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 Jr., Todd D. Armstrong, Elizabeth M. Jaffee, Neeha Zaidi
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 Jr., Todd D. Armstrong, Elizabeth M. Jaffee, Neeha Zaidi
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Research Article Oncology

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

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.

Authors

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 Jr., Todd D. Armstrong, Elizabeth M. Jaffee, Neeha Zaidi

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Figure 6

Tumor rechallenge with Panc02 results in sustained protection.

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Tumor rechallenge with Panc02 results in sustained protection. (A) 106 P...
(A) 106 Panc02 cells were implanted in the contralateral hind legs of mice that had cleared tumor following initial treatments with PancVAX, ADU-V16, AddaVax, OX40, and/or anti–PD-1 (as in Figure 4, B–D) but without additional treatment (n = 5 per group). (B) Tumor diameter of individual mice from the groups in A as a function of time. (C) Splenocytes were harvested from each mouse in the triple treatment group (PancVAX, OX40, and anti–PD-1), plated overnight at 2 × 106 cells in 1 ml CTL medium with each PancVAX peptide (2 μg/ml) or anti-CD3/28 magnetic beads in the presence of protein transport inhibitors. The following day, cells were washed and stained for intracellular cytokine staining to determine peptide specificities. Each number represents a single mouse; mouse 1 did not eradicate the rechallenge tumor. (D) Tumor-infiltrating lymphocytes were harvested from mouse 1, which did not respond to tumor rechallenge following triple therapy and showed the absence of IFN-γ and TNF-α production (left) as well as a marked number of immunosuppressive FoxP3+CD4+ Tregs (right).