Abstract

Chimeric antigen receptor (CAR) T cell therapy represents a major breakthrough in cancer care since the approval of tisagenlecleucel by the Food and Drug Administration in 2017 for the treatment of pediatric and young adult patients with relapsed or refractory acute lymphocytic leukemia. As of April 2023, six CAR T cell therapies have been approved, demonstrating unprecedented efficacy in patients with B-cell malignancies and multiple myeloma. However, adverse events such as cytokine release syndrome and immune effector cell-associated neurotoxicity pose significant challenges to CAR T cell therapy. The severity of these adverse events correlates with the pretreatment tumor burden, where a higher tumor burden results in more severe consequences. This observation is supported by the application of CD19-targeted CAR T cell therapy in autoimmune diseases including systemic lupus erythematosus and antisynthetase syndrome. These results indicate that initiating CAR T cell therapy early at low tumor burden or using debulking strategy prior to CAR T cell infusion may reduce the severity of adverse events. In addition, CAR T cell therapy is expensive and has limited effectiveness against solid tumors. In this article, we review the critical steps that led to this groundbreaking therapy and explore ongoing efforts to overcome these challenges. With the promise of more effective and safer CAR T cell therapies in development, we are optimistic that a broader range of cancer patients will benefit from this revolutionary therapy in the foreseeable future.

Keywords: TCR - T cell receptor; cancer immunotherapy; chimeric antigen receptor (CAR T); cytokine release syndrome; tumor burden.

Copyright © 2023 Mitra, Barua, Huang, Ganguly, Feng and He.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1 

The differences in tumor antigen…

Figure 2 

The timeline of key milestones…

Similar articles

• Systematic Review and Meta-analysis of CD19-Specific CAR-T Cell Therapy in Relapsed/Refractory Acute Lymphoblastic Leukemia in the Pediatric and Young Adult Population: Safety and Efficacy Outcomes.

  Aamir S, Anwar MY, Khalid F, Khan SI, Ali MA, Khattak ZE.Clin Lymphoma Myeloma Leuk. 2021 Apr;21(4):e334-e347. doi: 10.1016/j.clml.2020.12.010. Epub 2020 Dec 17.PMID: 33573914

• Impact of Bridging Chemotherapy on Clinical Outcomes of CD19-Specific CAR T Cell Therapy in Children/Young Adults with Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia.

  Shahid S, Ramaswamy K, Flynn J, Mauguen A, Perica K, Park JH, Forlenza CJ, Shukla NN, Steinherz PG, Margossian SP, Boelens JJ, Kernan NA, Curran KJ.Transplant Cell Ther. 2022 Feb;28(2):72.e1-72.e8. doi: 10.1016/j.jtct.2021.11.014. Epub 2021 Nov 28.PMID: 34852305 Free PMC article. Clinical Trial.

• Management of cytokine release syndrome and neurotoxicity in chimeric antigen receptor (CAR) T cell therapy.

  Acharya UH, Dhawale T, Yun S, Jacobson CA, Chavez JC, Ramos JD, Appelbaum J, Maloney DG.Expert Rev Hematol. 2019 Mar;12(3):195-205. doi: 10.1080/17474086.2019.1585238. Epub 2019 Mar 18.PMID: 30793644 Review.

• Toxicity and effectiveness of CD19 CAR T therapy in children with high-burden central nervous system refractory B-ALL.

  Tan Y, Pan J, Deng B, Ling Z, Song W, Xu J, Duan J, Wang Z, Yu X, Chang AH, Feng X.Cancer Immunol Immunother. 2021 Jul;70(7):1979-1993. doi: 10.1007/s00262-020-02829-9. Epub 2021 Jan 8.PMID: 33416942 Free PMC article.

• Advancing autoimmune Rheumatic disease treatment: CAR-T Cell Therapies - Evidence, Safety, and future directions.

  Ohno R, Nakamura A.Semin Arthritis Rheum. 2024 Aug;67:152479. doi: 10.1016/j.semarthrit.2024.152479. Epub 2024 May 24.PMID: 38810569 Review.

See all similar articles

Cited by

• The Current Landscape of Secondary Malignancies after CAR T-Cell Therapies: How Could Malignancies Be Prevented?

  Bouziana S, Bouzianas D.Int J Mol Sci. 2024 Sep 1;25(17):9518. doi: 10.3390/ijms25179518.PMID: 39273462 Free PMC article. Review.

• From Crypts to Cancer: A Holistic Perspective on Colorectal Carcinogenesis and Therapeutic Strategies.

  Gharib E, Robichaud GA.Int J Mol Sci. 2024 Aug 30;25(17):9463. doi: 10.3390/ijms25179463.PMID: 39273409 Free PMC article. Review.

• Recent clinical researches and technological development in TIL therapy.

  Matsueda S, Chen L, Li H, Yao H, Yu F.Cancer Immunol Immunother. 2024 Sep 12;73(11):232. doi: 10.1007/s00262-024-03793-4.PMID: 39264449 Free PMC article. Review.

• Challenges in validation of combination treatment strategies for CRC using patient-derived organoids.

  Benboubker V, Ramzy GM, Jacobs S, Nowak-Sliwinska P.J Exp Clin Cancer Res. 2024 Sep 11;43(1):259. doi: 10.1186/s13046-024-03173-x.PMID: 39261955 Free PMC article. Review.

• Navigating the Intersection of Technology and Depression Precision Medicine.

  Irmak-Yazicioglu MB, Arslan A.Adv Exp Med Biol. 2024;1456:401-426. doi: 10.1007/978-981-97-4402-2_20.PMID: 39261440 Review.

