LEN selectively inhibits the kinase activity of VEGFR1-3, FGFR1-4, KIT, PDGFRα, and RET, which are involved in tumor angiogenesis and proliferation in several cancer types. Currently, Phase 1b/2 clinical trials of the combination of LEN and pembrolizumab (a monoclonal antibody [mAb] that blocks the interaction between PD-1 and its ligands) are ongoing for selected types of cancer including melanoma and renal cancer. In order to understand the antitumor effect and mechanism of action of the combination of LEN and PD-1 blockade treatment, we analyzed immune response in syngeneic murine tumor models.
We examined antitumor activity of combination treatment of LEN (10mg/kg, qd) and anti-mouse PD-1 mAb (500 µg/mouse, twice weekly) against LL/2 murine lung carcinoma, H22 murine hepatocellular carcinoma, and CT26 murine colon cancer in syngeneic mouse models. For immune population analyses, tumor or spleen samples were analyzed by flow cytometry. The expression of soluble factors and genes was detected by ELISA or qPCR, respectively. We conducted a BioMap human cell co-culture system analysis with peripheral blood mononuclear cells, endothelial cells, and H1299 human lung cancer cells to evaluate effects of each single agent and combination treatments on Th1/Th2 immune response.
Combination of LEN with PD-1 mAb showed more potent inhibitory activity against tumor growth in all 3 models compared with each single agent. Notably, complete tumor regressions were detected in some mice with combination treatment in the H22 syngeneic mouse tumor model. Re-inoculation of fresh H22 cells into these cured mice was rejected. BioMap analysis showed that PD-1 mAb increased both Th1 and Th2 cytokines, LEN decreased Th2 cytokines, and combination treatment increased Th1 cytokines but decreased Th2 cytokines. ELISA and qPCR analysis also showed that Th1 cytokines were increased but Th2 cytokines were decreased with combination treatments in the LL/2 and CT26 syngeneic mouse models.
The results indicate that the combination of LEN with PD-1 mAb was more effective than single-agent treatment in multiple syngeneic tumor models and was accompanied with a potent antitumor immune response.
Clinical trial identification
Legal entity responsible for the study
Y. Kato, K. Tabata, Y. Hori, S. Tachino, Y. Funahashi, J. Matsui: Employee of Eisai Co., Ltd.
X. Bao, S. Macgrath, M. Matijevici: Employee of Eisai Inc.