CAIX-specific CAR-T Cells and Sunitinib Show Synergistic Effects Against Metastatic Renal Cancer Models

Abstract

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.

Cancer Stem Cells—Origins and Biomarkers: Perspectives for Targeted Personalized Therapies

“…The combination of the multikinase inhibitor sunitinib and CAR T -cells targeting carbonic anhydrase IX (CAIX) has been shown to be of advantage as sunitinib reduces immunosuppressive components of the TME ( 596 ). Improvements could also be made using Her2-directed CAR NK-92-cells (92/5.137.z) in combination with apatinib ( 597 ).…”

“…Furthermore, cabozantinib is known to reduce tumor infiltration of immuno-modulatory subpopulations like regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) (594,595). The combination of the multikinase inhibitor sunitinib and CAR T -cells targeting carbonic anhydrase IX (CAIX) has been shown to be of advantage as sunitinib reduces immunosuppressive components of the TME (596). Improvements could also be made using Her2-directed CAR NK-92-cells (92/5.137.z) in combination with apatinib (597).…”

Immunotherapy in Renal Cell Carcinoma: The Future Is Now

“…CAR T cells are currently tested in renal cell carcinoma, targeting various antigens such as ROR2, AXL, CD70, VEGFR2, MET or CAIX, as seen in Table 3. Moreover, pre-clinical data suggest the rationale of combining CAR T cells with TKI or radiotherapy [69].…”

RCC Immune Microenvironment Subsequent to Targeted Therapy: A Friend or a Foe?

“…Adoptive transfer data (94) indicated that the combination of carbonic anhydrase IX (CAIX)-chimeric antigen receptor T cell (CAR-T) therapy and sunitinib defensed against lung metastasis of human RCC in a mouse model and improved the survival, but it increased the frequency of T cell infiltration in the TME. Another clinical study (95) showed that CAIX-CAR-T led to antigen-specific response and liver toxicity in patients with the 2 × 10 8 T cells as the lowest dose.…”

“…The result in their 12 patients with mRCC receiving CAR-T cells demonstrated that blockage of the antigenic target could decrease the toxicity and help patients tolerate higher doses. More importantly, the concept of CAR-T therapy may be expanded that targeted therapy synergizes the efficacy of CAR-T, where sunitinib could upregulate intratumoral CAIX and decrease MDSCs ( 94 ) in the TME.…”