See all "Cited by" articles

References

1. 1. Dobosz P, Dzieciatkowski T. The intriguing history of cancer immunotherapy. Front Immunol (2019) 10:2965. doi: 10.3389/fimmu.2019.02965 - DOI - PMC - PubMed
2. 1. Mccarthy EF. The toxins of William b. coley and the treatment of bone and soft-tissue sarcomas. Iowa Orthop J (2006) 26:154–8. - PMC - PubMed
3. 1. Pearl R. On the pathological relations between cancer and tuberculosis. Proc Soc Exp Biol Med (1928) 26:73–5. doi: 10.3181/00379727-26-4143 - DOI
4. 1. Morales A, Eidinger D, Bruce AW. Intracavitary bacillus calmette-guerin in the treatment of superficial bladder tumors. J Urol (1976) 116:180–3. doi: 10.1016/S0022-5347(17)58737-6 - DOI - PubMed
5. 1. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer–a current perspective. Nat Rev Urol (2014) 11:153–62. doi: 10.1038/nrurol.2014.15 - DOI - PubMed
6. 1. Gresser I, Bourali C. Antitumor effects of interferon preparations in mice. J Natl Cancer Inst (1970) 45:365–76. - PubMed
7. 1. Gutterman JU, Blumenschein GR, Alexanian R, Yap HY, Buzdar AU, Cabanillas F, et al. . Leukocyte interferon-induced tumor regression in human metastatic breast cancer, multiple myeloma, and malignant lymphoma. Ann Intern Med (1980) 93:399–406. doi: 10.7326/0003-4819-93-3-399 - DOI - PubMed
8. 1. Quesada JR, Reuben J, Manning JT, Hersh EM, Gutterman JU. Alpha interferon for induction of remission in hairy-cell leukemia. N Engl J Med (1984) 310:15–8. doi: 10.1056/NEJM198401053100104 - DOI - PubMed
9. 1. Golomb HM, Jacobs A, Fefer A, Ozer H, Thompson J, Portlock C, et al. . Alpha-2 interferon therapy of hairy-cell leukemia: a multicenter study of 64 patients. J Clin Oncol (1986) 4:900–5. doi: 10.1200/JCO.1986.4.6.900 - DOI - PubMed
10. 1. Loftis JM, Hauser P. The phenomenology and treatment of interferon-induced depression. J Affect Disord (2004) 82:175–90. doi: 10.1016/j.jad.2004.04.002 - DOI - PubMed
11. 1. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N, Yoshimoto R, et al. . Structure and expression of a cloned cDNA for human interleukin-2. Nature (1983) 302:305–10. doi: 10.1038/302305a0 - DOI - PubMed
12. 1. Rosenberg SA, Lotze MT, Muul LM, Chang AE, Avis FP, Leitman S, et al. . A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med (1987) 316:889–97. doi: 10.1056/NEJM198704093161501 - DOI - PubMed
13. 1. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol (1995) 13:688–96. doi: 10.1200/JCO.1995.13.3.688 - DOI - PubMed
14. 1. Atkins MB, Lotze MT, Dutcher JP, Fisher RI, Weiss G, Margolin K, et al. . High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol (1999) 17:2105–16. doi: 10.1200/JCO.1999.17.7.2105 - DOI - PubMed
15. 1. Dafni U, Michielin O, Lluesma SM, Tsourti Z, Polydoropoulou V, Karlis D, et al. . Efficacy of adoptive therapy with tumor-infiltrating lymphocytes and recombinant interleukin-2 in advanced cutaneous melanoma: a systematic review and meta-analysis. Ann Oncol (2019) 30:1902–13. doi: 10.1093/annonc/mdz398 - DOI - PubMed
16. 1. Veatch JR, Simon S, Riddell SR. Tumor-infiltrating lymphocytes make inroads in non-small-cell lung cancer. Nat Med (2021) 27:1339–41. doi: 10.1038/s41591-021-01445-z - DOI - PubMed
17. 1. Weiden PL, Flournoy N, Thomas ED, Prentice R, Fefer A, Buckner CD, et al. . Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med (1979) 300:1068–73. doi: 10.1056/NEJM197905103001902 - DOI - PubMed
18. 1. Mcsweeney PA, Niederwieser D, Shizuru JA, Sandmaier BM, Molina AJ, Maloney DG, et al. . Hematopoietic cell transplantation in older patients with hematologic malignancies: replacing high-dose cytotoxic therapy with graft-versus-tumor effects. Blood (2001) 97:3390–400. doi: 10.1182/blood.V97.11.3390 - DOI - PubMed
19. 1. Simpson TR, Li F, Montalvo-Ortiz W, Sepulveda MA, Bergerhoff K, Arce F, et al. . Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J Exp Med (2013) 210:1695–710. doi: 10.1084/jem.20130579 - DOI - PMC - PubMed
20. 1. Sharma A, Subudhi SK, Blando J, Vence L, Wargo J, Allison JP, et al. . Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers-response. Clin Cancer Res (2019) 25:3469–70. doi: 10.1158/1078-0432.CCR-19-0402 - DOI - PMC - PubMed
21. 1. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med (2000) 6:443–6. doi: 10.1038/74704 - DOI - PubMed
22. 1. Rosenberg SA, Spiess P, Lafreniere R. A new approach to the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes. Science (1986) 233:1318–21. doi: 10.1126/science.3489291 - DOI - PubMed
23. 1. Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, et al. . Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. a preliminary report. N Engl J Med (1988) 319:1676–80. doi: 10.1056/NEJM198812223192527 - DOI - PubMed
24. 1. Rosenberg SA, Yang JC, Sherry RM, Kammula US, Hughes MS, Phan GQ, et al. . Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res (2011) 17:4550–7. doi: 10.1158/1078-0432.CCR-11-0116 - DOI - PMC - PubMed
