Abstract IA013: Intercepting pancreatic cancer development with mutant KRAS-targeted immunotherapy

The evolution of pancreatic ductal adenocarcinoma (PDAC) from tumor initiation to metastases requires years to decades, providing a window of opportunity for the prevention of premalignant progression. One of the first genetic mutations to occur early in development is in KRAS, an oncogene that is expressed by over 90% of PDACs. KRAS mutations (mKRAS) are attractive targets as they are recurrent hot–spot drivers that are expressed by, and drive the growth of all PDAC cells. Preclinical data provide compelling evidence that targeting mKRAS proteins using a Listeria-based vaccination approach in KPC mouse model results in prevention of progression from precursor lesions to PDAC. Based on these data, we hypothesize that targeting mKRAS in combination with bypassing early immune–suppressive signals will slow or even halt the progression of precursor lesions to PDA in subjects who are at high–risk. We have thus developed a clinical–grade long peptide vaccine targeting the six most common mKRAS proteins (G12V, G12R, G12A, G12C, G12D, and G13D) in PDAC patients. To establish initial safety and immunogenicity, our KRAS vaccine has been tested in 11 patients thus far in a Phase 1 clinical trial (NCT04117087) in combination with checkpoint blockade in patients who have undergone surgery and peri–operative chemotherapy and remained disease–free on imaging. Longitudinal immune data demonstrates an induction of activated and poly-functional mKRAS-specific CD4+ and CD8+ T cells, as well as effector and central memory T cells post–vaccination. In parallel, we performed paired single-cell RNA and TCR sequencing in PBMCs from a patient to obtain greater resolution of the vaccine–induced cytotoxic anti–tumor T cells. We captured 66,869 immune cells across three timepoints for analysis. Notably, we similarly observed an expansion of central memory CD4+ and CD8+ T cells post–vaccination. Using a novel computational algorithm (developed in collaboration with Dr. Elana Fertig’s lab) that takes into account physiochemical similarity of known mKRAS TCRs, we used our single–cell dataset to identify mKRAS-reactive TCRs` in the periphery that were functionally validated in vitro using CRISPR-Cas12a-based genome editing of human T cells. Overall, these studies suggest the induction of de novo, high quality mutant KRAS–specific T cells in the peripheral blood post–vaccination. Based on these immune data, we are enrolling onto a second clinical trial testing our mKRAS peptide vaccine i