Abstract 2318: Discovery and validation of a novel checkpoint target preferentially expressed in the tumor microenvironment

Abstract

Abstract Immunotherapeutic approaches targeting a single immune checkpoint, programmed death ligand 1, have resulted in unprecedented response rates and survival benefit across multiple cancer histologies. The efficacy of PD-1 blockade is augmented when delivered in combination with other immune checkpoints, specifically anti-CTLA-4, despite a significant increase in toxicity. The current challenge is identification of novel immunomodulatory targets with equivalent efficacy to PD1 blockade as monotherapy, and which can be applied in combination with anti-PD1 with a superior therapeutic index. As the majority of autoimmune toxicity occurs in healthy, non-malignant tissue, we developed a novel high throughput RNA screen to identify new immune checkpoint targets preferentially expressed in the tumor microenvironment. Across numerous tumor types including tumors targeted by monoclonal antibodies (Abs), ie rituximab, trastuzumab, among others, the screen reproducibly identified a list of novel targets for immunotherapy which through a secondary screen were refined for cell surface expression. By this approach we selected a novel type II transmembrane glycoprotein (TIITG) with dual function as an ectoenzyme and in signal transduction. Further experiments in-vitro and ex-vivo from tumor biopsies confirmed upregulation of the target on tumor-infiltrating, activated, immune cells including but not limited to innate immune effectors. In-vitro and in-vivo murine models using agonistic antibodies to the TIITG demonstrated (1) augmentation of natural killer cell spontaneous and antibody-dependent cytotoxicity, (2) inhibition of myeloid derived suppressor cell and regulatory T cell function, and (3) enhancement in depth and breadth of the adaptive response including post vaccination. Antagonistic Abs had minimal to no effect on the immune response, while agonistic Abs augmented type 1-cytokines (IFNg and TNFa) and cytotoxic markers, including CD107a, perforin, and granzyme. Surprisingly, in a murine autoimmune toxicity model established with prior immune checkpoint agonists, agonists of the TIITG elicited no apparent adverse effects, autoimmune or otherwise. Finally, human xenograft models support antitumor activity across over a dozen tumor histologies as monotherapy in addition to synergy with anti-PD1. In summary, using a novel screening technique we uncovered promising immune targets for cancer therapy. The first of which, TIITG, has completed lead selection and is being prepared to enter a first-in-human clinical trial. Citation Format: Narendiran Rajasekaran, Amani Makkouk, Russel K. Pachynski, Aruna Azameera, Cariad Chester, Xing Zhao, Atsushi Yonezawa, Holbrook E. Kohrt. Discovery and validation of a novel checkpoint target preferentially expressed in the tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2318.