Mutant KRAS vaccine with dual checkpoint blockade in resected pancreatic cancer: a phase I trial
Amanda Huff, S. Daniel Haldar, Alexander A. Gergis, Hejia Wang, Ludmila Danilova, Thatcher Heumann, Maureen Berg, Yuxuan Wang, Lalitya Andaloori, Alexei Hernandez, Gabriella Longway, Benjamin Barrett, Zirui Zhu, Emily F. Davis-Marcisak, Christopher J. Thoburn, James Leatherman, Sarah Mitchell, Jae Ryong Lee, Daniel H. Shu, Maximillian F. Konig, Brian J. Mog, Janelle M. Montagne, Erin M. Coyne, Katherine M. Bever, Marina Baretti, Mark Yarchoan, Robert A. Anders, Luciane T. Kagohara, Daniel Laheru, Amy M. Thomas, Jennifer N. Durham, Julie M. Nauroth, Jiayun Lu, Hao Wang, Elana J. Fertig, W. Ho, Nilofer S. Azad, Elizabeth M. Jaffee, Neeha Zaidi
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).