25. 1. Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, Danforth DN, et al. . Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol (2016) 34:2389–97. doi: 10.1200/JCO.2016.66.7220 - DOI - PMC - PubMed
26. 1. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science (2011) 331:1565–70. doi: 10.1126/science.1203486 - DOI - PubMed
27. 1. Leko V, Rosenberg SA. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell (2020) 38:454–72. doi: 10.1016/j.ccell.2020.07.013 - DOI - PMC - PubMed
28. 1. Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer (2019) 7:306. doi: 10.1186/s40425-019-0805-8 - DOI - PMC - PubMed
29. 1. Kuwana Y, Asakura Y, Utsunomiya N, Nakanishi M, Arata Y, Itoh S, et al. . Expression of chimeric receptor composed of immunoglobulin-derived V regions and T-cell receptor-derived c regions. Biochem Biophys Res Commun (1987) 149:960–8. doi: 10.1016/0006-291X(87)90502-X - DOI - PubMed
30. 1. Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-t-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U.S.A. (1989) 86:10024–8. doi: 10.1073/pnas.86.24.10024 - DOI - PMC - PubMed
31. 1. Eshhar Z, Waks T, Gross G, Schindler DG. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci U.S.A. (1993) 90:720–4. doi: 10.1073/pnas.90.2.720 - DOI - PMC - PubMed
32. 1. Bird RE, Hardman KD, Jacobson JW, Johnson S, Kaufman BM, Lee SM, et al. . Single-chain antigen-binding proteins. Science (1988) 242:423–6. doi: 10.1126/science.3140379 - DOI - PubMed
33. 1. Huston JS, Levinson D, Mudgett-Hunter M, Tai MS, Novotny J, Margolies MN, et al. . Protein engineering of antibody binding sites: recovery of specific activity in an anti-digoxin single-chain fv analogue produced in escherichia coli. Proc Natl Acad Sci U.S.A. (1988) 85:5879–83. doi: 10.1073/pnas.85.16.5879 - DOI - PMC - PubMed
34. 1. Eshhar Z. Tumor-specific T-bodies: towards clinical application. Cancer Immunol Immunother (1997) 45:131–6. doi: 10.1007/s002620050415 - DOI - PMC - PubMed
35. 1. Moritz D, Wels W, Mattern J, Groner B. Cytotoxic T lymphocytes with a grafted recognition specificity for ERBB2-expressing tumor cells. Proc Natl Acad Sci U.S.A. (1994) 91:4318–22. doi: 10.1073/pnas.91.10.4318 - DOI - PMC - PubMed
36. 1. Hwu P, Shafer GE, Treisman J, Schindler DG, Gross G, Cowherd R, et al. . Lysis of ovarian cancer cells by human lymphocytes redirected with a chimeric gene composed of an antibody variable region and the fc receptor gamma chain. J Exp Med (1993) 178:361–6. doi: 10.1084/jem.178.1.361 - DOI - PMC - PubMed
37. 1. Hwu P, Yang JC, Cowherd R, Treisman J, Shafer GE, Eshhar Z, et al. . In vivo antitumor activity of T cells redirected with chimeric antibody/T-cell receptor genes. Cancer Res (1995) 55:3369–73. - PubMed
38. 1. Weijtens ME, Willemsen RA, Valerio D, Stam K, Bolhuis RL. Single chain ig/gamma gene-redirected human T lymphocytes produce cytokines, specifically lyse tumor cells, and recycle lytic capacity. J Immunol (1996) 157:836–43. doi: 10.4049/jimmunol.157.2.836 - DOI - PubMed
39. 1. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, et al. . A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res (2006) 12:6106–15. doi: 10.1158/1078-0432.CCR-06-1183 - DOI - PMC - PubMed
40. 1. Lamers CH, Sleijfer S, Vulto AG, Kruit WH, Kliffen M, Debets R, et al. . Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J Clin Oncol (2006) 24:e20–22. doi: 10.1200/JCO.2006.05.9964 - DOI - PubMed
41. 1. Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, et al. . Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood (2008) 112:2261–71. doi: 10.1182/blood-2007-12-128843 - DOI - PMC - PubMed
42. 1. Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, et al. . Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther (2007) 15:825–33. doi: 10.1038/sj.mt.6300104 - DOI - PubMed
43. 1. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. . Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med (2008) 14:1264–70. doi: 10.1038/nm.1882 - DOI - PMC - PubMed
44. 1. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cell costimulation. Annu Rev Immunol (1996) 14:233–58. doi: 10.1146/annurev.immunol.14.1.233 - DOI - PubMed
45. 1. Krause A, Guo HF, Latouche JB, Tan C, Cheung NK, Sadelain M. Antigen-dependent CD28 signaling selectively enhances survival and proliferation in genetically modified activated human primary T lymphocytes. J Exp Med (1998) 188:619–26. doi: 10.1084/jem.188.4.619 - DOI - PMC - PubMed
46. 1. Maher J, Brentjens RJ, Gunset G, Riviere I, Sadelain M. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta/CD28 receptor. Nat Biotechnol (2002) 20:70–5. doi: 10.1038/nbt0102-70 - DOI - PubMed
47. 1. Savoldo B, Ramos CA, Liu E, Mims MP, Keating MJ, Carrum G, et al. . CD28 costimulation improves expansion and persistence of chimeric antigen receptor-modified T cells in lymphoma patients. J Clin Invest (2011) 121:1822–6. doi: 10.1172/JCI46110 - DOI - PMC - PubMed
48. 1. Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol (2004) 172:104–13. doi: 10.4049/jimmunol.172.1.104 - DOI - PubMed
