Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies
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Adoptive immunotherapy with chimeric antigen receptor-modified (CAR)-T cells is a rapidly growing therapeutic approach to treating patients with refractory cancer, with over 100 clinical trials in various malignancies in progress. The enthusiasm for CAR-T cells has been driven by the clinical success of CD19-targeted CAR-T cell therapy in B-cell acute lymphoblastic leukemia, and the promising data in B-cell non-Hodgkin’s lymphoma and chronic lymphocytic leukemia. Despite the success of targeting CD19 with CAR-T cells in early clinical studies, many challenges remain to improve outcomes, reduce toxicity, and determine the appropriate settings for CAR-T cell immunotherapy. Reviewing the lessons learned thus far in CD19 CAR-T cell trials and how some of these challenges may be overcome will help guide the development of CAR-T cell therapy for malignancies of B-cell origin, as well as for other hematopoietic and non-hematopoietic cancers.
KeywordsChronic Lymphocytic Leukemia Overall Response Rate Chimeric Antigen Receptor Chronic Lymphocytic Leukemia Patient Memorial Sloan Kettering Cancer Center
Compliance with Ethical Standards
KAH is supported by the University of British Columbia, Clinical Investigator Program Fellowship.
Conflict of interest
KAH declares no conflict of interest. CJT receives research funding from Juno Therapeutics and has received payment for participation on advisory boards and for speaking at educational events. CJT has patents pending related to CAR-T cells.
- 5.Jensen MC, Popplewell L, Cooper LJ, DiGiusto D, Kalos M, Ostberg JR, Forman SJ. Antitransgene rejection responses contribute to attenuated persistence of adoptively transferred CD20/CD19-specific chimeric antigen receptor redirected T cells in humans. Biol Blood Marrow Transpl. 2010;16:1245–56.CrossRefGoogle Scholar
- 21.Park JH, Riviere I, Wang X, Purdon T, Sadelain M, Brentjens RJ. Impact of disease burden on long-term outcome of 19-28z CAR modified T cells in adult patients with relapsed B-ALL. J Clin Oncol. 2016;34:7003 (suppl–abstr).Google Scholar
- 25.Brudno JN, Somerville R, Shi V, et al. Allogeneic T-cells expressing an anti-CD19 chimeric antigen receptor cause remissions of B-Cell malignancies after allogeneic hematopoietic stem cell transplantation without causing graft-versus-host disease. Blood. 2015;126:99.Google Scholar
- 26.Brudno JN, Somerville RPT, Shi V, 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. Clin Oncol. 2016;34:1112–21.CrossRefGoogle Scholar
- 27.Maude SL, Teachey DT, Rheingold SR, et al. Sustained remissions with CD19-specific chimeric antigen receptor (CAR)-modified T cells in children with relapsed/refractory ALL. J Clin Oncol. 2016;34:3011 (suppl–abstr).Google Scholar
- 28.Frey NV, Shaw PA, Hexner EO, et al. Optimizing chimeric antigen receptor (CAR) T cell therapy for adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL). J Clin Oncol. 2016;34:7002 (suppl–abstr).Google Scholar
- 31.Kochenderfer J, Somerville R, Lu T, et al. Anti-CD19 chimeric antigen receptor T cells preceded by low-dose chemotherapy to induce remissions of advanced lymphoma. J Clin Oncol. 2016;34:LBA3010 (suppl–abstr).Google Scholar
- 32.Schuster SJ, Svoboda J, Dwivedy Nasta S, et al. Sustained remissions following chimeric antigen receptor modified t cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood. 2015;126:183.Google Scholar
- 33.Porter DL, Frey NV, Melenhorst JJ, et al. Randomized, phase II dose optimization study of chimeric antigen receptor (CAR) modified T cells directed against CD19 in patients (pts) with relapsed, refractory (R/R) CLL. J Clin Oncol. 2016;34:3009 (suppl–abstr).Google Scholar
- 35.Turtle CJ, Hanafi L-A, Berger C, et al. Rate of durable complete response in ALL, NHL, and CLL after immunotherapy with optimized lymphodepletion and defined composition of CD19 CAR-T cells. J Clin Oncol. 2016;34:102 (suppl–abstr).Google Scholar
- 40.Gargett T, Yu W, Dotti G, Yvon ES, Christo SN, Hayball JD, Lewis ID, Brenner MK, Brown MP. GD2-specific CAR T cells undergo potent activation and deletion following antigen encounter but can be protected from activation-induced cell death by PD-1 blockade. Mol Ther. 2016;24:1135–49.CrossRefPubMedGoogle Scholar