Personalized Neoantigen Vaccine Shows Promise in MSS Colorectal Cancer with ctDNA Response Correlation
A phase 1/2 trial of an individualized chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine combined with nivolumab and ipilimumab demonstrated safety and immunogenicity in patients with advanced solid tumors. The vaccine induced durable neoantigen-specific CD8 T cell responses, with several microsatellite-stable colorectal cancer patients showing improved overall survival. Exploratory analysis revealed that ctDNA decrease correlated with prolonged survival, supporting ctDNA as a pharmacodynamic biomarker for cancer vaccine development.
The original study
Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results.
- Authors
- Palmer CD, Rappaport AR, Davis MJ, Hart MG, Scallan CD, Hong SJ, et al.
- Journal
- Nature medicine
- Type
- Clinical Trial, Phase I, Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't
- PMID
- 35970920
Original abstract
Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 1012 viral particles (VP) ChAd68 and 30 µg samRNA. Secondary endpoints included immunogenicity, feasibility of manufacturing and overall survival (OS). Vaccine manufacturing was feasible, with vaccination inducing long-lasting neoantigen-specific CD8 T cell responses. Several patients with microsatellite-stable colorectal cancer (MSS-CRC) had improved OS. Exploratory biomarker analyses showed decreased circulating tumor DNA (ctDNA) in patients with prolonged OS. Although small study size limits statistical and translational analyses, the increased OS observed in MSS-CRC warrants further exploration in larger randomized studies.