Abstract 4986: TIGIT directed human antibody modulates T-regulatory and effector cell function
Authors: Smith Alyson , Zeng Weiping , Grogan Bryan , Haass Jane , Blackmarr Amber , Peterson Scott , Gardai Shyra J. 
Published: August 2019

T-cell immune receptor with Ig and ITIM domains (TIGIT) is a receptor expressed on activated and memory T cells, immunosuppressive T regulatory cells (Tregs), and NK cells. Engagement with its ligands, CD155 and CD112, drives an inhibitory signal in T cells and supplants ligand binding from the co-stimulatory receptor CD226, collectively resulting in decreased cell functionality. Antibody blockade of TIGIT can release these inhibitory signals, drive T cell activation and augment anti-tumor responses. Additionally, TIGIT antibodies may directly affect Treg cell function and survival. FACS analysis of healthy donor PBMCs confirmed TIGIT expression on NK and T cell subsets with expression most frequent on Temra and Tregs. A fully human TIGIT monoclonal antibody (mAb) that recognizes human, murine, and cynomolgus TIGIT was created to assess TIGIT mAb functionality and antitumor activity. Assessment of a TIGIT directed mAb demonstrated preferential depletion of Tregs in ex-vivo PBMC cultures with NK cell/Treg co-culture experiments confirming Treg loss via ADCC. Anti-TIGIT treatment also supported a memory T cell recall response assessed following PBMC exposure to CMV lysate or pooled viral peptides. The TIGIT directed antibody also modulated memory and new effector CD8 T cell responses in a mixed lymphocyte reaction (MLR). TIGIT antibody treatment increased proliferation and IL-2 production, suggesting naïve and memory T cell activity was bolstered following TIGIT mAb treatment. TIGIT antibodies may be unique in their ability to elicit effector T cell responses as TIGIT mAb treatment of PBMC cultures resulted in activation of innate immune cells and cytokine production suggesting TIGIT mAbs may activate both adaptive and innate arms of the immune system. These in vitro results translated to in vivo antitumor activity in the CT26 colon cancer model, where TIGIT mAb treatment decreased intratumoral Tregs, increased total intratumoral CD8 effector memory T cells, and resulted in curative antitumor responses. These pharmacodynamics changes and anti-tumor responses were associated with generation of antigen-specific immunity and long-term memory T cell responses resulting in complete tumor rejection upon re-challenge. Furthermore, TIGIT mAb treatment of MC38 and A20 syngeneic tumor models resulted in tumor growth delay and up to 66% complete responses in the A20 model. Collectively this data demonstrates the anti-tumor therapeutic potential of a TIGIT targeting mAb and suggests activity comes both from reduction of Treg cells and amplification of naïve and memory T cell responses.

Citation Format: Alyson Smith, Weiping Zeng, Bryan Grogan, Jane Haass, Amber Blackmarr, Scott Peterson, Shyra J. Gardai. TIGIT directed human antibody modulates T-regulatory and effector cell function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4986.