TY - JOUR
T1 - Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors
T2 - phase 1 trial interim results
AU - Palmer, Christine D.
AU - Rappaport, Amy R.
AU - Davis, Matthew J.
AU - Hart, Meghan G.
AU - Scallan, Ciaran D.
AU - Hong, Sue Jean
AU - Gitlin, Leonid
AU - Kraemer, Lauren D.
AU - Kounlavouth, Sonia
AU - Yang, Aaron
AU - Smith, Lindsey
AU - Schenk, Desiree
AU - Skoberne, Mojca
AU - Taquechel, Kiara
AU - Marrali, Martina
AU - Jaroslavsky, Jason R.
AU - Nganje, Charmaine N.
AU - Maloney, Elizabeth
AU - Zhou, Rita
AU - Navarro-Gomez, Daniel
AU - Greene, Adrienne C.
AU - Grotenbreg, Gijsbert
AU - Greer, Renee
AU - Blair, Wade
AU - Cao, Minh Duc
AU - Chan, Shawn
AU - Bae, Kyounghwa
AU - Spira, Alexander I.
AU - Roychowdhury, Sameek
AU - Carbone, David P.
AU - Henick, Brian S.
AU - Drake, Charles G.
AU - Solomon, Benjamin J.
AU - Ahn, Daniel H.
AU - Mahipal, Amit
AU - Maron, Steve B.
AU - Johnson, Benny
AU - Rousseau, Raphael
AU - Yelensky, Roman
AU - Liao, Chih Yi
AU - Catenacci, Daniel V.T.
AU - Allen, Andrew
AU - Ferguson, Andrew R.
AU - Jooss, Karin
N1 - Funding Information:
C.D.P., A.R.R., M.G.H., C.D.S., L.G., S-.J.H., L.D.K., S.K., D.S., M.D., M.M., J.R.J., C.N.N., R.Z., D.N.G., A.C.G., M.D.C., S.C., K.B., R.R., A.A., A.R.F., K.J., A.Y., L.S., M.S., K.T., E.M., G.G., R.G., W.B. and R.Y. are stockholders and either current or previous employees at Gritstone bio and may be listed as co-inventors on various pending patent applications related to the vaccine platform presented in this study. D.V.T.C. consults/has consulted/has advisory/had advisory roles at Genentech/Roche, Eli Lilly, Merck, Daiichi Sankyo, BMS, Ono, Five Prime, Seattle Genetics, Amgen, Taiho, Astellas, Gritstone bio, Pieris, Zymeworks, Basilea, QED, Foundation Medicine, Pierian, Silverback Therapeutics, Servier, Blueprint Medicines, Arcus Biosciences, Tempus, Guardant Health, Archer and Natera. C.G.D. is currently employed by Janssen R&D. B.S.H. has/had consultant/advisory roles for AstraZeneca, Ideaya, Jazz Pharmaceuticals, and research support from Neximmune. B.J.S. consults/has consulted/had advisory roles for Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pfizer, Roche/Genentech, Amgen, Lilly, Sanofi-Regeneron, Glaxo-Smith Kline, Takeda, Novartis and Beigene; has received honoria from Bristol Myers Squibb, Merck Sharp & Dohme, AstraZeneca, Pfizer, Roche/Genentech, Amgen, Lilly, Sanofi-Regeneron, Glaxo-Smith Kline, Takeda, Novartis and Beigene; has received research funding from Sanofi-Regeneron; and has received royalties from UpToDate. B.J. consulted for/had advisory roles with Taiho Oncology, Insmed Oncology, Gritstone bio, Pfizer and Incyte and received research funding from Gateway for Cancer Research, Bristol Myers Squibb and Syntrix. A.M. is on the Advisory Board for AstraZeneca, QED, and Taiho Oncology. S.R. participated in Advisory Boards for Incyte Corporation (2017), AbbVie (2017), QED Therapeutics (2018, 2019) and Bayer (2020) (healthcare companies <10,000 USD). S.R. received honoraria from IDT (2017) and Illumina (2018) (technology companies). S.R. received consulting fees from QED Therapeutics (2018, 2019) and Merck (2019) (healthcare companies <10,000 USD). S.R. received travel reimbursement from Incyte Corporation (2019) (<999 USD). C.Y.L. received honoraria from Cancer Experts Now and has consulting/advisory board roles with Transthera, BluePrints Medicine, Genentech, QED Therapeutics, Histosonics and Ipsen and is part of the Speaker’s Bureau for Eisai and Incyte. S.B.M. received honoraria from Natera, Bicara, Novartis, Basilea and Daiichi Sankyo and owned stock in Calithera outside the submitted work. The remaining authors declare no competing interests.
Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/8
Y1 - 2022/8
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85135981406&partnerID=8YFLogxK
U2 - 10.1038/s41591-022-01937-6
DO - 10.1038/s41591-022-01937-6
M3 - Article
C2 - 35970920
AN - SCOPUS:85135981406
SN - 1078-8956
VL - 28
SP - 1619
EP - 1629
JO - Nature Medicine
JF - Nature Medicine
IS - 8
ER -