T cells capable of targeting neoepitopes (neoE) from tumor-specific mutations hold the potential to uniquely recognize and kill tumor cells. However, most cancer patients fail to mount a sufficient intrinsic T cell immune response to translate into clinical benefit. PACT Pharma has developed an ultra-sensitive and high-throughput technology (imPACT) for identifying and isolating neoE-specific T cells from peripheral blood. Whole exome sequencing of tumors and computational prediction identify patient-specific neoepitopes resulting from tumor-specific mutations. We then interrogate patient blood for neoE-specific T cells using human leukocyte antigen (HLA) protein-based reagents comprising a spectrum of human HLAs, thus enabling the evaluation of >99% of all individuals with cancer. We have identified and isolated neoE-specific T cells from the peripheral blood of >80% treatment-naive patients with bladder and colorectal cancers, melanoma and other solid tumors. Primary human T cells engineered with T cell receptor sequences (TCRs) cloned from the imPACT-isolated T cells gain the ability to kill cognate neoE-presenting tumor cells, thereby also confirming the specificity of the isolated TCR sequences to bind to the neoE target. This approach is also amenable to the longitudinal analysis of patients undergoing treatment for their cancers, to characterize the neoE-specific T cell populations likely to confer clinical benefit. In summary, the imPACT technology efficiently discovers potentially meaningful intrinsic neoE-specific TCRs from patients, enabling the development of personalized neoTCR-T cell therapies for the eradication of solid tumors.

Citation Format: Songming Peng, Boi Quach, Duo An, Salemiz Sandoval, Robert Bao, Zheng Pan, Michael Bethune, Olivier Dalmas, Michael Yi, Corey Meadows, Katherine Heeringa, Linlin Guo, Benjamin yuen, John Sorfleet, Kyle Jacoby, Robert Moot, William Lu, Diana Nguyen, Barbara Sennino, Andrew Conroy, Bhamini Purandare, Adam Litterman, Stefanie Mandl, Alex Franzusoff. An ultra-sensitive and high-throughput technology (imPACT) for the identification and isolation of intrinsic and emergent neoepitope-specific T cells from the peripheral blood and TILs of cancer patients [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 1435.