Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results

Christine D. Palmer, Amy R. Rappaport, Matthew J. Davis, Meghan G. Hart, Ciaran D. Scallan, Sue Jean Hong, Leonid Gitlin, Lauren D. Kraemer, Sonia Kounlavouth, Aaron Yang, Lindsey Smith, Desiree Schenk, Mojca Skoberne, Kiara Taquechel, Martina Marrali, Jason R. Jaroslavsky, Charmaine N. Nganje, Elizabeth Maloney, Rita Zhou, Daniel Navarro-GomezAdrienne C. Greene, Gijsbert Grotenbreg, Renee Greer, Wade Blair, Minh Duc Cao, Shawn Chan, Kyounghwa Bae, Alexander I. Spira, Sameek Roychowdhury, David P. Carbone, Brian S. Henick, Charles G. Drake, Benjamin J. Solomon, Daniel H. Ahn, Amit Mahipal, Steve B. Maron, Benny Johnson, Raphael Rousseau, Roman Yelensky, Chih Yi Liao, Daniel V.T. Catenacci, Andrew Allen, Andrew R. Ferguson, Karin Jooss

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1619-1629
Number of pages11
JournalNature Medicine
Volume28
Issue number8
DOIs
StatePublished - Aug 2022

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology

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