 (2016).
Riegler, L. L., Jones, G. P. & Lee, D. W. Current approaches in the grading and management of cytokine release syndrome after chimeric antigen receptor T-cell therapy. Ther. Clin. Risk Manag. 15, 323–335 (2019).
Acharya, U. H. et al. Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy. Expert Rev. Hematol. 12, 195–205 (2018).
Schubert, M.-L. et al. Side-effect management of chimeric antigen receptor (CAR) T-cell therapy. Ann. Oncol. 32, 34–48 (2021).
Uhlig, C., Silva, P. L., Deckert, S., Schmitt, J. & de Abreu, M. G. Albumin versus crystalloid solutions in patients with the acute respiratory distress syndrome: A systematic review and meta-analysis. Crit. Care 18, R10 (2014).
Gardner, R. A. et al. Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy. Blood 134, 2149–2158 (2019).
Varadarajan, I., Kindwall-Keller, T. L. & Lee, D. W. Chapter 5 - management of cytokine release syndrome. in Chimeric Antigen Receptor T-Cell Therapies for Cancer (eds. Lee, D. W. & Shah, N. N.) 45–64 (Elsevier, 2020). doi:10.1016/B978-0-323-66181-2.00005-6.
Locke, F. L. et al. Preliminary results of prophylactic tocilizumab after axicabtageneciloleucel (axi-cel; KTE-C19) treatment for patients with refractory, aggressive non-Hodgkin lymphoma (NHL). Blood 130, 1547 (2017).
Neelapu, S. S. Managing the toxicities of CAR T-cell therapy. Hematol. Oncol. 37, 48–52 (2019).
Halford, Z., Anderson, M. K. & Bennett, L. L. Axicabtagene ciloleucel: Clinical data for the use of CAR T-cell therapy in relapsed and refractory large B-cell lymphoma. Ann. Pharmacother. 55, 390–405 (2021).
Gust, J., Ponce, R., Liles, W. C., Garden, G. A. & Turtle, C. J. Cytokines in CAR T cell–associated neurotoxicity. Front. Immunol. 11, 577027 (2020).
Morris, E. C., Sadelain, M., Giavridis, T. & Neelapu, S. S. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat. Rev. Immunol. 22, 85–96 (2022).
Yáñez, L., Alarcón, A., Sánchez-Escamilla, M. & Perales, M.-A. How I treat adverse effects of CAR-T cell therapy. ESMO Open 4, e000746 (2020).
Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).
Gust, J. et al. Endothelial activation and blood–brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017).
Santomasso, B. D. et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 8, 958–971 (2018).
Neelapu, S. S. et al. Chimeric antigen receptor T-cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).
Mahadeo, K. M., Tambaro, F. P. & Gutierrez, C. Chapter 6 - special considerations for ICU management of patients receiving CAR therapy. in Chimeric Antigen Receptor T-Cell Therapies for Cancer (eds. Lee, D. W. & Shah, N. N.) 65–81 (Elsevier, 2020). doi:10.1016/B978-0-323-66181-2.00006-8.
Guenther, S. et al. Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans. Seizure 23, 666–669 (2014).
Schuster, S. J. et al. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 380, 45–56 (2018).
Fried, S. et al. Early and late hematologic toxicity following CD19 CAR-T cells. Bone Marrow Transplant. 54, 1643–1650 (2019).
Sookaromdee, P. & Wiwanitkit, V. COVID-19 vaccination and anti-CD19 CAR T cell-induced B cell aplasia. Transplant. Cell. Ther. 28, 515 (2022).
Arnold, D. E. et al. Subcutaneous immunoglobulin replacement following CD19‐specific chimeric antigen receptor T‐cell therapy for B‐cell acute lymphoblastic leukemia in pediatric patients. Pediatr. Blood Cancer 67, e28092 (2019).
Doan, A. & Pulsipher, M. A. Hypogammaglobulinemia due to CAR T‐cell therapy. Pediatr. Blood Cancer 65, e26914 (2018).
Hill, J. A. et al. Durable preservation of antiviral antibodies after CD19-directed chimeric antigen receptor T-cell immunotherapy. Blood Adv. 3, 3590–3601 (2019).
Logue, J. M. et al. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma. Haematologica 106, 978–986 (2021).
Teachey, D. T., Bishop, M. R., Maloney, D. G. & Grupp, S. A. Toxicity management after chimeric antigen receptor T cell therapy: One size does not fit ‘ALL’. Nat. Rev. Clin. Oncol. 15, 218 (2018).
Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).
Hill, J. A. et al. Infectious complications of CD19-targeted chimeric antigen receptor–modified T-cell immunotherapy. Blood 131, 121–130 (2018).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Howard, S. C., Trifilio, S., Gregory, T. K., Baxter, N. & McBride, A. Tumor lysis syndrome in the era of novel and targeted agents in patients with hematologic malignancies: A systematic review. Ann. Hematol. 95, 563–573 (2016).
Kochenderfer, J. N. et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139 (2013).
Belay, Y., Yirdaw, K. & Enawgaw, B. Tumor lysis syndrome in patients with hematological malignancies. J. Oncol. 2017, 9684909 (2017).
McBride, A., Trifilio, S., Baxter, N., Gregory, T. K. & Howard, S. C. Managing tumor lysis syndrome in the era of novel cancer therapies. J. Adv. Pract. Oncol. 8, 705–720 (2017).
Ravelli, A. et al. 2016 classification criteria for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation collaborative initiative. Arthritis Rheumatol. 68, 566–576 (2015).
Hashmi, H. et al. Haemophagocytic lymphohistiocytosis has variable time to onset following CD19 chimeric antigen receptor T cell therapy. Br. J. Haematol. 187, e35–e38 (2019).
Ceppi, F., Summers, C. & Gardner, R. A. Chapter 8 - hematologic and non-CRS toxicities. in Chimeric Antigen Receptor T-Cell Therapies for Cancer (eds. Lee, D. W. & Shah, N. N.) 107–112 (Elsevier, 2020). doi:10.1016/B978-0-323-66181-2.00008-1.
Scholler, J. et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci. Transl. Med. 4, 132ra53 (2012).