49. 1. Imai C, Mihara K, Andreansky M, Nicholson IC, Pui CH, Geiger TL, et al. . Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia (2004) 18:676–84. doi: 10.1038/sj.leu.2403302 - DOI - PubMed
50. 1. Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. . Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo . Mol Ther (2009) 17:1453–64. doi: 10.1038/mt.2009.83 - DOI - PMC - PubMed
51. 1. Kochenderfer JN, Wilson WH, Janik JE, Dudley ME, Stetler-Stevenson M, Feldman SA, et al. . Eradication of b-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood (2010) 116:4099–102. doi: 10.1182/blood-2010-04-281931 - DOI - PMC - PubMed
52. 1. Brentjens RJ, Riviere I, Park JH, Davila ML, Wang X, Stefanski J, et al. . Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory b-cell leukemias. Blood (2011) 118:4817–28. doi: 10.1182/blood-2011-04-348540 - DOI - PMC - PubMed
53. 1. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. . T Cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Trans Med (2011) 3(95):95ra73. doi: 10.1126/scitranslmed.3002842 - DOI - PMC - PubMed
54. 1. Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med (2011) 365:725–33. doi: 10.1056/NEJMoa1103849 - DOI - PMC - PubMed
55. 1. Dudley ME, Wunderlich JR, Robbins PF, Yang JC, Hwu P, Schwartzentruber DJ, et al. . Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science (2002) 298:850–4. doi: 10.1126/science.1076514 - DOI - PMC - PubMed
56. 1. Dudley ME, Wunderlich JR, Yang JC, Sherry RM, Topalian SL, Restifo NP, et al. . Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J Clin Oncol (2005) 23:2346–57. doi: 10.1200/JCO.2005.00.240 - DOI - PMC - PubMed
57. 1. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science (2015) 348:62–8. doi: 10.1126/science.aaa4967 - DOI - PMC - PubMed
58. 1. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. . Tisagenlecleucel in children and young adults with b-cell lymphoblastic leukemia. N Engl J Med (2018) 378:439–48. doi: 10.1056/NEJMoa1709866 - DOI - PMC - PubMed
59. 1. Locke FL, Ghobadi A, Jacobson CA, Miklos DB, Lekakis LJ, Oluwole OO, et al. . Long-term safety and activity of axicabtagene ciloleucel in refractory large b-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial. Lancet Oncol (2019) 20:31–42. doi: 10.1016/S1470-2045(18)30864-7 - DOI - PMC - PubMed
60. 1. Abramson JS, Palomba ML, Gordon LI, Lunning MA, Wang M, Arnason J, et al. . Lisocabtagene maraleucel for patients with relapsed or refractory large b-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet (2020) 396:839–52. doi: 10.1016/S0140-6736(20)31366-0 - DOI - PubMed
61. 1. Wang M, Munoz J, Goy A, Locke FL, Jacobson CA, Hill BT, et al. . KTE-X19 CAR T-cell therapy in relapsed or refractory mantle-cell lymphoma. N Engl J Med (2020) 382:1331–42. doi: 10.1056/NEJMoa1914347 - DOI - PMC - PubMed
62. 1. Feigal EG, Cosenza ME. Cellular-based therapies. In: Translational medicine. CRC Press; (2021). p. 359–80.
63. 1. Munshi NC, Anderson LD, Jr., Shah N, Madduri D, Berdeja J, Lonial S, et al. . Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med (2021) 384:705–16. doi: 10.1056/NEJMoa2024850 - DOI - PubMed
64. 1. Martin T, Usmani SZ, Berdeja JG, Agha M, Cohen AD, Hari P, et al. . Ciltacabtagene autoleucel, an anti-B-cell maturation antigen chimeric antigen receptor T-Cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-Year follow-up. J Clin Oncol (2023) 41:1265–74. doi: 10.1200/JCO.22.00842 - DOI - PMC - PubMed
65. 1. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. . Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med (2013) 368:1509–18. doi: 10.1056/NEJMoa1215134 - DOI - PMC - PubMed
66. 1. Shah NN, Lee DW, Yates B, Yuan CM, Shalabi H, Martin S, et al. . Long-term follow-up of CD19-CAR T-cell therapy in children and young adults with b-ALL. J Clin Oncol (2021) 39:1650–9. doi: 10.1200/JCO.20.02262 - DOI - PMC - PubMed
67. 1. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. . CD22-targeted CAR T cells induce remission in b-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med (2018) 24:20–8. doi: 10.1038/nm.4441 - DOI - PMC - PubMed
68. 1. Schultz LM, Ramakrishna S, Baskar R, Richards RM, Moon J, Baggott C, et al. . Long-term follow-up of CD19/22 CAR therapy in children and young adults with b-ALL reveals efficacy, tolerability and high survival rates when coupled with hematopoietic stem cell transplantation. Blood (2022) 140:10300–2. doi: 10.1182/blood-2022-167789 - DOI
69. 1. Wudhikarn K, Flynn JR, Riviere I, Gonen M, Wang X, Senechal B, et al. . Interventions and outcomes of adult patients with b-ALL progressing after CD19 chimeric antigen receptor T-cell therapy. Blood (2021) 138:531–43. doi: 10.1182/blood.2020009515 - DOI - PMC - PubMed
70. 1. Riches JC, Davies JK, Mcclanahan F, Fatah R, Iqbal S, Agrawal S, et al. . T Cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood (2013) 121:1612–21. doi: 10.1182/blood-2012-09-457531 - DOI - PMC - PubMed
