Immunotherapy has demonstrated remarkable responses in patients with metastatic tumors. Targeting the inhibitory CTLA-4 and PD-1 receptors expressed by T cells induces durable responses in a subset of cancer patients, including advanced melanoma. However, cancers, such as melanoma, remain largely resistant to many forms of immunotherapy, most likely due to exploitation of additional, and unidentified, negative feedback loops. It is widely appreciated that combination therapies will be required to extend the benefit of checkpoint blockade. Current approaches for discovery of combination therapies emphasize a 1 + 1 approach in which an active drug is tested in combination with an experimental agent. We hypothesize that many opportunities for synergistic combinations are missed with this strategy. We propose to develop a novel in vivo technique for discovery of combination therapies in the tumor microenvironment. Single-cell RNA-seq will be used to discover genes upregulated in dysfunctional T cells during PD-1 or CTLA-4 monotherapy in a mouse model of melanoma. We will then screen a library of identified targets in CD8 T cells for synergistic combinations using checkpoint blockade along with CRSIPR/Cas9 genome editing. Enrichment within the tumor of specific targets will then be further investigated to determine the most efficacious combinations for the treatment of melanoma.

Citation Format: Adam N. Cartwright, Rong En Tay, Kai W. Wucherpfennig. Systematic discovery of combinationimmunotherapy targets in vivo [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A055.