Abstract C101: Comprehensive identification of novel therapeutic targets for treatment of PD-1 resistant solid tumors via a genome-scale CRISPR/Cas9 in vivo T-cell screen

Although immunotherapy with PD-1/PD-L1 antagonists has significantly advanced patient care, the majority of cancer patients currently do not benefit from checkpoint inhibitor therapies. To identify novel targets for the treatment of PD-1 insensitive cancers, we developed a novel Immune-CRISPRomicsTM platform that enabled genome-wide CRISPR/Cas9 screens in primary T cells in an in vivo setting. Notably, the screen identified clinically active molecules, such as PD-1 and also predicted recent clinical failures. In addition, we identified multiple targets that enhanced anti-tumor T-cell function similar to or better than PD-1 as a monotherapy. The anti-tumor activity of targets was assessed across a collection of PD-1 sensitive and PD-1 refractory syngeneic tumor models. One of the targets identified, IO-7, was found to possess robust activity across multiple PD-1 refractory models. We found that inhibition of IO-7 leads to long-term T-cell memory and prevents tumor growth upon re-challenge. Moreover, mechanistic follow-up studies demonstrate that IO-7 inhibition leads to an expansion of central memory T-cell subsets, which have been implicated in driving the durable clinical response of checkpoint inhibitors. We describe the first genome-wide in vivo T-cell CRISPR/Cas9 screen, which identified multiple therapeutic targets that present promising therapeutic opportunities for the treatment of PD-1 resistant solid tumors. Citation Format: Isabelle Le Mercier, Jason J. Merkin, Sean Keegan, Conor Calnan, Anja F. Hohmann, Nick Colletti, Eric Fagerberg, Sol Shenker, Caroline Bullock, Chris Wrocklage, Noah Tubo, Tianlei Xu, Matt Noyes, Rami Rahal, Sean Arlauckas, Aria Pearlman Morales, Frank Stegmeier, Louise Cadzow, Mike Schlabach, Gregory Kryukov, Micah J. Benson. Comprehensive identification of novel therapeutic targets for treatment of PD-1 resistant solid tumors via a genome-scale CRISPR/Cas9 in vivo T-cell screen [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C101. doi:10.1158/1535-7163.TARG-19-C101