Cornetta, K. et al. Absence of replication-competent lentivirus in the clinic: Analysis of infused T cell products. Mol. Ther. J. Am. Soc. Gene Ther. 26, 280–288 (2018).
Ruella, M. et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat. Med. 24, 1499–1503 (2018).
Vogel, W. H. Infusion reactions: Diagnosis, assessment, and management. Clin. J. Oncol. Nurs. 14, E10-21 (2010).
Cruz, C. R. et al. Adverse events following infusion of T cells for adoptive immunotherapy: A 10-year experience. Cytotherapy 12, 743–749 (2010).
Sarfati, S. et al. Case report: CAR-T cell therapy-induced cardiac tamponade. Front. Cardiovasc. Med. 10, 1132503 (2023).
Moriyama, S. et al. Case report: Cardiac tamponade in association with cytokine release syndrome following CAR-T cell therapy. Front. Cardiovasc. Med. 9, 848091 (2022).
Salem, J.-E., Ederhy, S., Lebrun-Vignes, B. & Moslehi, J. J. Cardiac events associated with chimeric antigen receptor T-cells (CAR-T): A VigiBase perspective. JACC 75, 2521–2523 (2020).
Cao, Y. et al. Cardiac involvement in a patient with B-cell lymphoblastic lymphoma/acute lymphoblastic leukemia and a history of allogeneic hematopoietic stem cell transplantation and CAR T-cell therapy: A case report. Front. Immunol. 13, 1052336 (2023).
Tao, J. J., Mahmood, S. S., Roszkowska, N. & Majure, D. T. Coronary vasospasm during infusion of CD-19 directed chimeric antigen receptor T-cell therapy: A case report. Eur. Heart J. 7, ytad342 (2023).
Alvi, R. M. et al. Cardiovascular events among adults treated with chimeric antigen receptor T-cells (CAR-T). JACC 74, 3099–3108 (2019).
Haas, A. R. et al. Two cases of severe pulmonary toxicity from highly active mesothelin-directed CAR T cells. Mol. Ther. 31, 2309–2325 (2023).
Hsueh, E. C. & Morton, D. L. Antigen-based immunotherapy of melanoma: Canvaxin therapeutic polyvalent cancer vaccine. Semin. Cancer Biol. 13, 401–407 (2003).
Ma, S. et al. Current progress in CAR-T cell therapy for solid tumors. Int. J. Biol. Sci. 15, 2548–2560 (2019).
Kershaw, M. H. et al. Redirecting migration of T cells to chemokine secreted from tumors by genetic modification with CXCR2. Hum. Gene Ther. 13, (2004).
Di Stasi, A. et al. T lymphocytes coexpressing CCR4 and a chimeric antigen receptor targeting CD30 have improved homing and antitumor activity in a Hodgkin tumor model. Blood 113, 6392–6402 (2009).
Beatty, G. L. et al. Exclusion of T cells from pancreatic carcinomas in mice is regulated by Ly6Clow F4/80+ extratumoral macrophages. Gastroenterology 149, 201–210 (2015).
Jayatilleke, K. M. & Hulett, M. D. Heparanase and the hallmarks of cancer. J. Transl. Med. 18, (2020).
Caruana, I. et al. Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes. Nat. Med. 21, 524–529 (2015).
Zarour, H. M. Reversing T-cell dysfunction and exhaustion in cancer. Clin. Cancer Res. 22, 1856–1864 (2016).
Bollard, C. M. et al. Adapting a transforming growth factor β–related tumor protection strategy to enhance antitumor immunity. Blood 99, 3179–3187 (2002).
Zhang, L. et al. Inhibition of TGF-β signaling in genetically engineered tumor antigen-reactive T cells significantly enhances tumor treatment efficacy. Gene Ther. 20, 575–580 (2013).
Hamid, O. & Carvajal, R. D. Anti-programmed death-1 and anti-programmed death-ligand 1 antibodies in cancer therapy. Expert Opin. Biol. Ther. 13, 847–861 (2013).
Türeci, Ö. et al. Targeting the heterogeneity of cancer with individualized neoepitope vaccines. Clin. Cancer Res. 22, 1885–1896 (2016).
Chmielewski, M., Hombach, A. A. & Abken, H. Of CARs and TRUCKs: Chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol. Rev. 257, 83–90 (2014).
King, I. L. & Segal, B. M. Cutting edge: IL-12 induces CD4+CD25− T cell activation in the presence of T regulatory cells. J. Immunol. 175, 641–645 (2005).
Steding, C. E. et al. The role of interleukin-12 on modulating myeloid-derived suppressor cells, increasing overall survival and reducing metastasis. Immunology 133, 221–238 (2011).
Leonard, J. P. et al. Effects of single-dose interleukin-12 exposure on interleukin-12–associated toxicity and interferon-γ production. Blood 90, 2541–2548 (1997).
Hu, Q. et al. Inhibition of post-surgery tumour recurrence via a hydrogel releasing CAR-T cells and anti-PDL1-conjugated platelets. Nat. Biomed. Eng. 5, 1038–1047 (2021).
Shahzad, M. et al. Outcomes with chimeric antigen receptor t-cell therapy in relapsed or refractory acute myeloid leukemia: A systematic review and meta-analysis. Front. Immunol. 14, 1152457 (2023).
Cancer stat facts: Leukemia — acute myeloid leukemia (AML). National Cancer Institute. https://seer.cancer.gov/statfacts/html/amyl.html (2023).
Döhner, H., Weisdorf, D. J. & Bloomfield, C. D. Acute myeloid leukemia. N. Engl. J. Med. 373, 1136–1152 (2015).
Yu, M. et al. Efficacy and safety of dual-targeting chimeric antigen receptor-T therapy for relapsed or refractory B cell lymphoid malignancies: A systematic review and meta-analysis. Hum. Gene Ther. 34, 192–202 (2023).
Fergusson, N. J., Adeel, K., Kekre, N., Atkins, H. & Hay, K. A. A systematic review and meta-analysis of CD22 CAR T-cells alone or in combination with CD19 CAR T-cells. Front. Immunol. 14, 1178403 (2023).
