Potential strategies against resistance to CAR T-cell therapy in haematological malignancies

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is a rapidly developing method for adoptive immunotherapy of tumours in recent years. CAR T-cell therapies have demonstrated unprecedented efficacy in the treatment of patients with haematological malignancies. A 90% complete response (CR) rate has been reported in patients with advanced relapse or refractory acute lymphoblastic leukaemia, while >50% CR rates have been reported in cases of chronic lymphocytic leukaemia and partial B-cell lymphoma. Despite the high CR rates, a subset of the patients with complete remission still relapse. The mechanism of development of resistance is not clearly understood. Some patients have been reported to demonstrate antigen-positive relapse, whereas others show antigen-negative relapses. Patients who relapse following CAR T-cell therapy, have very poor prognosis and novel approaches to overcome resistance are required urgently. Herein, we have reviewed current literature and research that have investigated the strategies to overcome resistance to CAR T-cell therapy.

Keywords: CAR T-cell therapy; drug resistance; haematological malignancies.

Figure 1.

Schematic representation of CAR structure. CAR T cells are composed of three parts: (1) an scFv, (2) a transmembrane domain, and (3) a signal transduction domain of the TCR. First-generation CARs used a CD3ζ as the signal transduction domain of the TCR, whereas second-generation CARs include additional co-stimulatory signaling domains (CD28 or 4-1BB). Third-generation CARs consist of two distinct co-stimulatory domains, such as both CD28 and 4-1BB. Fourth-generation CARs are additionally armored with genes that enable, for example, the expression of cytokines. CAR, chimeric antigen receptor; scFv, single-chain variable domain of an antibody; TCR, T-cell receptor.

Figure 2.

Mechanisms of resistance to CAR-T cell therapy. (A) Lentiviral modification of a single leukemic cell allowed for joint CAR19 and CD19 expression on their cell surface, effectively masking the CD19 epitope from CAR T cells. (B) Tumour cells can switch to a genetically related but phenotypically different disease. (C) Tumour cells, through genetic mutations, can either completely lose CD19 receptor expression or modify the CD19 receptor that lack the extracellular epitopes recognised by CAR T cells. (D) Tumour cells downregulate the surface target antigen to levels below those needed for CAR T cells activation. CAR, chimeric antigen receptor.

Figure 3.

Targeting more than one antigen receptor approaches. (A) Coadministration-producing two separate CAR-T cell products and infusing together or sequentially. (B) Bicistronic CAR-using a single vector that encodes two or three different CARs on a single T cell. (C) Tandem CAR-encoding two CARs on same chimeric protein using a single vector. CAR, chimeric antigen receptor.