Basic StudyCAIX-specific CAR-T Cells and Sunitinib Show Synergistic Effects Against Metastatic Renal Cancer ModelsLi, Huizhong*,†; Ding, Jiage*,†; Lu, Mengmeng*,†; Liu, Hongyan*,†,‡; Miao, Yangna*,†; Li, Liantao*,†; Wang, Gang*,†; Zheng, Junnian*,†; Pei, Dongsheng§; Zhang, Qing*,†Author Information *Cancer Institute, Xuzhou Medical University †Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University §Department of Pathology, Xuzhou Medical University, Xuzhou ‡The Second People’s Hospital of Lianyungang, Lianyungang, Jiangsu, People’s Republic of China H.L. and J.D. contributed equally. Reprints: Qing Zhang, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu 221002, People’s Republic of China (e-mail: firstname.lastname@example.org); Dongsheng Pei, Department of Pathology, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People’s Republic of China (e-mail: email@example.com); and Junnian Zheng, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, 221002, People’s Republic of China (e-mail: firstname.lastname@example.org). Received January 10, 2019 Accepted August 26, 2019 Online date: September 30, 2019 Journal of Immunotherapy: January 2020 - Volume 43 - Issue 1 - p 16-28 doi: 10.1097/CJI.0000000000000301 Buy Metrics 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. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.