Elmarasi, M. et al. CAR-T cell therapy: Efficacy in management of cancers, adverse effects, dose-limiting toxicities and long-term follow up. Int. Immunopharmacol. 135, 112312 (2024).
Westin, J. R. et al. Survival with axicabtagene ciloleucel in large B-cell lymphoma. N. Engl. J. Med. 389, 148–157 (2023).
Yang, Q. et al. Efficacy and safety of CAR-T therapy for relapse or refractory multiple myeloma: A systematic review and meta-analysis. Int. J. Med. Sci. 18, 1786–1797 (2021).
Zhang, L. et al. Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma. Ann. Med. 53, 1547–1559 (2021).
San-Miguel, J. et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N. Engl. J. Med. 389, 335–347 (2023).
Xia, J. et al. Anti–G protein–coupled receptor, class C group 5 member D chimeric antigen receptor T cells in patients with relapsed or refractory multiple myeloma: A single-arm, phase Ⅱ trial. J. Clin. Oncol. 41, 2583–2593 (2023).
Shah, P. D. et al. Phase I trial of autologous RNA-electroporated cMET-directed CAR T cells administered intravenously in patients with melanoma and breast carcinoma. Cancer Res. Commun. 3, 821–829 (2023).
Del Bufalo, F. et al. GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N. Engl. J. Med. 388, 1284–1295 (2023).
Hong, D. S. et al. Autologous T cell therapy for MAGE-A4+ solid cancers in HLA-A*02+ patients: A phase 1 trial. Nat. Med. 29, 104–114 (2023).
Qi, C. et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: Phase 1 trial interim results. Nat. Med. 28, 1189–1198 (2022).
Narayan, V. PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: A phase 1 trial. Nat. Med. 28, 724–734 (2022).
Zhou, D. et al. Clinical pharmacology profile of AMG 119, the first chimeric antigen receptor T (CAR‐T) cell therapy targeting delta‐like ligand 3 (DLL3), in patients with relapsed/refractory small cell lung cancer (SCLC). J. Clin. Pharmacol. 64, 362–370 (2023).
Maalej, K. M. et al. CAR-cell therapy in the era of solid tumor treatment: Current challenges and emerging therapeutic advances. Mol. Cancer 22, 20 (2023).
Komura, K. CD19: A promising target for systemic sclerosis. Front. Immunol. 15, 1454913 (2024).
Pasquini, M. C. et al. Real-world evidence of tisagenlecleucel for pediatric acute lymphoblastic leukemia and non-Hodgkin lymphoma. Blood Adv. 4, 5414–5424 (2020).
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).
Pan, J. et al. Sequential CD19-22 CAR T therapy induces sustained remission in children with r/r B-ALL. Blood 135, 387–391 (2020).
Shalabi, H. et al. CD19/22 CAR T cells in children and young adults with B-ALL: Phase 1 results and development of a novel bicistronic CAR. Blood 140, 451–463 (2022).
Sun, D. et al. CAR‑T cell therapy: A breakthrough in traditional cancer treatment strategies (review). Mol. Med. Rep. 29, 1–9 (2024).
Cheung, T. C. & Ware, C. F. Tumor necrosis factor receptors. in Encyclopedia of Biological Chemistry (Second Edition) (eds. Lennarz, W. J. & Lane, M. D.) 454–459 (Elsevier, 2013). doi:10.1016/B978-0-12-378630-2.00358-3.
Que, Y. et al. Anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma patients with extramedullary disease: A single center analysis of two clinical trials. Front. Immunol. 12, 755866 (2021).
Piedra-Quintero, Z. L., Wilson, Z., Nava, P. & Guerau-de-Arellano, M. CD38: An immunomodulatory molecule in inflammation and autoimmunity. Front. Immunol. 11, 597959 (2020).
Tang, Y. et al. High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma. J. Exp. Clin. Cancer Res. 41, 2 (2022).
Feng, K. et al. Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Sci. China Life Sci. 59, 468–479 (2016).
Zhang, Y. et al. Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients. J. Cancer Res. Clin. Oncol. 147, 3725–3734 (2021).
O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).
Lv, J. & Li, P. Mesothelin as a biomarker for targeted therapy. Biomark. Res. 7, 18 (2019).
Pastan, I. & Hassan, R. Discovery of mesothelin and exploiting it as a target for immunotherapy. Cancer Res. 74, 2907–2912 (2014).
Fang, J. et al. αPD-1-mesoCAR-T cells partially inhibit the growth of advanced/refractory ovarian cancer in a patient along with daily apatinib. J. Immunother. Cancer 9, e001162 (2021).
Lheureux, S., Braunstein, M. & Oza, A. M. Epithelial ovarian cancer: Evolution of management in the era of precision medicine. CA. Cancer J. Clin. 69, 280–304 (2019).
Haas, A. R., Tanyi, J. L., O’Hara, M. H., June, C. H. & Albelda, S. M. Phase I study of lentiviral-transduced chimeric antigen receptor-modified T cells recognizing mesothelin in advanced solid cancers. Mol. Ther. 27, 1919–1929 (2019).
Adusumilli, P. S. et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti–PD-1 agent pembrolizumab. Cancer Discov. 11, 2748–2763 (2021).
Junghans, R. P. et al. Phase I trial of anti-PSMA designer CAR-T cells in prostate cancer: possible role for interacting interleukin 2-T cell pharmacodynamics as a determinant of clinical response. The Prostate 76, 1257–1270 (2016).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2) –specific chimeric antigen receptor–modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).
Ahmed, N. et al. HER2-specific chimeric antigen receptor–modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncol. 3, 1094–1101 (2017).
Feng, K. et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell 9, 838–847 (2018).
Vitanza, N. A. et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: An interim analysis. Nat. Med. 27, 1544–1552 (2021).
Li, Z. CD133: A stem cell biomarker and beyond. Exp. Hematol. Oncol. 2, 17 (2013).
Song, W. et al. Expression and clinical significance of the stem cell marker CD133 in hepatocellular carcinoma. Int. J. Clin. Pract. 62, 1212–1218 (2008).
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA. Cancer J. Clin. 68, 394–424 (2018).
Yu, D. et al. Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin. Cancer Res. 13, 3814–3824 (2007).