71. 1. Mamonkin M, Rouce RH, Tashiro H, Brenner MK. A T-cell-directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood (2015) 126:983–92. doi: 10.1182/blood-2015-02-629527 - DOI - PMC - PubMed
72. 1. Maciocia PM, Wawrzyniecka PA, Philip B, Ricciardelli I, Akarca AU, Onuoha SC, et al. . Targeting the T cell receptor beta-chain constant region for immunotherapy of T cell malignancies. Nat Med (2017) 23:1416–23. doi: 10.1038/nm.4444 - DOI - PubMed
73. 1. Li F, Zhang H, Wang W, Yang P, Huang Y, Zhang J, et al. . T Cell receptor beta-chain-targeting chimeric antigen receptor T cells against T cell malignancies. Nat Commun (2022) 13:4334. doi: 10.1038/s41467-022-32092-8 - DOI - PMC - PubMed
74. 1. Melenhorst JJ, Chen GM, Wang M, Porter DL, Chen C, Collins MA, et al. . Decade-long leukaemia remissions with persistence of CD4(+) CAR T cells. Nature (2022) 602:503–9. doi: 10.1038/s41586-021-04390-6 - DOI - PMC - PubMed
75. 1. Cappell KM, Sherry RM, Yang JC, Goff SL, Vanasse DA, Mcintyre L, et al. . Long-term follow-up of anti-CD19 chimeric antigen receptor T-cell therapy. J Clin Oncol (2020) 38:3805–15. doi: 10.1200/JCO.20.01467 - DOI - PMC - PubMed
76. 1. Elsallab M, Ellithi M, Hempel S, Abdel-Azim H, Abou-El-Enein M. Long-term response to autologous anti-CD19 chimeric antigen receptor T cells in relapsed or refractory b cell acute lymphoblastic leukemia: a systematic review and meta-analysis. Cancer Gene Ther (2023). doi: 10.1038/s41417-023-00593-3 - DOI - PMC - PubMed
77. 1. Bachy E, Le Gouill S, Di Blasi R, Sesques P, Manson G, Cartron G, et al. . A real-world comparison of tisagenlecleucel and axicabtagene ciloleucel CAR T cells in relapsed or refractory diffuse large b cell lymphoma. Nat Med (2022) 28:2145–54. doi: 10.1038/s41591-022-01969-y - DOI - PMC - PubMed
78. 1. Ferreros P, Trapero I. Interleukin inhibitors in cytokine release syndrome and neurotoxicity secondary to CAR-T therapy. Diseases (2022) 10(3):41. doi: 10.3390/diseases10030041 - DOI - PMC - PubMed
79. 1. Narkhede M, Di Stasi A, Bal S, Shea LK, Goyal G, Sledge A, et al. . Interim analysis of investigator-initiated phase 2 trial of siltuximab in treatment of cytokine release syndrome and immune effector cell associated neurotoxicity related to CAR T-cell therapy. In: 2023 tandem meetings| transplantation & cellular therapy meetings of ASTCT and CIBMTR. Tandem Meetings; (2023).
80. 1. Giavridis T, van der Stegen SJC, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med (2018) 24:731–8. doi: 10.1038/s41591-018-0041-7 - DOI - PMC - PubMed
81. 1. Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. . Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med (2018) 24:739–48. doi: 10.1038/s41591-018-0036-4 - DOI - PubMed
82. 1. Parker KR, Migliorini D, Perkey E, Yost KE, Bhaduri A, Bagga P, et al. . Single-cell analyses identify brain mural cells expressing CD19 as potential off-tumor targets for CAR-T immunotherapies. Cell (2020) 183:126–142.e117. doi: 10.1016/j.cell.2020.08.022 - DOI - PMC - PubMed
83. 1. Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, et al. . Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood (2017) 130:2295–306. doi: 10.1182/blood-2017-06-793141 - DOI - PMC - PubMed
84. 1. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. . CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med (2013) 5:177ra138. doi: 10.1126/scitranslmed.3005930 - DOI - PMC - PubMed
85. 1. Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. . Efficacy and toxicity management of 19-28z CAR T cell therapy in b cell acute lymphoblastic leukemia. Sci Transl Med (2014) 6:224ra225. doi: 10.1126/scitranslmed.3008226 - DOI - PMC - PubMed
86. 1. Li M, Xue SL, Tang X, Xu J, Chen S, Han Y, et al. . The differential effects of tumor burdens on predicting the net benefits of ssCART-19 cell treatment on r/r b-ALL patients. Sci Rep (2022) 12:378. doi: 10.1038/s41598-021-04296-3 - DOI - PMC - PubMed
87. 1. Mougiakakos D, Kronke G, Volkl S, Kretschmann S, Aigner M, Kharboutli S, et al. . CD19-targeted CAR T cells in refractory systemic lupus erythematosus. N Engl J Med (2021) 385:567–9. doi: 10.1056/NEJMc2107725 - DOI - PubMed
88. 1. Mackensen A, Muller F, Mougiakakos D, Boltz S, Wilhelm A, Aigner M, et al. . Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med (2022) 28:2124–32. doi: 10.1038/s41591-022-02017-5 - DOI - PubMed
89. 1. Müller F, Boeltz S, Knitza J, Aigner M, Völkl S, Kharboutli S, et al. . CD19-targeted CAR T cells in refractory antisynthetase syndrome. Lancet (London, England) (2023) 401(10379):815–8. doi: 10.1016/S0140-6736(23)00023-5 - DOI - PubMed
90. 1. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol (2019) 94:1266–87. doi: 10.1002/ajh.25595 - DOI - PubMed
91. 1. Puckett Y, Chan O. Acute lymphocytic leukemia. In: StatPearls. Treasure Island (FL): StatPearls Publishing; (2022).
