Hejia Wang, Amanda L. Huff, S. Daniel Haldar, Maureen Berg, Christopher J. Thoburn, Thatcher R. Heumann, Robert A. Anders, Benjamin Barrett, Katherine M. Bever, Michael J. Pishvaian, Valerie Lee, Dung T. Le, Eric S. Christenson, Marina Baretti, Mark Yarchoan, Daniel A. Laheru, Amy Thomas, Jennifer N. Durham, Julie M. Nauroth, J H Lu, Hao Wang, Elizabeth M. Jaffee, Nilofer S. Azad, Neeha Zaidi
Immune checkpoint inhibitors (ICIs) have limited activity in mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC). KRAS mutations, present in approximately 40% of these cancers, can generate neoantigens that are targets for therapeutic vaccines. In this single-arm, phase I study (NCT04117087), we evaluated mKRAS-VAX, a pooled mutant KRAS (mKRAS) peptide vaccine targeting six KRAS mutations with nivolumab and ipilimumab in 13 patients with pretreated metastatic MMRp/MSS CRC. Both primary endpoints of safety and immunogenicity (within 17 weeks post-vaccination) were met. Secondary endpoints included treatment efficacy defined by RECIST v1.1 criteria. All adverse events attributed to mKRAS-VAX were grade 1 or 2, and the addition of mKRAS-VAX did not increase the frequency of severe immune-related adverse events beyond the expected profile of dual ICIs alone. mKRAS-VAX elicited an increase in tumor-specific mKRAS-reactive T-cells in 8/12 biomarker-evaluable patients (75%) by direct ex vivo IFNγ ELISpot and in 12 patients (100%) following in vitro expansion. Our findings support further development of mKRAS vaccines with ICIs for advanced MMRp/MSS CRC. Patients with mismatch repair proficient or microsatellite stable (MMRp/MSS) colorectal cancer (CRC) often fail to respond to immune checkpoint. Here, the authors report a phase I trial evaluating the safety and immunogenicity of mKRAS-VAX (mutant KRAS vaccine) in combination with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in patients with heavily pretreated, metastatic MMRp/MSS CRC.