Dai, H. et al. Efficacy and biomarker analysis of CD133-directed CAR T cells in advanced hepatocellular carcinoma: A single-arm, open-label, phase II trial. OncoImmunology 9, 1846926 (2020).
Cao, W. et al. Claudin18.2 is a novel molecular biomarker for tumor-targeted immunotherapy. Biomark. Res. 10, 38 (2022).
Lyons, T. G. & Ku, G. Y. Systemic therapy for esophagogastric cancer: Targeted therapies. Chin. Clin. Oncol. 6, 48–48 (2017).
Zhan, X. et al. Phase I trial of claudin 18.2-specific chimeric antigen receptor T cells for advanced gastric and pancreatic adenocarcinoma. J. Clin. Oncol. 37, 2509 (2019).
Jaén, M., Martín-Regalado, Á., Bartolomé, R. A., Robles, J. & Casal, J. I. Interleukin 13 receptor alpha 2 (IL13Rα2): Expression, signaling pathways and
therapeutic applications in cancer. Biochim. Biophys. Acta - Rev. Cancer 1877, 188802 (2022).
Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).
Brown, C. E. et al. Bioactivity and safety of IL13Rα2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clin. Cancer Res. 21, 4062–4072 (2015).
Machy, P., Mortier, E. & Birklé, S. Biology of GD2 ganglioside: Implications for cancer immunotherapy. Front. Pharmacol. 14, 1249929 (2023).
Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).
Louis, C. U. et al. Antitumor activity and long-term fate of chimeric antigen receptor–positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).
Berger, C. et al. Safety of targeting ROR1 in primates with chimeric antigen receptor–modified T cells. Cancer Immunol Res. 3, 206–216 (2015).
Kipps, T. J. ROR1: An orphan becomes apparent. Blood 140, 1583–1591 (2022).
Specht, J. M. et al. Phase I study of immunotherapy for advanced ROR1+ malignancies with autologous ROR1-specific chimeric antigen receptor-modified (CAR)-T cells. J. Clin. Oncol. 36, TPS79–TPS79 (2018).
Lázaro-Gorines, R. et al. A novel carcinoembryonic antigen (CEA)-targeted trimeric immunotoxin shows significantly enhanced antitumor activity in human colorectal cancer xenografts. Sci. Rep. 9, 11680 (2019).
Yang, L., Wang, Y. & Wang, H. Use of immunotherapy in the treatment of gastric cancer (review). Oncol. Lett. 18, 5681–5690 (2019).
Kankanala, V. L., Zubair, M. & Mukkamalla, S. K. R. Carcinoembryonic antigen. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2024).
Zhang, C. et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA+ metastatic colorectal cancers. Mol. Ther. 25, 1248–1258 (2017).
Katz, S. C. et al. HITM-SIR: Phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases. Cancer Gene Ther. 27, 341–355 (2020).
Bębnowska, D. et al. CAR-T cell therapy—an overview of targets in gastric cancer. J. Clin. Med. 9, 1894 (2020).
Chen, W. et al. MUC1: Structure, function, and clinic application in epithelial cancers. Int. J. Mol. Sci. 22, 6567 (2021).
Oh, D. et al. 46P Development of an allogeneic CAR-T targeting MUC1-C (MUC1, cell surface associated, C-terminal) for epithelial derived tumors. Immuno-Oncol. Technol. 16, 100151 (2022).
Flieswasser, T. et al. The CD70-CD27 axis in oncology: the new kids on the block. J. Exp. Clin. Cancer Res. 41, 12 (2022).
Pal, S. K. et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 14, 1176–1189 (2024).
Patel, U. et al. CAR T cell therapy in solid tumors: A review of current clinical trials. eJHaem 3, 24–31 (2021).
Wolf, P., Alzubi, J., Gratzke, C. & Cathomen, T. The potential of CAR T cell therapy for prostate cancer. Nat. Rev. Urol. 18, 556–571 (2021).
Johnson, P. C. et al. Longitudinal patient-reported outcomes in patients receiving chimeric antigen receptor T-cell therapy. Blood Adv. 7, 3541–3550 (2023).
Chen, Y.-J., Abila, B. & Mostafa Kamel, Y. CAR-T: What is next? Cancers 15, 663 (2023).
U.S. Food and Drug Administration. Package insert and medication guide – KYMRIAH. FDA. https://www.fda.gov/media/107296/download (2017).
U.S. Food and Drug Administration. Package insert and medication guide – YESCARTA. FDA. https://www.fda.gov/media/108377/download (2017).
U.S. Food and Drug Administration. Package insert and medication guide – TECARTUS. FDA. https://www.fda.gov/media/140409/download (2020).
U.S. Food and Drug Administration. Package insert and medication guide – BREYANZI. FDA. https://www.fda.gov/media/145711/download (2021).
U.S. Food and Drug Administration. Package insert and medication guide – ABECMA. FDA. https://www.fda.gov/media/147055/download (2021).
U.S. Food and Drug Administration. Package insert and medication guide – CARVYKTI. FDA. https://www.fda.gov/media/156560/download (2022).
Hay, A. E. & and Cheung, M. C. CAR T-cells: Costs, comparisons, and commentary. J. Med. Econ. 22, 613–615 (2019).
Lopes, G. de L. & Nahas, G. R. Chimeric antigen receptor T cells, a savior with a high price. Chin. Clin. Oncol. 7, 21–21 (2018).
Di, M. et al. Costs of care during chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell lymphomas. JNCI Cancer Spectr. 8, pkae059 (2024).
Ghanem, B. & Shi, L. The economic burden of CAR T cell therapies ciltacabtagene autoleucel and idecabtagene vicleucel for the treatment of adult patients with relapsed or refractory multiple myeloma in the US. BioDrugs 36, 773–780 (2022).
Rajkumar, S. V. Value and cost of myeloma therapy. Am. Soc. Clin. Oncol. Educ. Book 38, 662–666 (2018).
Berry, D., Wellman, J., Allen, J. & Mayer, C. Assessing the state of Medicaid coverage for gene and cell therapies. Mol. Ther. 30, 2879–2880 (2022).
