Resistance against anti-CD19 and anti-BCMA CAR T cells: Recent advances and coping strategies

Abstract

Chimeric antigen receptor T (CAR T) cell therapy is a new treatment paradigm that has revolutionized the treatment of CD19-positive B cell malignancies and BCMA-positive plasma cell malignancies. The response rates are highly impressive in comparison to historical cohorts, but the responses are not durable. The most recent results from pivotal trials show that current CAR T cell products fail to demonstrate optimal long-term disease control. Resistance to CAR T cells is related to CAR structure, T cell factors, tumor factors and the immunosuppressive microenvironment. Novel strategies are needed following failure with CAR T cell treatment. In this review, we discuss the resistance mechanisms to CAR T cell treatment according to disease and the emerging strategies to overcome resistance.

Keywords: BCMA; CD19; Chimeric antigen receptor T cells; Immunotherapy; Resistance.

Graphical abstract

Fig. 1

Resistance mechanisms of CD19 CAR T cells. A. Murine scFV is an immunogeneic epitope B. Different spacer and transmembrane domains effect CAR T cell efficacy. Costimulation domains regulate persistence and exhaustion C. Tonic signaling can limit the power of CAR T cells. D. T cell characteristics may effect the clinical response (T cell phenotype, T cell aging, T cell exhaustion). E. In antigen negative relapses loss of antigen, splicing variations, lineage swiching, trogocytosis are important mechanisms. F. Tumors may be lack of pro-apoptotic molecules.