Rationally improving T cell-mediated immunotherapy using Sleeping Beauty mutagenesis

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Project Summary/Abstract I, Dr. Laura Rogers, PhD, am currently a mentored postdoctoral researcher at the University of Iowa Holden Comprehensive Cancer Center. I intend to pursue an independent tenure-track faculty position at a competitive research institution, so that I may continue to expand the exciting translational cancer immunotherapy project I have developed during my postdoctoral research career. This project aims to address a major problem in the dynamic field of cancer immunotherapy, namely, how to help cancer patients who lack intratumoral T cells respond more robustly to immunotherapy. I have devised a genetic screen approach to identify T cell genes that impact intratumoral T cell accumulation using Sleeping Beauty (SB) mutagenesis in two immunocompetent murine models of cancer (melanoma and lymphoma). We have identified a number of novel candidate immunotherapy targets that may enhance T cell mediated immunotherapies, including CAR-T cell adoptive transfer and immune checkpoint blockade (anti-PD-1). Aim 1 of this proposal directly tests the impact of promising candidate, Aak1, on T cell infiltration into tumors and its effect on anti-PD-1 efficacy, and Aim 2 expands on a successful pilot screen in order to identify additional candidates targets that are likely to synergize with anti-PD-1 therapy. Together these studies will promote the rational design of novel immunotherapeutic agents to enhance existing cancer therapy. I have extensive experience using SB mutagenesis, and my current training environment has allowed me to expand my research interests into the cancer immunotherapy field. The K22 award will be highly beneficial to my transition into an independent investigator, in part by allowing me to gain technical expertise in bioinformatics analysis as I seek formal training through the Masters in Bioinformatics program at the University of Iowa. These critical skills will allow me to fluently address pressing questions within the cancer immunology field, where the complexity of the tumor microenvironment necessitates a systems biology approach. Finally, my plan to advance to an independent investigator and establish a competitive independent research program includes applying for R01 level funding for this project in 2018. The K22 award will facilitate this process greatly, as the proposed work would lay the scientific foundation for a mechanistic grant proposal. Combined with my unique background and novel approach, NCI's K22 will help me launch a highly impactful, interdisciplinary research career in translational cancer immunology.