Mutant KRAS targeted vaccines for the interception of pancreatic cancer development

ABSTRACT The incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing, and despite the use of conventional therapies, including immune checkpoint inhibitors, 5–year survival remains dismal, at ~12%1. Late detection and therapeutic resistance constitute the two cardinal challenges in PDAC management. However, it is now clear that, following the initial KRAS mutation, it takes over a decade for overt cancer to develop from premalignant lesions, called pancreatic intraepithelial neoplasia (PanIN). Recent studies have also identified individuals at a high risk of PDAC who have a strong family history or harbor pathogenic variants of cancer susceptibility genes. Imaging further identifies premalignant pathologies, such as intrapapillary mucinous neoplasia (IPMN). Both advances––genetic testing and imaging––together with the exceptionally protracted, >10–year–long, window of silent PDAC progression underscore the opportunities to intercept progression. Here, we have targeted mutated KRAS (mKRAS) that drives up to 90% PDACs. We found previously that a KrasG12D vaccine halts PanIN progression in 40% of KPC mice that harbor a heterozygous KrasG12D mutation. This study provided the premise for testing our mKRAS vaccine comprising six peptides corresponding to the most common KRAS mutations in patients with resected PDAC (NCT04117087). We provide evidence for safety, induction of mKRAS–specific predominantly CD4 T cells, and improved disease–free survival. These data prompted us to initiate a study to evaluate the safety and immunogenicity of vaccine in genetically predisposed individuals (NCT05013216, Aim 1). Promising preliminary data establish conceptual and technological feasibility. We hypothesize that the mKRAS vaccine will (a) trigger mKRAS–specific anti–tumor immunity in individuals with premalignant lesions–– PanINs or IPMN––and (b) slow progression of PanINs to PDAC with a survival benefit in KPC mice when given prior to the induction of the KrasG12D mutation. Aim 1 (already initiated) and Aim 2 will study the safety and immunogenicity of mKRAS vaccine in individuals with genetic predisposition and high–risk IPMN, respectively. We will study mKRAS–specific T cells in terms of memory, exhaustion, and polyfunctionality, as well as clonality and richness of the T cell repertoire. In Aim 1, we will also identify TCR clones with cytotoxic gene signatures and validate their function by knocking in the selected TCRs into human T cells. Aim 2 will allow us to examine the effect of vaccine on premalignant IPMN tissue using image mass cytometry. In the spirit of bidirectional translation, we will move back, in Aim 3, to the inducible version of the KPC mouse to determine the optimal timepoints for vaccine interception, characterize longitudinal changes in the immune compartment of PanIN lesions, and investigate the role of CD4 T cells in preventing PanIN–to–PDAC progression. Establishing vaccine effects in high–risk cohorts, together with murine studies on changes in the cellular architecture and evolving immunosuppressive or pro–oncogenic signals, should allow for novel combinatorial strategies in which vaccines would be co–administered with immune modulators to ensure long–term efficacy in high–risk groups.