92. 1. Rivero SJ, Diaz-Jouanen E, Alarcon-Segovia D. Lymphopenia in systemic lupus erythematosus. clinical, diagnostic, and prognostic significance. Arthritis Rheum (1978) 21:295–305. doi: 10.1002/art.1780210302 - DOI - PubMed
93. 1. Arce E, Jackson DG, Gill MA, Bennett LB, Banchereau J, Pascual V. Increased frequency of pre-germinal center b cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol (2001) 167:2361–9. doi: 10.4049/jimmunol.167.4.2361 - DOI - PubMed
94. 1. Dzangue-Tchoupou G, Allenbach Y, Preusse C, Stenzel W, Benveniste O. Mass cytometry reveals an impairment of b cell homeostasis in anti-synthetase syndrome. J Neuroimmunol (2019) 332:212–5. doi: 10.1016/j.jneuroim.2019.04.014 - DOI - PubMed
95. 1. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood (2016) 127:3321–30. doi: 10.1182/blood-2016-04-703751 - DOI - PMC - PubMed
96. 1. Rahmani B, Patel S, Seyam O, Gandhi J, Reid I, Smith N, et al. . Current understanding of tumor lysis syndrome. Hematol Oncol (2019) 37:537–47. doi: 10.1002/hon.2668 - DOI - PubMed
97. 1. Hernandez I, Prasad V, Gellad WF. Total costs of chimeric antigen receptor T-cell immunotherapy. JAMA Oncol (2018) 4:994–6. doi: 10.1001/jamaoncol.2018.0977 - DOI - PMC - PubMed
98. 1. Kagoya Y, Guo T, Yeung B, Saso K, Anczurowski M, Wang CH, et al. . Genetic ablation of HLA class I, class II, and the T-cell receptor enables allogeneic T cells to be used for adoptive T-cell therapy. Cancer Immunol Res (2020) 8:926–36. doi: 10.1158/2326-6066.CIR-18-0508 - DOI - PubMed
99. 1. Mailankody S, Matous JV, Chhabra S, Liedtke M, Sidana S, Oluwole OO, et al. . Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med (2023) 29(2):422–9. doi: 10.1038/s41591-023-02306-7 - DOI - PubMed
100. 1. Zijlstra M, Bix M, Simister NE, Loring JM, Raulet DH, Jaenisch R. Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. Nature (1990) 344:742–6. doi: 10.1038/344742a0 - DOI - PubMed
101. 1. Chiesa R, Georgiadis C, Ottaviano G, Syed F, Braybrook T, Etuk A, et al. . Tvt CAR7: phase 1 clinical trial of base-edited universal” CAR7 T cells for paediatric Relapsed/Refractory T-ALL. Blood (2022) 140:4579–80. doi: 10.1182/blood-2022-169114 - DOI
102. 1. Diorio C, Murray R, Naniong M, Barrera L, Camblin A, Chukinas J, et al. . Cytosine base editing enables quadruple-edited allogeneic CART cells for T-ALL. Blood (2022) 140:619–29. doi: 10.1182/blood.2022015825 - DOI - PMC - PubMed
103. 1. Jo S, Das S, Williams A, Chretien AS, Pagliardini T, Le Roy A, et al. . Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing. Nat Commun (2022) 13:3453. doi: 10.1038/s41467-022-30896-2 - DOI - PMC - PubMed
104. 1. Rurik JG, Tombacz I, Yadegari A, Mendez Fernandez PO, Shewale SV, Li L, et al. . CAR T cells produced in vivo to treat cardiac injury. Science (2022) 375:91–6. doi: 10.1126/science.abm0594 - DOI - PMC - PubMed
105. 1. Rive CM, Yung E, Dreolini L, Brown SD, May CG, Woodsworth DJ, et al. . Selective b cell depletion upon intravenous infusion of replication-incompetent anti-CD19 CAR lentivirus. Mol Ther Methods Clin Dev (2022) 26:4–14. doi: 10.1016/j.omtm.2022.05.006 - DOI - PMC - PubMed
106. 1. Svoboda J, Gerson JN, Landsburg DJ, Chong EA, Barta SK, Dwivedy Nasta S, et al. . Interleukin-18 secreting autologous anti-CD19 CAR T-cells (huCART19-IL18) in patients with non-Hodgkin lymphomas relapsed or refractory to prior CAR T-cell therapy. Blood (2022) 140:4612–4. doi: 10.1182/blood-2022-162393 - DOI
107. 1. Ghassemi S, Durgin JS, Nunez-Cruz S, Patel J, Leferovich J, Pinzone M, et al. . Rapid manufacturing of non-activated potent CAR T cells. Nat BioMed Eng (2022) 6:118–28. doi: 10.1038/s41551-021-00842-6 - DOI - PMC - PubMed
108. 1. Curran KJ, Seinstra BA, Nikhamin Y, Yeh R, Usachenko Y, Van Leeuwen DG, et al. . Enhancing antitumor efficacy of chimeric antigen receptor T cells through constitutive CD40L expression. Mol Ther (2015) 23:769–78. doi: 10.1038/mt.2015.4 - DOI - PMC - PubMed
109. 1. Kloss CC, Lee J, Zhang A, Chen F, Melenhorst JJ, Lacey SF, et al. . Dominant-negative TGF-beta receptor enhances PSMA-targeted human CAR T cell proliferation and augments prostate cancer eradication. Mol Ther (2018) 26:1855–66. doi: 10.1016/j.ymthe.2018.05.003 - DOI - PMC - PubMed
110. 1. Kuhn NF, Purdon TJ, Van Leeuwen DG, Lopez AV, Curran KJ, Daniyan AF, et al. . CD40 ligand-modified chimeric antigen receptor T cells enhance antitumor function by eliciting an endogenous antitumor response. Cancer Cell (2019) 35:473–488.e476. doi: 10.1016/j.ccell.2019.02.006 - DOI - PMC - PubMed
111. 1. Ye L, Park JJ, Peng L, Yang Q, Chow RD, Dong MB, et al. . A genome-scale gain-of-function CRISPR screen in CD8 T cells identifies proline metabolism as a means to enhance CAR-T therapy. Cell Metab (2022) 34:595–614.e514. doi: 10.1016/j.cmet.2022.02.009 - DOI - PMC - PubMed
112. 1. Labanieh L, Mackall CL. CAR immune cells: design principles, resistance and the next generation. Nature (2023) 614:635–48. doi: 10.1038/s41586-023-05707-3 - DOI - PubMed
