Combination Of Anti-Tigit And Anti-Pd-1 Antibodies Enhance Antitumor Response In A Pd-1/Tigit Double Hugemm (Tm) Model Engrafted With Mouse Syngeneic Tumors

Introduction: Ample clinical and preclinical evidence have shown the remarkable antitumor effects of anti-PD-1 antibodies. However, the fact that only around 20% of patients respond to anti-PD-1 immunotherapy indicates that additional inhibitory circuits may be activated to suppress efficient antitumor response, mediated by innate or adaptive immune cells. Notably, TIGIT (T cell immunoreceptor with Ig and ITIM domains) is identified as a co-inhibitory molecule belonging to the PVR family of immunoglobulin (Ig) proteins, and has been shown to inhibit immune cells at multiple steps in the cancer immunity cycle through at least three distinct mechanisms of action: 1. The binding of TIGIT on NK cells to PVR on tumor cells can inhibit NK cell effector function.2. The binding of TIGIT on T cells (Teff and Treg) with PVR on dendritic cells (DCs) or tumor cells can suppress tumor antigen presentation.3. TIGIT on CD8+ T cells can inhibit adjacent CD226 co-stimulatory signaling by binding to PVR at a higher affinity or disrupting the homodimerization of CD226.Therefore, various therapeutic monoclonal antibodies against TIGIT have been developed and are now undergoing clinical testing, for example, tiragolumab (Phase II), BMS-986207 (Phase II), AB-154 (Phase I), MK-7684 (Phase I), etc. However, we are still lacking suitable preclinical models for the efficacy assessment and PK/PD evaluation of human TIGIT antibodies. Methods: We have developed a human TIGIT single knock-in model (TIGIT HuGEMM) as well as a human PD-1/TIGIT double knock-in model (PD-1/TIGIT dKI HuGEMM), of which the extracellular domain of the mouse proteins is replaced by human counterparts, leading to expression of chimeric TIGIT or PD-1 with a human extracellular domain and mouse trans-membrane and intracellular domains. Results: FACS analysis was used to characterize the surface expression of human/mouse chimeric TIGIT on CD4+ and CD8+ T cells. The expression pattern of humanized TIGIT in splenocytes of HuGEMM mice is the same as wild-type mice, with high levels of TIGIT detectable in Treg. We then inoculated Hepa 1-6 syngeneic tumors into TIGIT HuGEMM mice and treated with 1mg/kg or 5mg/kg tiragolumab. Both doses of the TIGIT antibody led to \u003e90% tumor growth inhibition (TGI). We also used Balb/c background PD-1/TIGIT dKI HuGEMM mice to test the antitumor effects of tiragolumab monotherapy and its combination with the anti-PD1 antibody Keytruda®, where CT26.WT syngeneic tumors were treated. We found that tiragolumab monotherapy resulted in modest antitumor effects (41% TGI), while its combination with low dose Keytruda led to much enhanced efficacy (68% TGI). We also observed increased CD8+ T cell infiltration following combination treatment. Conclusions: Our TIGIT KI HuGEMM and PD-1/TIGIT dKI HuGEMM provide powerful preclinical models to assess the efficacy of human TIGIT antibodies and their combination with human anti-PD-1 or other immune modulators. Citation Format: Daniel Xianfei He, Chenpan Nie, Lei Zheng, Ruilin Sun, Mingkun Zhang, Annie Xiaoyu An, Cunxiang Ju, Henry Q. X. Li, Davy Xuesong Ouyang. Combination of anti-TIGIT and anti-PD-1 antibodies enhance antitumor response in a PD-1/TIGIT double HuGEMM™ model engrafted with mouse syngeneic tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5614.