2. Academic Validation
  3. Cabozantinib enhances CAIX specific CAR-T cells against renal cancer by improving effector functions and augmenting tumor immune microenvironment

Cabozantinib enhances CAIX specific CAR-T cells against renal cancer by improving effector functions and augmenting tumor immune microenvironment

  • Biochem Biophys Res Commun. 2024 Nov 19:734:150781. doi: 10.1016/j.bbrc.2024.150781.
Qihong Li 1,  Lin Yang 2,  Shuyu Li 3,  Wanxin Zhao 3,  Ying Xue 3,  Zhuyu Lu 4,  Jingwei Tang 3,  Xiaoge Gao 1,  Junnian Zheng 5,  Qing Zhang 6,  Shishuo Sun 7
Affiliations

Affiliations

  • 1 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
  • 2 General Surgery Department, Xuzhou Mine Hospital, Xuzhou, Jiangsu, PR China.
  • 3 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
  • 4 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
  • 5 Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
  • 6 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China. Electronic address: qingzhang@xzhmu.edu.cn.
  • 7 Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China; Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, PR China. Electronic address: sssun@xzhmu.edu.cn.
PMID: 39368372 DOI: 10.1016/j.bbrc.2024.150781
Abstract

Despite demonstrating promising outcomes in treating hematologic malignancies, the efficacy of chimeric antigen receptor-modified T (CAR-T) cell therapy remains limited when applied to solid tumors due to tumor immune microenvironment (TIME). Strategies to augment CAR-T cell efficacy against solid tumors have been investigated by ameliorating TIME to a certain extent. In this study, Cabozantinib was utilized in combination with CAR-T cells targeting Carbonic Anhydrase IX (CAIX) for the treatment of renal Cancer. Our findings indicate that combination therapy with CAIX-CAR-T and Cabozantinib demonstrated synergistic efficacy against an orthotopic xenograft tumor model and a subcutaneous tumor model of renal cell carcinoma in mice. Mechanistically, it was observed that CAR-T cells combined with Cabozantinib led to an increase in the infiltration of tumor-infiltrating T cells, while reducing tumor-associated macrophages and M2 polarization. Additionally, Cabozantinib blocked the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis by decreasing the expression of PD-L1 in tumor cells and PD-1 in T cells. Furthermore, Cabozantinib promoted CAR-T cell effector function and reduced T cell exhaustion. This combination therapy represents a novel approach to enhancing CAR-T cell efficacy against solid tumors and holds significant promise for advancing CAR-T cell therapy in clinical settings.

Keywords

CAR-T; Cabozantinib; Combination therapy; Tumor microenvironment.

Figures
Products