113. 1. Allen GM, Frankel NW, Reddy NR, Bhargava HK, Yoshida MA, Stark SR, et al. . Synthetic cytokine circuits that drive T cells into immune-excluded tumors. Science (2022) 378:eaba1624. doi: 10.1126/science.aba1624 - DOI - PMC - PubMed
114. 1. Rupp LJ, Schumann K, Roybal KT, Gate RE, Ye CJ, Lim WA, et al. . CRISPR/Cas9-mediated PD-1 disruption enhances anti-tumor efficacy of human chimeric antigen receptor T cells. Sci Rep (2017) 7:737. doi: 10.1038/s41598-017-00462-8 - DOI - PMC - PubMed
115. 1. Choi BD, Yu X, Castano AP, Darr H, Henderson DB, Bouffard AA, et al. . CRISPR-Cas9 disruption of PD-1 enhances activity of universal EGFRvIII CAR T cells in a preclinical model of human glioblastoma. J Immunother Cancer (2019) 7:304. doi: 10.1186/s40425-019-0806-7 - DOI - PMC - PubMed
116. 1. Jain N, Zhao Z, Feucht J, Koche R, Iyer A, Dobrin A, et al. . TET2 guards against unchecked BATF3-induced CAR T cell expansion. Nature (2023) 615(7951):315–22. doi: 10.1038/s41586-022-05692-z - DOI - PMC - PubMed
117. 1. Chen J, Lopez-Moyado IF, Seo H, Lio CJ, Hempleman LJ, Sekiya T, et al. . NR4A transcription factors limit CAR T cell function in solid tumours. Nature (2019) 567:530–4. doi: 10.1038/s41586-019-0985-x - DOI - PMC - PubMed
118. 1. Wei J, Long L, Zheng W, Dhungana Y, Lim SA, Guy C, et al. . Targeting REGNASE-1 programs long-lived effector T cells for cancer therapy. Nature (2019) 576:471–6. doi: 10.1038/s41586-019-1821-z - DOI - PMC - PubMed
119. 1. Zheng W, Wei J, Zebley CC, Jones LL, Dhungana Y, Wang YD, et al. . Regnase-1 suppresses TCF-1+ precursor exhausted T-cell formation to limit CAR-t-cell responses against ALL. Blood (2021) 138:122–35. doi: 10.1182/blood.2020009309 - DOI - PMC - PubMed
120. 1. Patel U, Abernathy J, Savani BN, Oluwole O, Sengsayadeth S, Dholaria B. CAR T cell therapy in solid tumors: a review of current clinical trials. EJHaem (2022) 3:24–31. doi: 10.1002/jha2.356 - DOI - PMC - PubMed
121. 1. Pulsipher MA. Hypogammaglobulinemia due to CAR T-cell therapy. Pediatr Blood Cancer (2018) 65(4):e26914. doi: 10.1002/pbc.26914 - DOI - PMC - PubMed
122. 1. Duong CP, Westwood JA, Berry LJ, Darcy PK, Kershaw MH. Enhancing the specificity of T-cell cultures for adoptive immunotherapy of cancer. Immunotherapy (2011) 3:33–48. doi: 10.2217/imt.10.81 - DOI - PubMed
123. 1. Kloss CC, Condomines M, Cartellieri M, Bachmann M, Sadelain M. Combinatorial antigen recognition with balanced signaling promotes selective tumor eradication by engineered T cells. Nat Biotechnol (2013) 31:71–5. doi: 10.1038/nbt.2459 - DOI - PMC - PubMed
124. 1. Majzner RG, Ramakrishna S, Yeom KW, Patel S, Chinnasamy H, Schultz LM, et al. . GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature (2022) 603:934–41. doi: 10.1038/s41586-022-04489-4 - DOI - PMC - PubMed
125. 1. Del Bufalo F, De Angelis B, Caruana I, Del Baldo G, De Ioris MA, Serra A, et al. . GD2-CART01 for relapsed or refractory high-risk neuroblastoma. N Engl J Med (2023) 388:1284–95. doi: 10.1056/NEJMoa2210859 - DOI - PubMed
126. 1. Cheung NK, Guo H, Hu J, Tassev DV, Cheung IY. Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo . Oncoimmunology (2012) 1:477–86. doi: 10.4161/onci.19864 - DOI - PMC - PubMed
127. 1. Walker AJ, Majzner RG, Zhang L, Wanhainen K, Long AH, Nguyen SM, et al. . Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol Ther (2017) 25:2189–201. doi: 10.1016/j.ymthe.2017.06.008 - DOI - PMC - PubMed
128. 1. Bishop DC, Clancy LE, Simms R, Burgess J, Mathew G, Moezzi L, et al. . Development of CAR T-cell lymphoma in 2 of 10 patients effectively treated with piggyBac-modified CD19 CAR T cells. Blood (2021) 138:1504–9. doi: 10.1182/blood.2021010813 - DOI - PubMed
129. 1. Micklethwaite KP, Gowrishankar K, Gloss BS, Li Z, Street JA, Moezzi L, et al. . Investigation of product-derived lymphoma following infusion of piggyBac-modified CD19 chimeric antigen receptor T cells. Blood (2021) 138:1391–405. doi: 10.1182/blood.2021010858 - DOI - PMC - PubMed
130. 1. Straathof KC, Pule MA, Yotnda P, Dotti G, Vanin EF, Brenner MK, et al. . An inducible caspase 9 safety switch for T-cell therapy. Blood (2005) 105:4247–54. doi: 10.1182/blood-2004-11-4564 - DOI - PMC - PubMed
131. 1. Iuliucci JD, Oliver SD, Morley S, Ward C, Ward J, Dalgarno D, et al. . Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers. J Clin Pharmacol (2001) 41:870–9. doi: 10.1177/00912700122010771 - DOI - PubMed
132. 1. Foster MC, Savoldo B, Lau W, Rubinos C, Grover N, Armistead P, et al. . Utility of a safety switch to abrogate CD19.CAR T-cell-associated neurotoxicity. Blood (2021) 137:3306–9. doi: 10.1182/blood.2021010784 - DOI - PMC - PubMed
133. 1. Stavrou M, Philip B, Traynor-White C, Davis CG, Onuoha S, Cordoba S, et al. . A rapamycin-activated caspase 9-based suicide gene. Mol Ther (2018) 26:1266–76. doi: 10.1016/j.ymthe.2018.03.001 - DOI - PMC - PubMed
