Targeting an immunologically “cold” tumor, Kinkead et al. used a long peptide neoantigen vaccine with STING agonist in a mouse model of pancreatic adenocarcinoma. 16% of predicted neoantigens (including some with deliberate anchor residue changes) generated a CD8+ T cell response in healthy mice. A subset of 12 peptides combined with STING agonist were used in vivo with moderate antitumor effect alone but significant synergistic efficacy with anti-PD-1 or agonist OX40 antibody singly and in combination. Antigen-specific T cells increased in the tumor and agonist OX40 antibody uniquely enhanced T cell quality and immunological memory.
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.
Author Info: (1) Sidney Kimmel Comprehensive Cancer Center, Skip Viragh Center for Pancreatic Cancer, The Bloomberg~Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of
Author Info: (1) 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. (2) 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. (3) 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. (4) 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. (5) 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. (6) 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. (7) 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. (8) 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. (9) Aduro Biotechnologies Inc., Berkeley, California, USA. Actym Therapeutics Inc., Berkeley, California, USA. (10) Aduro Biotechnologies Inc., Berkeley, California, USA. (11) Aduro Biotechnologies Inc., Berkeley, California, USA. (12) Aduro Biotechnologies Inc., Berkeley, California, USA. Tempest Therapeutics, San Francisco, California, USA. (13) 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. (14) 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. (15) 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.