Centers for Medicare & Medicaid Services. Chimeric antigen receptor (CAR) T-cell therapy. Medicare Coverage Database. https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?ncdid=374 (2019).
Costa, L. J. et al. Comparison of cilta-cel, an anti-BCMA CAR-T cell therapy, versus conventional treatment in patients with relapsed/refractory multiple myeloma. Clin. Lymphoma Myeloma Leuk. 22, 326–335 (2022).
Zhai, Y. et al. Comparison of blinatumomab and CAR T-cell therapy in relapsed/refractory acute lymphoblastic leukemia: A systematic review and meta-analysis. Expert Rev. Hematol. 17, 67–76 (2024).
Shargian, L., Raanani, P., Yeshurun, M., Gafter-Gvili, A. & Gurion, R. Chimeric antigen receptor T-cell therapy is superior to standard of care as second-line therapy for large B-cell lymphoma: A systematic review and meta-analysis. Br. J. Haematol. 198, 838–846 (2022).
Depil, S., Duchateau, P., Grupp, S. A., Mufti, G. & Poirot, L. ‘Off-the-shelf’ allogeneic CAR T cells: Development and challenges. Nat. Rev. Drug Discov. 19, 185–199 (2020).
Caldwell, K. J., Gottschalk, S. & Talleur, A. C. Allogeneic CAR cell therapy—more than a pipe dream. Front. Immunol. 11, 618427 (2021).
Chen, S. & van den Brink, M. R. M. Allogeneic “off-the-shelf” CAR T cells: Challenges and advances. Best Pract. Res. Clin. Haematol. 37, 101566 (2024).
Shah, N. N. & Fry, T. J. Mechanisms of resistance to CAR T cell therapy. Nat. Rev. Clin. Oncol. 16, 372–385 (2019).
Torikai, H. et al. A foundation for universal T-cell based immunotherapy: T cells engineered to express a CD19-specific chimeric-antigen-receptor and eliminate expression of endogenous TCR. Blood 119, 5697–5705 (2012).
Leen, A. M. et al. Multicenter study of banked third-party virus-specific T cells to treat severe viral infections after hematopoietic stem cell transplantation. Blood 121, 5113–5123 (2013).
Martin, T. G. & Gajewski, J. L. Allogeneic Stem Cell Transplantation for Acute Lymphocytic Leukemia in Adults. Hematol. Oncol. Clin. North Am. 15, 97–120 (2001).
Wingard, J. R., Hsu, J. & Hiemenz, J. W. Hematopoietic stem cell transplantation: An overview of infection risks and epidemiology. Hematol. Clin. 25, 101–116 (2011).
Cruz, C. R. Y. et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: A phase 1 study. Blood 122, 2965–2973 (2013).
Makkouk, A. et al. Off-the-shelf Vδ1 gamma delta T cells engineered with glypican-3 (GPC-3)-specific chimeric antigen receptor (CAR) and soluble IL-15 display robust antitumor efficacy against hepatocellular carcinoma. J. Immunother. Cancer 9, e003441 (2021).
Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: A phase 1 dose-escalation trial. The Lancet 385, 517–528 (2015).
Grupp, S. A. et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Qasim, W. et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Sci. Transl. Med. 9, eaaj2013 (2017).
Lin, H., Cheng, J., Mu, W., Zhou, J. & Zhu, L. Advances in universal CAR-T cell therapy. Front. Immunol. 12, 744823 (2021).
Zhao, J., Lin, Q., Song, Y. & Liu, D. Universal CARs, universal T cells, and universal CAR T cells. J. Hematol. Oncol. 11, 132 (2018).
Hu, Y. et al. CRISPR/Cas9-engineered universal CD19/CD22 dual-targeted CAR-T cell therapy for relapsed/refractory B-cell acute lymphoblastic leukemia. Clin. Cancer Res. 27, 2764–2772 (2021).
Benjamin, R. et al. Preliminary data on safety, cellular kinetics and anti-leukemic activity of UCART19, an allogeneic anti-CD19 CAR T-cell product, in a pool of adult and pediatric patients with high-risk CD19+ relapsed/refractory B-cell acute lymphoblastic leukemia. Blood 132, 896 (2018).
Wang, W. et al. Joint profiling of chromatin accessibility and CAR-T integration site analysis at population and single-cell levels. Proc. Natl. Acad. Sci. 117, 5442–5452 (2020).
Loff, S. et al. Rapidly switchable universal CAR-T cells for treatment of CD123-positive leukemia. Mol. Ther. - Oncolytics 17, 408–420 (2020).
Cerrano, M. et al. The advent of CAR T-cell therapy for lymphoproliferative neoplasms: Integrating research into clinical practice. Front. Immunol. 11, 888 (2020).
Valton, J. et al. A multidrug-resistant engineered CAR T cell for allogeneic combination immunotherapy. Mol. Ther. 23, 1507–1518 (2015).
Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).
Stenger, D. et al. Endogenous TCR promotes in vivo persistence of CD19-CAR-T cells compared to a CRISPR/Cas9-mediated TCR knockout CAR. Blood 136, 1407–1418 (2020).
Wang, D., Quan, Y., Yan, Q., Morales, J. E. & Wetsel, R. A. Targeted disruption of the β2-microglobulin gene minimizes the immunogenicity of human embryonic stem cells. Stem Cells Transl. Med. 4, 1234–1245 (2015).
Ren, J. et al. Multiplex genome editing to generate universal CAR T cells resistant to PD1 inhibition. Clin. Cancer Res. 23, 2255–2266 (2017).
Poirot, L. et al. Multiplex genome-edited T-cell manufacturing platform for “off-the-shelf” adoptive T-cell immunotherapies. Cancer Res. 75, 3853–3864 (2015).
Chakrabarti, S. et al. Adenovirus infections following allogeneic stem cell transplantation: Incidence and outcome in relation to graft manipulation, immunosuppression, and immune recovery. Blood 100, 1619-1627. (2002).
Wang, X. et al. Abstract CT052: Clinical safety and efficacy study of TruUCARTM GC027: The first-in-human, universal CAR-T therapy for adult relapsed/refractory T-cell acute lymphoblastic leukemia (r/r T-ALL). Cancer Res. 80, CT052 (2020).
