Combining STING-based neoantigen-targeted vaccine with checkpoint modulators enhances antitumor immunity in murine pancreatic cancer
Heather L. Kinkead, … , Elizabeth M. Jaffee, Neeha Zaidi
Heather L. Kinkead, … , Elizabeth M. Jaffee, Neeha Zaidi
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e122857. https://doi.org/10.1172/jci.insight.122857.
View: Text | PDF
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

×

Figure 4

Checkpoint modulation with PancVAX results in tumor clearance.

Options: View larger image (or click on image) Download as PowerPoint
Checkpoint modulation with PancVAX results in tumor clearance. (A) Treat...
(A) Treatment timeline for Panc02-bearing C57BL6 mice. On the left, 1 week following Panc02 implantation, mice received PancVAX (50 μg each of the 12 20-mer peptides), ADU-V16, AddaVax, agonist OX40 antibody (150 μg), and anti–PD-1 antibody (100 μg), as shown (results in B–D). On the right, PancVAX, ADU-V16, AddaVax, low-dose agonist OX40 antibody (50 μg), and anti–PD-1 antibody (100 μg) were given 2 weeks after transplantation, as shown (results in E and F). (B) Kaplan-Meier curves displaying the percentage of tumor-free mice following various treatments (as shown). Statistics by log-rank Mantel-Cox test. (C) Average tumor diameter (mm) was measured in the same group of mice (as in B) by calipers every 3 to 4 days, starting day 11, until tumors reached 10 × 10 mm. Statistical comparisons were made with PancVAX plus isotype Abs. *P < 0.05 for triple therapy from day 25 onward, **P < 0.002 at day 35, triple therapy versus PancVax + Isotype Abs; other groups, namely, PancVAX plus OX40, PancVAX plus PD-1, were nonsignificant, except as noted. Statistics by Student’s t test, corrected for multiple comparisons. (D) Average tumor diameter for each mouse for the treatments, as noted. The number indicates the number of mice that were tumor free at day 43. (E) Average tumor diameter (mm) was measured by calipers every 3 to 4 days until tumors reached 10 × 10 mm; Statistics by Student’s t test adjusted for multiple comparisons. *P < 0.05, comparing PancVAX, OX40, and PD-1 versus OX40 and PD-1 or PancVAX and isotype Abs from day 24 onward (except day 28, P = 0.082 for the latter comparison). In all cases 10 mice per group were used at the outset. Of note, mice in whom tumor diameter could not be reliably measured due to poor demarcation of the tumor edge were excluded. (F) Kaplan-Meier curves displaying the percentage of tumor-free mice following various treatments. Statistics by log-rank Mantel-Cox test.