Relapse after CAR-T cell therapy in B-cell malignancies: challenges and future approaches

Abstract

Chimeric antigen receptor-T (CAR-T) cell therapy, as a novel cellular immunotherapy, has dramatically reshaped the landscape of cancer treatment, especially in hematological malignancies. However, relapse is still one of the most troublesome obstacles to achieving broad clinical application. The intrinsic factors and superior adaptability of tumor cells mark a fundamental aspect of relapse. The unique biological function of CAR-T cells governed by their special CAR construction also affects treatment efficacy. Moreover, complex cross-interactions among CAR-T cells, tumor cells, and the tumor microenvironment (TME) profoundly influence clinical outcomes concerning CAR-T cell function and persistence. Therefore, in this review, based on the most recent discoveries, we focus on the challenges of relapse after CAR-T cell therapy in B-cell malignancies from the perspective of tumor cells, CAR-T cells, and the TME. We also discuss the corresponding basic and clinical approaches that may overcome the problem in the future. We aim to provide a comprehensive understanding for scientists and physicians that will help improve research and clinical practice.

Keywords: B-cell malignancies; Chimeric antigen receptor-T (CAR-T); Mechanisms of relapse; Strategy.

Fig. 1. Landscape behind relapse after CAR-T cell therapy. The tumor cells, CAR-T cells, and the tumor microenvironment can each affect relapse after CAR-T cell therapy. CAR-T: chimeric antigen receptor-T. Created with BioRender.com.

Fig. 2. Mechanisms of CD19 antigen escape during relapse after CAR-T cell therapy. (a) Nonsense mutation with loss-of-heterozygosity CD19 expression; (b) Missense mutation produces CD19 with altered epitope; (c) Alternative splicing produces alternative CD19 isoform. CD19: cluster of differentiation 19. Created with BioRender.com.

Fig. 3. Treatment strategies for relapse after CAR-T cell therapy. 1: sequential infusion of CAR-T cells with different targets; 2: application of bispecific CAR-T cells produced by transduction of a co-transduction or bicistronic vector; 3: application of tandem CAR-T cells produced by transduction of a tandem vector. CAR-T: chimeric antigen receptor-T. Created with BioRender.com.

Fig. 4. Combinational treatment strategies indicated in relapse after CAR-T cell therapy. 1: CAR-T cells with self-secreting ICB, such as anti-PD-1 scFv; 2: CAR-T cells with self-secreting cytokines, such as IL-7, IL-12, IL-15, and CCL19; 3: CAR-T cells with intrinsic PD-1 knockout; 4: the application of small-molecule drugs to enhance CAR-T cell functions; 5: antagonist effect of plerixafor on CXCR4 to inhibit tumor cell homing. CAR-T: chimeric antigen receptor-T; PD-1: programmed cell death protein-1; BET: bromodomain and extra-terminal; ICB: immune checkpoint blockade; Treg: regulatory T cell; TAM: tumor-associated macrophage; MDSC: myeloid-derived suppressor cell; MSC: mesenchymal stem cell; scFv: single-chain variable fragment; IL: interleukin; CCL19: C-C motif chemokine ligand 19; CXCR4: CXC chemokine receptor 4. Created with BioRender.com.