Capsomidis, A. et al. Chimeric antigen receptor-engineered human gamma delta T cells: Enhanced cytotoxicity with retention of cross presentation. Mol. Ther. 26, 354–365 (2018).
Khairallah, C., Chu, T. H. & Sheridan, B. S. Tissue adaptations of memory and tissue-resident gamma delta T cells. Front. Immunol. 9, 2636 (2018).
Wilhelm, M. et al. Successful adoptive transfer and in vivo expansion of haploidentical γδ T cells. J. Transl. Med. 12, 45 (2014).
Scheper, W., Sebestyen, Z. & Kuball, J. Cancer immunotherapy using γδT cells: dealing with diversity. Front. Immunol. 5, 601 (2014).
Deniger, D. C. Bispecific T-cells expressing polyclonal repertoire of endogenous γδ T-cell receptors and introduced CD19-specific chimeric antigen receptor. Mol. Ther. 21, 638–647 (2013).
Kabelitz, D., Peters, C., Kouakanou, L. & Kalyan, S. Cancer immunotherapy with γδ T cells: Many paths ahead of us. Cell. Mol. Immunol. 17, 925–939 (2020).
Olson, J. A. et al. NK cells mediate reduction of GVHD by inhibiting activated, alloreactive T cells while retaining GVT effects. Blood 115, 4293–4301 (2010).
Algarra, I., García-Lora, A., Cabrera, T., Ruiz-Cabello, F. & Garrido, F. The selection of tumor variants with altered expression of classical and nonclassical MHC class I molecules: Implications for tumor immune escape. Cancer Immunol. Immunother. 53, 904–910 (2004).
Costello, R. T., Gastaut, J. A. & Olive, D. Tumor escape from immune surveillance. Arch. Immunol. Ther. Exp. (Warsz.) 47, 83–88 (1999).
Tang, X. et al. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am. J. Cancer Res. 8, 1083–1089 (2018).
Esser, R. et al. NK cells engineered to express a GD2-specific antigen receptor display built-in ADCC-like activity against tumour cells of neuroectodermal origin. J. Cell. Mol. Med. 16, 569–581 (2012).
Müller, T. et al. Expression of a CD20-specific chimeric antigen receptor enhances cytotoxic activity of NK cells and overcomes NK-resistance of lymphoma and leukemia cells. Cancer Immunol. Immunother. 57, 411–423 (2007).
Mehta, R. S. & Rezvani, K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Front. Immunol. 9, 283 (2018).
Chen, Y. et al. CAR-macrophage: A new immunotherapy candidate against solid tumors. Biomed. Pharmacother. 139, 111605 (2021).
CAR-NK – search results. ClinicalTrials.gov. https://clinicaltrials.gov/search?term=CAR-NK&viewType=Table (2025).
Liu, E. et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N. Engl. J. Med. 382, 545–553 (2020).
Veluchamy, J. P. et al. The rise of allogeneic natural killer cells as a platform for cancer immunotherapy: Recent innovations and future developments. Front. Immunol. 8, 631 (2017).
Fujisaki, H. et al. Expansion of highly cytotoxic human natural killer cells for cancer cell therapy. Cancer Res. 69, 4010–4017 (2009).
Shimasaki, N., Coustan-Smith, E., Kamiya, T. & Campana, D. Expanded and armed natural killer cells for cancer treatment. Cytotherapy 18, 1422–1434 (2016).
Cichocki, F. et al. iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy. Sci. Transl. Med. 12, eaaz5618 (2020).
Brennan, P. J., Brigl, M. & Brenner, M. B. Invariant natural killer T cells: An innate activation scheme linked to diverse effector functions. Nat. Rev. Immunol. 13, 101–117 (2013).
Exley, M. et al. CD1d structure and regulation on human thymocytes, peripheral blood T cells,B cells and monocytes. Immunology 100, 37–47 (2000).
Molling, J. W. et al. Peripheral blood IFN-γ-secreting Vα24+Vβ11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int. J. Cancer 116, 87–93 (2005).
Molling, J. W. et al. Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J. Clin. Oncol. 25, 862–868 (2007).
Heczey, A. et al. Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood 124, 2824–2833 (2014).
Heczey, A. et al. Anti-GD2 CAR-NKT cells in patients with relapsed or refractory neuroblastoma: An interim analysis. Nat. Med. 26, 1686–1690 (2020).
Rotolo, A. et al. Enhanced anti-lymphoma activity of CAR19-iNKT cells underpinned by dual CD19 and CD1d targeting. Cancer Cell 34, 596–610 (2018).
Leveson-Gower, D. B. et al. Low doses of natural killer T cells provide protection from acute graft-versus-host disease via an IL-4–dependent mechanism. Blood 117, 3220–3229 (2011).
Shin, H. & Iwasaki, A. Tissue-resident memory T cells. Immunol. Rev. 255, 165–181 (2013).
Anderson, B. E. et al. Memory CD4+ T cells do not induce graft-versus-host disease. J. Clin. Invest. 112, 101–108 (2003).
Golubovskaya, V. & Wu, L. Different subsets of T cells, memory, effector functions, and CAR-T immunotherapy. Cancers 8, 36 (2016).
Koch, S. et al. Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun. Ageing 5, 6 (2008).
Sabatino, M. et al. Generation of clinical-grade CD19-specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood 128, 519–528 (2016).
Chan, W. K. et al. Chimeric antigen receptor-redirected CD45RA-negative T cells have potent antileukemia and pathogen memory response without graft-versus-host activity. Leukemia 29, 387–395 (2015).
Shook, D. R. et al. Haploidentical stem cell transplantation augmented by CD45RA negative lymphocytes provides rapid engraftment and excellent tolerability. Pediatr. Blood Cancer 62, 666–673 (2015).
Talleur, A. C. et al. Allogeneic CD27-depleted cells in adoptive cell therapy. Adv. Cell Gene Ther. 2, e45 (2019).
Deol, A. & Lum, L. G. Role of donor lymphocyte infusions in relapsed hematological malignancies after stem cell transplantation revisited. Cancer Treat. Rev. 36, 528–538 (2010).
Brudno, J. N. et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34, 1112–1121 (2016).
