Lenalidomide overcomes the resistance to third-generation CD19-CAR-T cell therapy in preclinical models of diffuse large B-cell lymphoma

Chimeric antigen receptor (CAR)-T cells against CD19 have been proven to be effective in treating B-cell hematological malignancies. However, the efficacy of this promising therapy is limited by many factors. In this study, the germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) cell line OCI-Ly1, and patient-derived xenografted (PDX) mice (CY-DLBCL) were used as the CAR-T cell-resistant model. Meanwhile, the activated B-cell-like (ABC) DLBCL cell line OCI-Ly3 and PDX mice (ZML-DLBCL) were defined as the CAR-T sensitive model. The enhancement of CAR-T cell function by lenalidomide (LEN) was examined in vitro and in vivo. Lenalidomide effectively enhanced the function of third-generation CD19-CAR-T cells by polarizing CD8+ CAR-T cells to CD8 early-differentiated stage and Th1 type, reducing CAR-T cell exhaustion and improving cell expansion. It was further demonstrated that CAR-T cells combined with LEN substantially reduce the tumor burden and prolong the survival time in various DLBCL mouse models. LEN was also found to promote the infiltration of CD19-CAR-T cells into the tumor site by modulating the tumor microenvironment. In summary, the results of the present study suggest that LEN can improve the function of CD19-CAR-T cells, providing a basis for clinical trials using this combination therapy against DLBCL.