Bortezomib improves adoptive carbonic anhydrase IX‑specific chimeric antigen receptor‑modified NK92 cell therapy in mouse models of human renal cell carcinoma.

Adoptive chimeric antigen receptor (CAR) T or NK cells offer new options for cancer treatment. Clinical results indicate that CAR-modified T cell (CAR-T) therapy has curative therapeutic efficacy for hematological malignancies. However, the efficacy of the therapy in most solid tumors, including advanced renal cell carcinoma (RCC), remains highly limited. New regimens, including combination of CAR-T cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. In the present study, a carbonic anhydrase IX (CAIX)-specific third-generation CAR was transduced into NK92 cells by lentiviral vectors. The immune effects, including cytokine release and cytotoxicity, of the CAR-NK92 cells against CAIX-positive RCC cells were evaluated in vitro. Combination therapeutic effects of bortezomib and CAR-NK92 cells were analyzed in a mouse model with human RCC xenografts. The results revealed that CAIX-specific CAR-NK92 cells specifically recognized in vitro cultured CAIX-positive RCC cells and released cytokines, including IFN-, perforin and granzyme B, and exhibited specific cytotoxicity. The cytotoxicity of the CAR-NK92 cells was enhanced after treating RCC cells with bortezomib in vitro. The suppressive efficacy of bortezomib combined with CAR-NK92 cells against established CAIX-positive tumor xenografts was more significant than that of the monotherapy with either CAR-NK92 cells or bortezomib. Therefore, bortezomib can enhance the effects of the CAR-NK92 cells against RCC in vitro and in vivo. This study provided an experimental basis for the novel clinical regimen of CAIX-specific CAR-modified NK or T cells for the treatment of RCC.