Abstract 584: From code to cure: Computational discovery of novel immune checkpoints

Antibody blockade of CTLA4 and PD-1 immune checkpoints emerged as an effective treatment modality for cancer. However, the majority of patients do not achieve sustained long term benefit, suggesting a need for targeting of additional immune checkpoints. To identify additional B7/CD28 immune checkpoint targets, we developed a unique compendium of computational algorithms that identified multiple novel targets including TIGIT in 2008, which was an unknown protein at the time of discovery [Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):17858-63], and PVRIG which we recently disclosed. Since their initial discovery, these targets have been functionally validated and anti-tumor activity was demonstrated with antibodies that target them. In this presentation, we will describe the computational algorithms that led to the discovery of these novel immune checkpoints. These algorithms combine two complementary aspects: (i) endogenous immune checkpoint function prediction and (ii) prediction of immuno-modulatory activity in cancer. Immune checkpoint function was predicted based on gene structure similarity to B7/CD28 family members that is reminiscent of ancient common evolutionary origins. A gene structure alignment tool was developed to identify functional homologs of B7/CD28 genes even in the absence of sequence similarity. Next, the expression profile of these candidates was modeled and compared to profiles of known immune checkpoints in normal and cancer tissues. We will review the details of TIGIT and PVRIG discovery, which were among the immune checkpoints predicted in this process. Our approach demonstrates the powerful ability of computational biology to translate genomic knowledge into rational and reliable drug target discovery. Citation Format: Yair Benita, Amit Novik, Gady Cojocaru, Itamar Borukhov, Assaf Wool, Yossef Kliger, Tomer Zekharya, Zurit Levine, Sergey Nemzer, Ofer Levy, Amir Toporik. From code to cure: Computational discovery of novel immune checkpoints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 584. doi:10.1158/1538-7445.AM2017-584