A phase I study of a pooled synthetic long peptide mutant KRAS vaccine in patients with pancreatic cystic neoplasms at risk for developing pancreatic cancer.

TPS2699 Background: Mutant KRAS (mKRAS) is an oncogenic driver expressed in > 90% of patients with pancreatic ductal adenocarcinoma (PDAC) and the majority of pancreatic precursors, including > 90% of intraductal papillary mucinous neoplasms (IPMNs) and pancreatic intraepithelial neoplasia (PanIN) (Kanda et al., 2012). If left untreated, approximately 40-60% of high-risk IPMNs will have malignant transformation (Fonseca et al., 2018). mKRAS vaccines have recently demonstrated encouraging results in generating mKRAS-specific T cell responses that correlate with clinical benefit in patients with resected PDAC. We previously reported that a mKRAS-targeted Listeria -based vaccine given with Treg-depleting agents results in slowing of PanIN progression to PDAC in a murine model (Keenan et al., 2014). Based on these data, we have initiated a clinical trial testing this vaccine in individuals at high-risk of developing pancreatic cancer. In our first Cohort [A], we have tested this vaccine in individuals at high-risk due to a known germline mutation or familial predisposition (n = 20). Our current study [Cohort B] aims to determine the safety and immunogenicity of a pooled synthetic long peptide (SLP) mKRAS vaccine with poly-ICLC adjuvant in patients with pancreatic cystic neoplasm at risk for developing PDAC and who are scheduled to undergo surgical resection . Methods: This is a single-arm, open-label phase I trial evaluating mKRAS vaccine in patients with pancreatic cystic neoplasms at risk for developing PDAC and scheduled to undergo surgical resection (n = 10). The vaccine consists of SLPs corresponding to six common mKRAS mutations: G12D, G12V, G12R, G12C, G12A, G13D admixed with poly-ICLC adjuvant. A two-dose series of the mKRAS vaccine is administered at weeks 1 and 2 followed by pancreatic surgery at week 4. Peripheral blood will be collected pre-vaccination (week 1) and post-vaccination (weeks 4 and 8). Following completion of the treatment phase, patients have the option to continue annual follow-up visits until study closure. Eligible patients must have clinical, radiographic, or histologic evidence of a pancreatic cystic neoplasm with features warranting surgical resection per the discretion of the treating hepatobiliary surgeon. Co-primary endpoints include the safety profile per NCI CTCAE v5.0 and maximal percent change of mutant-KRAS-specific T cells measured by IFNg ELISPOT at weeks 4 and 8 post-vaccination compared to pre-vaccination baseline. Correlative studies of resected specimens will include characterization of the pre-malignant microenvironment and mKRAS-specific T cell trafficking post-vaccination. Methods of analyses include bulk RNA and T cell receptor (TCR) sequencing, spatial transcriptomics, and imaging mass cytometry. Patient accrual began in December 2024 and is currently ongoing. Clinical trial information: NCT05013216 .