Current Status of CAR T Cell Therapy for Leukemias

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has become the standard of care for children and young adults with relapsed and refractory B-cell acute lymphoblastic leukemia (B-ALL), and it is a highly promising therapy under investigation for adults with relapsed disease. Despite having potentially life-threatening toxicities, such as cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, the benefits of CAR T-cell therapy far outweigh these risks, particularly as increased experience and improved supportive care measures are mitigating these toxicities. CAR T cells can result in complete remission for significant proportion of patients with relapsed and refractory B-ALL and permit them to proceed to potentially curative allogeneic hematopoietic stem cell transplantation (allo-HSCT). CAR T cells may also be curative by themselves. Herein lie the greatest challenges and questions for clinical investigators, specifically, how are CAR T cells best employed and how do we overcome mechanisms of resistance to them? The primary clinical question is the timing and even the necessity of allo-HSCT. Relative to resistance, we know that target antigen loss, specifically CD19, is a major contributor to resistance. However, current investigations of alternative targets, such CD22, and CAR T cells expressing dual targeting antigen receptors have demonstrated encouraging initial results and provide a high degree of optimism that the efficacy and the broader application of CAR T-cell therapy will gradually increase in B-ALL. That optimism is not as high and the challenges are increased for the application of CAR T cells in T-cell leukemias and acute myeloid leukemia due to the relative lack of suitable leukemia surface targets that are not also expressed on normal hematopoietic progenitors. Despite these significant challenges, considerable research is being conducted into the development of CAR T cells for these diseases utilizing unique technologies, which may be applicable to other diseases.

Keywords: Acute lymphoblastic leukemia; CAR T cells; Immunotherapy; Leukemia; Mechanisms of resistance; Toxicities.