Adoptive chimeric antigen receptor-modified T or NK cells (CAR-T or CAR-NK) offer new options for cancer treatment. CAR-T therapy has achieved encouraging breakthroughs in the treatment of hematological malignancies. However, their therapeutic efficacy against solid tumors is limited. New regimens, including combinations with chemical drugs, need to be studied to enhance the therapeutic efficacy of CAR-T or NK cells for solid tumors. An epithelial cell adhesion molecule- (EpCAM-) specific second-generation CAR was constructed and transduced into NK-92 cells by lentiviral vectors. Immune effects, including cytokine release and cytotoxicity of the CAR-NK-92 cells against EpCAM-positive colon cancer cells, were evaluated in vitro. Synergistic effects of regorafenib and CAR-NK-92 cells were analyzed in a mouse model with human colorectal cancer xenografts. The CAR-NK-92 cells can specifically recognize EpCAM-positive colorectal cancer cells and release cytokines, including IFN-γ, perforin, and granzyme B, and show specific cytotoxicity in vitro. The growth suppression efficacy of combination therapy with regorafenib and CAR-NK-92 cells on established EpCAM-positive tumor xenografts was more significant than that of monotherapy with CAR-NK-92 cells or regorafenib. Our results provided a novel strategy to treat colorectal cancer and enhance the therapeutic efficacy of CAR-modified immune effector cells for solid tumors.

Treatment with chimeric antigen receptor-modified T cell (CAR-T) has demonstrated promising therapeutic efficacy in hematologic malignancies. However, the therapeutic efficacy is still very limited for solid tumors. An immunosuppressive microenvironment is one of the main reasons for the limited efficacy. Some chemotherapeutic agents exhibit immune microenvironment modulation. Therefore, combination with chemotherapeutic agents may be one of the promising strategies to enhance the therapeutic efficacy of CAR-T against solid tumors. Sunitinib modulates the antitumor immune response by improving T-cell infiltration and function while reducing immunosuppressive factors. The authors constructed a second-generation CAR targeting human renal cell carcinoma (RCC)-specific antigen carbonic anhydrase IX (CAIX) with the costimulatory domain of 4-1BB. The results of cytokine releasing and cell killing assays showed that the CAIX-CAR-T cells have specific effector functions against CAIX+ renal cancer cells in vitro. Combination therapy with CAIX-CAR-T and sunitinib showed synergistic efficacy against a mouse lung metastasis model of human RCC. CAIX-CAR-T cells in the mice of the combination therapy group showed stronger proliferation and tumor infiltration than that in the mice of the CAIX-CAR-T monotherapy group. The possible mechanisms of the synergistic efficacy are: (1) sunitinib caused upregulation of CAIX in tumor cells; (2) sunitinib decreased frequency of myeloid-derived suppressor cells in the tumor microenvironment. Our study supplied an innovative immunotherapeutic approach whereby combining CAIX-CAR-T with sunitinib induces a potent antitumor response in an experimental model of metastatic RCC. The combination strategy should be considered as a potential approach to augment adoptive CAR-T cell immunotherapy.

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 CART cells with chemical drugs, must be studied to enhance the therapeutic efficacy of CART 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-γ, 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.

Tumor DNA vaccine as an effective therapeutic approach can induce systemic immunity against malignant tumors, but its therapeutic effect is still not satisfactory in advanced renal cancer. Herein, a novel DNA vaccine containing dual antigens of fibrinogen-like protein 1 (FGL1) and carbonic anhydrase IX (CAIX) was developed and intramuscularly delivered by PLGA/PEI nanoparticles for renal cancer therapy. Compared with PLGA/PEI-pCAIX immunization, PLGA/PEI-pFGL1/pCAIX co-immunization significantly inhibited the subcutaneous tumor growth and promoted the differentiation and maturation of CD11c + DCs and CD11c + CD11b + DCs subset. Likewise, the increased capabilities of CD8 T cell proliferation, CTL responses, and multi-functional CD8 + T cell immune responses were observed in PLGA/PEI-pFGL1/pCAIX vaccine group. Interestingly, depletion of CD8 + T cells by using CD8 mAb resulted in a loss of anti-tumor function of PLGA/PEI-pFGL1/pCAIX vaccine, suggesting that the anti-tumor activity of the vaccine was dependent on CD8 + T cell immune responses. Furthermore, PLGA/PEI-pFGL1/pCAIX co-immunization also suppressed the lung metastasis of tumor mice by enhancing the multi-functional CD8 + T cell responses. Therefore, these results indicate that PLGA/PEI-pFGL1/pCAIX vaccine could provide an effective protective effect for renal cancer by enhanced DC-mediated multi-functional CD8 + T cell immune responses. This vaccine strategy offers a potential approach for solid or metastatic tumor treatment.

No abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

No abstract

No abstract