Combination of Fruquintinib and Anti-PD-1 for the Treatment of Colorectal Cancer

• Published in: The Journal of immunology (1950) 2020-11, Vol.205 (10), p.2905-2915
• Main Authors: Wang, Yuanyuan, Wei, Bin, Gao, Jianhua, Cai, Xiaomin, Xu, Lingyan, Zhong, Haiqing, Wang, Binglin, Sun, Yang, Guo, Wenjie, Xu, Qiang, Gu, Yanhong
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Benzofurans - pharmacology; Benzofurans - therapeutic use; CD8 Antigens - genetics; Cell Line, Tumor - transplantation; Chemotherapy, Adjuvant - methods; Colectomy; Colorectal Neoplasms - diagnosis; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Colorectal Neoplasms - therapy; Disease Models, Animal; Drug Synergism; Humans; Immune Checkpoint Inhibitors - therapeutic use; Male; Mice; Mice, Knockout; Microsatellite Instability; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Programmed Cell Death 1 Receptor - metabolism; Quinazolines - pharmacology; Quinazolines - therapeutic use; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; Treatment Outcome; Tumor Microenvironment - drug effects; Tumor Microenvironment - genetics; Tumor Microenvironment - immunology; Young Adult
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.2000463

Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti-PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti-PD-1 treatment. Then the effect of fruquintinib plus anti-PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti-PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8 T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti-PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti-PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.