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

Heather L. Kinkead, Alexander Hopkins, Eric Lutz, Annie A. Wu, Mark Yarchoan, Kayla Cruz, Skylar Woolman, Teena Vithayathil, Laura H. Glickman, Chudi O. Ndubaku, Sarah M. McWhirter, Thomas W. Dubensky, Todd D. Armstrong, Elizabeth M. Jaffee, Neeha Zaidi

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
JournalJCI Insight
Volume3
Issue number20
DOIs
StatePublished - Oct 18 2018

Keywords

  • Cancer immunotherapy
  • Oncology

ASJC Scopus subject areas

  • Medicine(all)

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  • Cite this

    Kinkead, H. L., Hopkins, A., Lutz, E., Wu, A. A., Yarchoan, M., Cruz, K., Woolman, S., Vithayathil, T., Glickman, L. H., Ndubaku, C. O., McWhirter, S. M., Dubensky, T. W., Armstrong, T. D., Jaffee, E. M., & Zaidi, N. (2018). Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer. JCI Insight, 3(20). https://doi.org/10.1172/jci.insight.122857