Abstract IA001: Intercepting pancreatic cancer development with oncogene targeted immunotherapy


 Pancreatic adenocarcinoma (PDAC) progression is triggered by a complex interaction of genetic mutations, stromal cell interactions and tumor microenvironmental (TME) signals. Diagnosis usually occurs late in disease progression, making treatment challenging and survival rates extremely poor. PDACs are also considered non-immunogenic, therefore newly emerging immunotherapies that have been successful in other cancers have not significantly progressed PDAC treatment options. Resistance to immunotherapies progresses as normal cells undergo the earliest genetic changes that transform them into early pre-malignant lesions. The two most common premalignant lesions are pancreatic intra-epithelial neoplasms (PanINs) and intraductal papillary mucinous neoplasm (IPMN). Both types of premalignant lesions eventually accumulate additional genetic changes that lead to early-stage invasive cancer and eventually, to late stage PDAC. This transformation process is influenced by both tumor-intrinsic and extrinsic forces within the developing TME. Accumulating data suggests that immune resistance mechanisms also evolve with this progression, which has led to the hypothesis that early immune intervention may be the best time to intervene to slow or even halt disease progression and improve treatment outcomes.
 We know that tumor initiation to metastases takes years to decades, providing a unique window of opportunity for the prevention of premalignant progression. KRAS mutations are an early oncogenic event present in over 90% of PanINs and 75% of IPMNs. Initial studies examining cancer vaccines targeted to early oncogenic mutations are showing promise in animal models. A listeria-based vaccine engineered to express oncogenic KrasG12D combined with and without regulatory T cell depletion by an anti-CD25 antibody (PC61) and cyclophosphamide showed increased T cell infiltration, decreased disease progression, and increased survival in Kras-driven and p53 mutated genetically engineered mice (KrasG12D/+Trp53R172H/+;Pdx-1-Cre (KPC) mice) with early PanIN lesions but not those with later stage PanINs (Keenan et. al. 2014. Gastroenterology 146: 1784). Other early oncogenic mutations in PDACs may prove to be therapeutic targets for vaccine development.
 We recently initiated a pilot study to examine the feasibility and safety of targeting mKRAS in patients with resected PDAC. For this, we developed a clinical–grade pooled peptide vaccine targeting 6 common KRAS mutations. This vaccine has been tested in combination with checkpoint blockade in 10 PDAC patients who had undergone surgery plus peri–operative chemotherapy and had remained disease–free (NCT04117087). Longitudinal immune phenotyping showed a robust peripheral mKRAS–specific T cell response against the most vaccinated epitopes. Flow cytometry revealed that these CD4 and CD8 T cells were activated, polyfunctional and displayed a memory phenotype. Based on the favorable immunogenicity and safety profile of our peptide vaccine in patients with resected PDAC, we have initiated a Prevention Study testing our mKRAS vaccine in individuals at high risk for PDAC. This study is currently enrolling and early results will be described.
 Citation Format: Elizabeth M. Jaffee. Intercepting pancreatic cancer development with oncogene targeted immunotherapy [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr IA001.