Combination strategies to optimize the efficacy of chimeric antigen receptor T cell therapy in haematological malignancies

Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the therapeutic landscape of haematological malignancies. However, resistance and relapse remain prominent limitations, and they are related to the limited persistence and efficacy of CAR T cells, downregulation or loss of tumour antigens, intrinsic resistance of tumours to death signalling, and immune suppressive microenvironment. Rational combined modality treatments are regarded as a promising strategy to further unlock the antitumor potential of CAR T cell therapy, which can be applied before CAR T cell infusion as a conditioning regimen or in ex vivo culture settings as well as concomitant with or after CAR T cell infusion. In this review, we summarize the combinatorial strategies, including chemotherapy, radiotherapy, haematopoietic stem cell transplantation, targeted therapies and other immunotherapies, in an effort to further enhance the effectiveness of this impressive therapy and benefit more patients.

Keywords: CAR T cell; chemotherapy; combination therapy; haematological stem cell transplantation; radiotherapy; relapse; resistance; targeted therapy.

Figure 1

Challenges of efficacy of CAR T cell therapy. Limited efficacy of CAR T cell therapy in haematological malignancies can be attributed to poor persistence of CAR T cells, antigen modulation and intrinsic resistance to death signalling of tumour cells and immunosuppressive microenvironment.

Figure 2

Mechanisms of combination strategies with CAR T cell therapy. The combined agents mainly focus on three aspects to optimize antitumor effects, including tumour cells, CAR T cells and the TME. For CAR T cells, attention is given to targeting different pathways to prevent terminal differentiation and exhaustion. In addition, inhibition of the Fas pathway prevents AICD, the other mechanism to prolong CAR T cell survival. For tumour cells, combined therapies are expected to both directly inhibit tumour survival and boost the cytotoxicity of CAR T cells by sensitizing tumours to apoptotic signalling or upregulating antigen expression. Components of the inhibitory microenvironment are also emerging as promising targets to enhance the effectiveness of CAR T cell therapy. BCR, B cell receptor; sBCMA, soluble B cell maturation antigen; mAb, monoclonal antibody; BiTE, bispecific T cell engager; TCR, T cell receptor; ROS, reactive oxygen species.

Figure 3

HSCT in combination with CAR T cell therapy to enhance efficacy. (A) Standard-of-care CAR T cell therapy following consolidative allo-HSCT. (B) Concurrent infusion of allo-CAR T cells and allo-HSCT to enhance antitumor effects and prolong the persistence of allo-CAR T cells without additional gene editing against graft rejection. (C) Allo-HSCT following allo-CAR T cell therapy for MRD clearance. (D) High-dose chemotherapy conditioning and autologous stem cell transplantation to remodel the immune environment for subsequent CAR T cell therapy. allo-HSC, allogeneic haemopoietic stem cell.

Figure 4

Two combinations of CD19 and CD22 CAR T cell products as an example of combinations among different types of CAR T cells. (A) Cocktail infusion of CD19 and CD22 CAR T cells for addressing antigen-negative relapse. (B) Sequential infusion of CD19 and CD22 CAR T cells according to the in vivo activity of CAR T cells and patient status to overcome both short duration and antigen escape.