Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial

TL;DR

This phase I trial tests a vaccine targeting KRAS mutations in pancreatic cancer patients, showing safety and immune response.

Contribution

A novel vaccine targeting six KRAS mutations combined with checkpoint inhibitors is evaluated for the first time in resected pancreatic cancer.

Findings

11 out of 12 patients showed increased T cell response to mutant KRAS antigens.

The vaccine generated cross-reactive T cells recognizing multiple KRAS mutations.

Immunophenotyping revealed Th1 CD4 and CD8 T cell responses, indicating anti-tumor immunity.

Abstract

In this phase I study, we test a pooled synthetic long peptide vaccine targeting the six KRAS mutations (G12V, G12A, G12R, G12C, G12D, G13D) with ipilimumab and nivolumab in resected pancreatic adenocarcinoma. Co-primary endpoints include safety and maximal percent change of IFNγ-producing mutant KRAS T cell responses in the blood within 17 weeks. Secondary endpoints include disease-free survival, overall survival, and maximal percent change of IFNγ-producing mutant KRAS T cell responses at any time after vaccination. Vaccine-related adverse events are grade 1-2. 11/12 and 10/12 patients generate a significant increase in average T cell response to 6 mutant KRAS antigens and tumor-specific response, respectively. Immunophenotyping demonstrate Th1 CD4 central memory and effector memory T cells, and CD8 effector memory T cells at a lower frequency. The vaccine also generates cross-reactive T cells that recognize more than one mutant KRAS antigen. These findings support the safety and diverse anti-tumor immunity of mutant KRAS vaccines (NCT04117087).

KRAS mutations are keenly associated with pancreatic ductal adenocarcinoma and represent a potential therapeutic target. Here the authors present the findings from a phase I clinical trial testing pooled KRAS mutant peptides in combination with immune checkpoint blockade in patients with resected pancreatic ductal adenocarcinoma.

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