Chimeric antigen receptor-T cell therapy for T cell-derived hematological malignancies

Abstract

Relapsed/refractory T cell-derived malignancies present with high heterogeneity and poor prognoses. Recently, chimeric antigen receptor (CAR)-T cell therapy has shown remarkable safety and efficacy in the treatment of B cell-derived malignancies. However, the treatment of CAR-T cells in T cell-derived malignancies has more limitations, such as fratricide, T cell aplasia, and tumor contamination, mainly because of the similarity between normal and malignant T cells. Pan-T antigen CAR-T cells (such as CD5 and CD7 targets), the most widely used CAR-T cells in clinical trials, can cover almost all T cell-derived malignant cells but can also induce severe killing of CAR-T cells and normal T cells. Compared to autologous sources of CAR-T cells, allogeneic CAR-T cells can prevent tumor contamination and become universal products by gene-editing. However, none of these CAR-T cells could completely prevent immune deficiency and disease relapse after T-targeted CAR-T cell therapy. In this review, we summarize the current challenges of CAR-T cell therapy for T cell-derived malignancies in clinical practice and potential strategies to address these limitations.

Keywords: Allogeneic CAR-T cells; Autologous CAR-T cells; CAR-T cell therapy; Clinical trials; Fratricide; HSCT; T cell aplasia; T cell malignancies.

Fig. 1

Challenges of CAR-T cell therapy for T cell-derived malignancies. A: Fratricide is caused by recognizing target antigens on other CAR-T cells, and can result in the poor expansion of CAR-T cells in vitro culture. B: The recognition of target antigens on the surface of normal T cells and subsequent killing can lead to T cell aplasia. C: For autologous CAR-T cells, CAR molecules can also be transfected to the contaminated tumor cells, which may cause antigen escape

Fig. 2

Different target antigens of T cell-derived malignancies for CAR-T cell therapy. CAR-T cells can recognize their target antigens (such as CD5, CD7, CD4, TRBC1) on the surface of tumor cells and then kill tumor cells through secreting granzymes, perforin, IFN-γ, and so on

Fig. 3

Strategies for universal CAR-T cell manufacturing. A: Knocking out target antigens (such as CD7) through CRISPR/Cas9 or base editing in CAR-T cells can prevent fratricide maximally. B, C: Knocking out TCR/CD3 may alleviate GvHD, while knocking out HLA molecules or CD52 may alleviate HvG. D: To enhance function of CAR-T cells, knocking out inhibitory molecules (like PD-1, CTLA-4, and TIM-3) may be useful

Fig. 4

Complications of CAR-T cell therapy for T cell-derived malignancies. The common complications of various CAR-T cells include CRS, ICANS, GvHD, insertional mutagenesis, and second tumor. There are some complications that are specific for T-targeted CAR-T cell therapy, like opportunistic infections caused by T cel aplasia (such as EBV and CMV reactivation), persistent cytopenia caused by myelosuppression, and target antigen-negative relapse (such as CD7-negative relapse)