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

Palmer, CD; Rappaport, AR; Davis, MJ; Hart, MG; Scallan, CD; Hong, SJ; Gitlin, L; Kraemer, LD; Kounlavouth, S; Yang, A; Smith, L; Schenk, D; Skoberne, M; Taquechel, K; Marrali, M; Jaroslavsky, JR; Nganje, CN; Maloney, E; Zhou, R; Navarro-Gomez, D; Greene, AC; Grotenbreg, G; Greer, R; Blair, W; Cao, MD; Chan, S; Bae, K; Spira, AI; Roychowdhury, S; Carbone, DP; Henick, BS; Drake, CG; Solomon, BJ; Ahn, DH; Mahipal, A; Maron, SB; Johnson, B; Rousseau, R; Yelensky, R; Liao, CY; Catenacci, DVT; Allen, A; Ferguson, AR; Jooss, K

Author(s): Palmer, CD; Rappaport, AR; Davis, MJ; Hart, MG; Scallan, CD; Hong, SJ; Gitlin, L; Kraemer, LD; Kounlavouth, S; Yang, A; Smith, L; Schenk, D; Skoberne, M; Taquechel, K; Marrali, M; Jaroslavsky, JR; Nganje, CN; Maloney, E; Zhou, R; Navarro-Gomez, D; Greene, AC; Grotenbreg, G; Greer, R; Blair, W; Cao, MD; Chan, S; Bae, K; Spira, AI; Roychowdhury, S; Carbone, DP; Henick, BS; Drake, CG; Solomon, BJ; Ahn, DH; Mahipal, A; Maron, SB; Johnson, B; Rousseau, R; Yelensky, R; Liao, CY; Catenacci, DVT; Allen, A; Ferguson, AR; Jooss, K;
Details: Publication Year 2022-08,Volume 28,Issue #8,Page 1619-1629
Journal Title: Nature Medicine
Publication Type: Research article
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 10(12) viral particles (VP) ChAd68 and 30 microg 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.
Keywords: Adenoviridae/genetics; Animals; *Colorectal Neoplasms/drug therapy; Fever; Humans; *Pan troglodytes; RNA, Messenger/therapeutic use
Department(s): Medical Oncology
PubMed ID: 35970920
Publisher's Version: https://doi.org/10.1038/s41591-022-01937-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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