Pavletic, S. Z. et al. NCI first international workshop on the biology, prevention, and treatment of relapse after allogeneic hematopoietic stem cell transplantation: Report from the Committee on the Epidemiology and Natural History of Relapse following Allogeneic Cell Transplantation. Biol. Blood Marrow Transplant. 16, 871–890 (2010).
Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).
Khouri, I. F. & Champlin, R. E. Nonmyeloablative allogeneic stem cell transplantation for non-Hodgkin lymphoma. Cancer J. 18, 457–462 (2012).
van den Brink, M. R. M. et al. Relapse after allogeneic hematopoietic cell therapy. Biol. Blood Marrow Transplant. 16, S138–S145 (2010).
Spyridonidis, A. et al. Outcomes and prognostic factors of adults with acute lymphoblastic leukemia who relapse after allogeneic hematopoietic cell transplantation. An analysis on behalf of the Acute Leukemia Working Party of EBMT. Leukemia 26, 1211–1217 (2012).
Thomson, K. J. et al. Favorable long-term survival after reduced-intensity allogeneic transplantation for multiple-relapse aggressive non-Hodgkin’s lymphoma. J. Clin. Oncol. 27, 426–432 (2009).
Kebriaei, P. et al. Pre-emptive donor lymphocyte infusion with CD19-directed, CAR-modified T cells infused after allogeneic hematopoietic cell transplantation for patients with advanced CD19+ malignancies. Blood 126, 862 (2015).
Wagner, J. et al. CAR T cell therapy for solid tumors: Bright future or dark reality? Mol. Ther. 28, 2320–2339 (2020).
Lai, Y. et al. Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T cells. Leukemia 32, 801–808 (2018).
Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).
Nguyen, P. et al. Route of 41BB/41BBL costimulation determines effector function of B7-H3-CAR.CD28ζ T cells. Mol. Ther. Oncolytics 18, 202–214 (2020).
Kuhn, N. F. et al. CD40 ligand-modified chimeric antigen receptor T cells enhance antitumor function by eliciting an endogenous antitumor response. Mol. Ther. - Oncolytics 35, 473–488 (2019).
Liu, Y. et al. Armored inducible expression of IL-12 enhances antitumor activity of glypican-3–targeted chimeric antigen receptor–engineered T cells in hepatocellular carcinoma. J. Immunol. 203, 198–207 (2019).
Hurton, L. V. et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. PNAS 113, E7788–E7797 (2016).
Zhang, L. et al. Tumor-infiltrating lymphocytes genetically engineered with an inducible gene encoding interleukin-12 for the immunotherapy of metastatic melanoma. Clin. Cancer Res. 21, 2278–2288 (2015).
Renaud-Gabardos, E. et al. Internal ribosome entry site-based vectors for combined gene therapy. World J. Exp. Med. 5, 11–20 (2015).
Shum, T. et al. Constitutive signaling from an engineered IL7 receptor promotes durable tumor elimination by tumor-redirected T cells. Cancer Discov. 7, 1238–1247 (2017).
Zhou, P. et al. In vivo discovery of immunotherapy targets in the tumour microenvironment. Nature 506, 52–57 (2014).
Shifrut, E. et al. Genome-wide CRISPR screens in primary human T cells reveal key regulators of immune function. Cell 175, 1958–1971 (2018).
Wei, J. et al. Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature 576, 471–476 (2019).
Gautam, S. et al. The transcription factor c-Myb regulates CD8+ T cell stemness and antitumor immunity. Nat. Immunol. 20, 337–349 (2019).
Seo, H. et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proc. Natl. Acad. Sci. 116, 12410–12415 (2019).
Chen, J. et al. NR4A transcription factors limit CAR T cell function in solid tumours. Nature 567, 530–534 (2019).
Lynn, R. C. et al. c-Jun overexpression in CAR T cells induces exhaustion resistance. Nature 576, 293–300 (2019).
Song, P. et al. CRISPR/Cas-based CAR-T cells: Production and application. Biomark. Res. 12, 54 (2024).
Tieu, V. et al. A versatile CRISPR-Cas13d platform for multiplexed transcriptomic regulation and metabolic engineering in primary human T cells. Cell 187, 1278–1295 (2024).
Li, Z. et al. Critical role of the gut microbiota in immune responses and cancer immunotherapy. J. Hematol. Oncol. 17, 33 (2024).
Abid, M. B., Shah, N. N., Maatman, T. C. & Hari, P. N. Gut microbiome and CAR-T therapy. Exp. Hematol. Oncol. 8, 31 (2019).
Stein-Thoeringer, C. K. et al. A non-antibiotic-disrupted gut microbiome is associated with clinical responses to CD19-CAR-T cell cancer immunotherapy. Nat. Med. 29, 906–916 (2023).
Smith, M. et al. Gut microbiome correlates of response and toxicity following anti-CD19 CAR T cell therapy. Nat. Med. 28, 713–723 (2022).
Hu, Y. et al. CAR-T cell therapy-related cytokine release syndrome and therapeutic response is modulated by the gut microbiome in hematologic malignancies. Nat. Commun. 13, 5313 (2022).
Yu, L. et al. Patient-derived organoids of bladder cancer recapitulate antigen expression profiles and serve as a personal evaluation model for CAR-T cells in vitro. Clin. Transl. Immunol. 10, e1248 (2021).
Oei, R. W. et al. Convolutional neural network for cell classification using microscope images of intracellular actin networks. PLoS ONE 14, e0213626 (2019).
Zhang, R. et al. RCMNet: A deep learning model assists CAR-T therapy for leukemia. Comput. Biol. Med. 150, 106084 (2022).
Wei, Z. et al. Prediction of severe CRS and determination of biomarkers in B cell-acute lymphoblastic leukemia treated with CAR-T cells. Front. Immunol. 14, 1273507 (2023).
Daniels, K. G. et al. Decoding CAR T cell phenotype using combinatorial signaling motif libraries and machine learning. Science 378, 1194–1200 (2022).
Milone, M. C. & O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 32, 1529–1541 (2018).
Perry, C. & Rayat, A. C. M. E. Lentiviral vector bioprocessing. Viruses 13, 268 (2021).
