Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer.

Autor:	Kinkead HL; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Hopkins A; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Lutz E; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Wu AA; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Yarchoan M; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Cruz K; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Woolman S; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Vithayathil T; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Glickman LH; Aduro Biotechnologies Inc., Berkeley, California, USA.; Actym Therapeutics Inc., Berkeley, California, USA., Ndubaku CO; Aduro Biotechnologies Inc., Berkeley, California, USA., McWhirter SM; Aduro Biotechnologies Inc., Berkeley, California, USA., Dubensky TW Jr; Aduro Biotechnologies Inc., Berkeley, California, USA.; Tempest Therapeutics, San Francisco, California, USA., Armstrong TD; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Jaffee EM; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA., Zaidi N; Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2018 Oct 18; Vol. 3 (20). Date of Electronic Publication: 2018 Oct 18.
DOI:	10.1172/jci.insight.122857
Abstrakt:	Tumor neoantigens arising from somatic mutations in the cancer genome are less likely to be subject to central immune tolerance and are therefore attractive targets for vaccine immunotherapy. We utilized whole-exome sequencing, RNA sequencing (RNASeq), and an in silico immunogenicity prediction algorithm, NetMHC, to generate a neoantigen-targeted vaccine, PancVAX, which was administered together with the STING adjuvant ADU-V16 to mice bearing pancreatic adenocarcinoma (Panc02) cells. PancVAX activated a neoepitope-specific T cell repertoire within the tumor and caused transient tumor regression. When given in combination with two checkpoint modulators, namely anti-PD-1 and agonist OX40 antibodies, PancVAX resulted in enhanced and more durable tumor regression and a survival benefit. The addition of OX40 to vaccine reduced the coexpression of T cell exhaustion markers, Lag3 and PD-1, and resulted in rejection of tumors upon contralateral rechallenge, suggesting the induction of T cell memory. Together, these data provide the framework for testing personalized neoantigen-based combinatorial vaccine strategies in patients with pancreatic and other nonimmunogenic cancers.
Databáze:	MEDLINE
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