134. 1. Griffioen M, Van Egmond EH, Kester MG, Willemze R, Falkenburg JH, Heemskerk MH. Retroviral transfer of human CD20 as a suicide gene for adoptive T-cell therapy. Haematologica (2009) 94:1316–20. doi: 10.3324/haematol.2008.001677 - DOI - PMC - PubMed
135. 1. Tasian SK, Kenderian SS, Shen F, Li Y, Ruella M, Fix WC, et al. . Efficient termination of CD123-redirected chimeric antigen receptor T cells for acute myeloid leukemia to mitigate toxicity. Blood (2015) 126:565. doi: 10.1182/blood.V126.23.565.565 - DOI
136. 1. Valton J, Guyot V, Boldajipour B, Sommer C, Pertel T, Juillerat A, et al. . A versatile safeguard for chimeric antigen receptor T-cell immunotherapies. Sci Rep (2018) 8:8972. doi: 10.1038/s41598-018-27264-w - DOI - PMC - PubMed
137. 1. Sommer C, Boldajipour B, Kuo TC, Bentley T, Sutton J, Chen A, et al. . Preclinical evaluation of allogeneic CAR T cells targeting BCMA for the treatment of multiple myeloma. Mol Ther (2019) 27:1126–38. doi: 10.1016/j.ymthe.2019.04.001 - DOI - PMC - PubMed
138. 1. Wu CY, Roybal KT, Puchner EM, Onuffer J, Lim WA. Remote control of therapeutic T cells through a small molecule-gated chimeric receptor. Science (2015) 350:aab4077. doi: 10.1126/science.aab4077 - DOI - PMC - PubMed
139. 1. Foster AE, Duong M, Lu A, Chang P, Mahendravada A, Shinners N, et al. . Inducible MyD88/CD40 (iMC) costimulation provides ligand-dependent tumor eradication by CD123-specific chimeric antigen receptor T cells. Blood (2016) 128:4551. doi: 10.1182/blood.V128.22.4551.4551 - DOI
140. 1. Labanieh L, Majzner RG, Klysz D, Sotillo E, Fisher CJ, Vilches-Moure JG, et al. . Enhanced safety and efficacy of protease-regulated CAR-T cell receptors. . Cell (2022) 185:1745–1763.e1722. doi: 10.1016/j.cell.2022.03.041 - DOI - PMC - PubMed
141. 1. Li HS, Israni DV, Gagnon KA, Gan KA, Raymond MH, Sander JD, et al. . Multidimensional control of therapeutic human cell function with synthetic gene circuits. Science (2022) 378:1227–34. doi: 10.1126/science.ade0156 - DOI - PMC - PubMed
142. 1. Mestermann K, Giavridis T, Weber J, Rydzek J, Frenz S, Nerreter T, et al. . The tyrosine kinase inhibitor dasatinib acts as a pharmacologic on/off switch for CAR T cells. Sci Transl Med (2019) 11(499):eaau5907. doi: 10.1126/scitranslmed.aau5907 - DOI - PMC - PubMed
143. 1. Weber EW, Lynn RC, Sotillo E, Lattin J, Xu P, Mackall CL. Pharmacologic control of CAR-T cell function using dasatinib. Blood Adv (2019) 3:711–7. doi: 10.1182/bloodadvances.2018028720 - DOI - PMC - PubMed
144. 1. Mitsuyasu RT, Anton PA, Deeks SG, Scadden DT, Connick E, Downs MT, et al. . Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects. Blood (2000) 96:785–93. doi: 10.1182/blood.V96.3.785.015k10_785_793 - DOI - PubMed
145. 1. Scholler J, Brady TL, Binder-Scholl G, Hwang WT, Plesa G, Hege KM, et al. . Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med (2012) 4:132ra153. doi: 10.1126/scitranslmed.3003761 - DOI - PMC - PubMed
146. 1. Aghajanian H, Kimura T, Rurik JG, Hancock AS, Leibowitz MS, Li L, et al. . Targeting cardiac fibrosis with engineered T cells. Nature (2019) 573:430–3. doi: 10.1038/s41586-019-1546-z - DOI - PMC - PubMed
147. 1. Amor C, Feucht J, Leibold J, Ho YJ, Zhu C, Alonso-Curbelo D, et al. . Senolytic CAR T cells reverse senescence-associated pathologies. Nature (2020) 583:127–32. doi: 10.1038/s41586-020-2403-9 - DOI - PMC - PubMed
148. 1. Seif M, Einsele H, Loffler J. CAR T cells beyond cancer: hope for immunomodulatory therapy of infectious diseases. Front Immunol (2019) 10:2711. doi: 10.3389/fimmu.2019.02711 - DOI - PMC - PubMed
149. 1. Heczey A, Courtney AN, Montalbano A, Robinson S, Liu K, Li M, et al. . Anti-GD2 CAR-NKT cellsin patients with relapsed or refractory neuroblastoma: an interim analysis. Nat Med (2020) 26:1686–90. doi: 10.1038/s41591-020-1074-2 - DOI - PubMed
150. 1. Wang S, Yang Y, Ma P, Zha Y, Zhang J, Lei A, et al. . CAR-macrophage: an extensive immune enhancer to fight cancer. EBioMedicine (2022) 76:103873. doi: 10.1016/j.ebiom.2022.103873 - DOI - PMC - PubMed
151. 1. Chang Y, Syahirah R, Wang X, Jin G, Torregrosa-Allen S, Elzey BD, et al. . Engineering chimeric antigen receptor neutrophils from human pluripotent stem cells for targeted cancer immunotherapy. Cell Rep (2022) 40:111128. doi: 10.1016/j.celrep.2022.111128 - DOI - PMC - PubMed
152. 1. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. . Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med (2020) 382:545–53. doi: 10.1056/NEJMoa1910607 - DOI - PMC - PubMed
153. 1. Baulu E, Gardet C, Chuvin N, Depil S. TCR-engineered T cell therapy in solid tumors: state of the art and perspectives. Sci Adv (2023) 9:eadf3700. doi: 10.1126/sciadv.adf3700 - DOI - PMC - PubMed
154. 1. Hwang MS, Miller MS, Thirawatananond P, Douglass J, Wright KM, Hsiue EH, et al. . Structural engineering of chimeric antigen receptors targeting HLA-restricted neoantigens. Nat Commun (2021) 12:5271. doi: 10.1038/s41467-021-25605-4 - DOI - PMC - PubMed

Publication types

• Review
• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't