Iaffaldano, B. J., Marino, M. P. & Reiser, J. CRISPR library screening to develop HEK293-derived cell lines with improved lentiviral vector titers. Front. Genome Ed. 5, 1218328 (2023).
Daya, S. & Berns, K. I. Gene therapy using adeno-associated virus vectors. Am. Soc. Microbiol. 21, 583–593 (2008).
Cao, D. et al. Redirecting anti-Vaccinia virus T cell immunity for cancer treatment by AAV-mediated delivery of the VV B8R gene. Mol. Ther. 25, 264–275 (2022).
Wang, D., Zhou, Q., Qiu, X., Liu, X. & Zhang, C. Optimizing rAAV6 transduction of primary T cells for the generation of anti-CD19 AAV-CAR-T cells. Biomed. Pharmacother. 150, 113027 (2022).
Wang, S. et al. Viral vectored vaccines: Design, development, preventive and therapeutic applications in human diseases. Signal Transduct. Target. Ther. 8, 149 (2023).
Billingsley, M. M. et al. In vivo mRNA CAR T cell engineering via targeted ionizable lipid nanoparticles with extrahepatic tropism. Small 20, 2304378 (2024).
Zhou, J. et al. Lipid nanoparticles produce chimeric antigen receptor T cells with interleukin-6 knockdown in vivo. J. Controlled Release 350, 298–307 (2022).
Morfino, P. et al. Treatment of cardiac fibrosis: From neuro-hormonal inhibitors to CAR-T cell therapy. Heart Fail. Rev. 28, 555–569 (2022).
Muyldermans, S. et al. Camelid immunoglobulins and nanobody technology. Vet. Immunol. Immunopathol. 128, 178–183 (2009).
Revets, H., De Baetselier, P. & Muyldermans, S. Nanobodies as novel agents for cancer therapy. Expert Opin. Biol. Ther. 5, 111–124 (2005).
Xie, Y. J. et al. Improved antitumor efficacy of chimeric antigen receptor T cells that secrete single-domain antibody fragments. Cancer Immunol. Res. 8, 518–529 (2020).
De Pauw, T. et al. Current status and future expectations of nanobodies in oncology trials. Expert Opin. Investig. Drugs 32, 705–721 (2023).
Cilta-cel OK’d for multiple myeloma. Cancer Discov. 12, 1176 (2022).
Arcangeli, S. et al. CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome. J. Clin. Invest. 132, 150807 (2022).
Larson, S. M. et al. CD19/CD20 bispecific chimeric antigen receptor (CAR) in naive/memory T cells for the treatment of relapsed or refractory non-Hodgkin lymphoma. Cancer Discov. 13, 580–597 (2023).
Fergusson, J. R., Fleming, V. M. & Klenerman, P. CD161-expressing human T cells. Front. Immunol. 2, 36 (2011).
Kondur, V. et al. A subset of cytotoxic effector memory T cells enhances CAR T cell efficacy in a model of pancreatic ductal adenocarcinoma. Sci. Transl. Med. 13, eabc3196 (2021).
Chen, S. et al. Macrophages in immunoregulation and therapeutics. Signal Transduct. Target. Ther. 8, 207 (2023).
Klichinsky, M. et al. Human chimeric antigen receptor macrophages for cancer immunotherapy. Nat. Biotechnol. 38, 947–953 (2020).
Carisma Therapeutics Inc. A Phase 1, First in Human Study of Adenovirally Transduced Autologous Macrophages Engineered to Contain an Anti-HER2 Chimeric Antigen Receptor in Subjects with HER2 Overexpressing Solid Tumors. https://clinicaltrials.gov/study/NCT04660929 (2024).
Soundara Rajan, T., Gugliandolo, A., Bramanti, P. & Mazzon, E. In vitro-transcribed mRNA chimeric antigen receptor T cell (IVT mRNA CAR T) therapy in hematologic and solid tumor management: A preclinical update. Int. J. Mol. Sci. 21, 6514 (2020).
Miliotou, A. N. & Papadopoulou, L. C. In vitro-transcribed (IVT)-mRNA CAR therapy development. in Chimeric Antigen Receptor T Cells: Development and Production (eds. Swiech, K., Malmegrim, K. C. R. & Picanço-Castro, V.) 87–117 (Springer US, New York, NY, 2020). doi:10.1007/978-1-0716-0146-4_7.
Zhao, Y. et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70, 9053–9061 (2010).
Wagner, S., Mullins, C. S. & Linnebacher, M. Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens. World J. Gastroenterol. 24, 5418–5432 (2018).
Lehner, M. et al. Redirecting T cells to Ewing’s sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection. PLoS ONE 7, e31210 (2012).
Schutsky, K. et al. Rigorous optimization and validation of potent RNA CAR T cell therapy for the treatment of common epithelial cancers expressing folate receptor. Oncotarget 6, 28911–28928 (2015).
Hung, C.-F. et al. Development of anti-human mesothelin-targeted chimeric antigen receptor messenger RNA–transfected peripheral blood lymphocytes for ovarian cancer therapy. Hum. Gene Ther. 29, 614–625 (2018).
Tchou, J. et al. Safety and efficacy of intratumoral injections of chimeric antigen receptor (CAR) T cells in metastatic breast cancer. Cancer Immunol. Res. 5, 1152–1161 (2017).
Nathan Singh et al. Nature of tumor control by permanently and transiently modified GD2 chimeric antigen receptor T cells in xenograft models of neuroblastoma. Cancer Immunol. Res. 2, 1059–1070 (2014).
Caruso, H. G. et al. Redirecting T-cell specificity to EGFR using mRNA to self-limit expression of chimeric antigen receptor. J. Immunother. 39, 205 (2016).
Svoboda, J. et al. Nonviral RNA chimeric antigen receptor–modified T cells in patients with Hodgkin lymphoma. Blood 132, 1022–1026 (2018).
Cummins, K. D. et al. Treating relapsed / refractory (RR) AML with biodegradable anti-CD123 CAR modified T cells. Blood 130, 1359 (2017).
Downloads
Posted
Categories
License
Copyright (c) 2025 Alexandre Gervaud
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.