Chimeric Antigen Receptor (CAR) T Cells: Lessons Learned from Targeting of CD19 in B-Cell Malignancies

Abstract

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.

Fig. 1

Chimeric antigen receptor (CAR) design. A first generation CAR incorporates a CD19-specific single chain variable fragment (scFv) fused through linker sequences to CD3ζ. When introduced into a T cell by genetic modification, the CAR allows redirection of T cell specificity to CD19. Second and third generation CARs incorporate additional costimulatory domains.

Fig. 2

Timeline of a typical course for a patient undergoing CAR-T cell immunotherapy. After leukapheresis to isolate T cells, CAR manufacturing takes approximately 1–3 weeks. The patient usually receives lymphodepletion chemotherapy shortly before CAR-T infusion. Over 1–3 weeks after infusion the CAR-T cells proliferate in vivo (red line) then contract, leaving a fraction of persistent CAR-T cells. Patients are closely monitored for cytokine release syndrome (CRS) and neurotoxicity during the first 3–4 weeks after infusion.