Relapse Mechanism and Treatment Strategy After Chimeric Antigen Receptor T-Cell Therapy in Treating B-Cell Hematological Malignancies

Abstract

Over the past few decades, immunotherapy has revolutionized the modern medical oncology field. Chimeric antigen receptor (CAR)-T cell therapy has a promising curative effect in the treatment of hematological malignancies. Anti-CD19 CAR-T cells are the most mature CAR-T cells recently studied and in recent years it has achieved a complete remission rate of approximately 90% in the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Although CAR-T cell therapy has greatly alleviated the disease in patients with leukemia or lymphoma, some of them still relapse after treatment. Therefore, in this article, we discuss the factors that may contribute to disease relapse following CAR-T cell therapy and summarize potential strategies to overcome these obstacles, thus providing the possibility of improving standard treatment regimens.

Keywords: B-ALL; CAR-t; CD19; antigen escape; hematological malignancies; relapse.

Figure 1.

Chimeric antigen receptors (CARs) can be divided into 4 generations based on their structure. The first generation of CAR structures contain only antigen-recognition signals. The second- and third-generation CARs have 1 and 2 co-stimulatory molecules added respectively in the signal transduction region to improve T-cell proliferation activity, and cytotoxicity, and prolong T-cell survival time. The fourth-generation CAR inserts additional molecular elements into the CAR to express functional transgenic proteins, such as secreted cytokines, suicide genes, and regulatory switches, to improve the effectiveness and safety of CAR-T cells.

Figure 2.

Mechanism of antigen escape after chimeric antigen receptor (CAR)-T cell therapy. (a) CAR-T cells recognize and bind tumor-specific antigens to exert antitumor activity. (b) Reduced antigen density leads to antigen escape. (c) CAR mutation or alternative splicing, CAR-T cells cannot bind antigen. (d) The tumor surface antigen undergoes a lineage switch, and CD19 cannot bind to CAR-T cells. (e) For some reason, CAR metastasizes to the surface of tumor cells and binds to CD19 to mask its epitope, and CAR-T cells cannot attack the tumor.

Figure 3.

Schematic drawings of 3 dual-target CAR-T structures. (a) Sequential infusion of CAR-T cells targeting 2 different antigens. (b) CARs of bicistronic CAR-T cells are expressed independently. (c) Tandem CAR has 2 independent scFv fragments, but shares the same co-stimulatory molecules and signaling domains.