TY - JOUR
T1 - Mucosal HPV E6/E7 peptide vaccination in combination with immune checkpoint modulation induces regression of HPV þ oral cancers
AU - Dorta-Estremera, Stephanie
AU - Chin, Renee L.
AU - Sierra, Gloria
AU - Nicholas, Courtney
AU - Yanamandra, Ananta V.
AU - Nookala, Sita M.K.
AU - Yang, Guojun
AU - Singh, Shailbala
AU - Curran, Michael A.
AU - Jagannadha Sastry, K.
N1 - Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/9/15
Y1 - 2018/9/15
N2 - High-risk human papillomavirus (HPV)–associated squamous cell carcinomas of the oropharynx (SCCOP) are among the fastest growing cancers. After standard-of-care treatment, however, patients with HPV þ SCCOP have better overall and disease-specific survival than patients with HPV SCCOP, suggesting the importance of HPV-specific immunity. We reasoned that therapeutic vaccination targeting the HPV-16 E6 and E7 oncogenes could elicit high-affinity, high-frequency tumor antigen–specific T-cell responses, which could then be augmented and shielded from suppression in the tumor microenvironment by immune checkpoint modulation. In this study, we used a preclinical syngeneic mouse model of oral cancer comprised of mouse tonsil-derived epithelial cells stably expressing HPV-16 E6 and E7 genes along with H-ras oncogene (mEER) to identify combinations of vaccination and checkpoint antibodies capable of promoting tumor regression. Intranasal HPV E6/E7 peptide vaccination and single checkpoint antibodies failed to elicit responses in more than half of animals; however, 4-1BB agonist antibody along with either CD40 agonist antibody or CTLA-4 blockade eliminated the majority of established mEER tumors. The combination of intranasal HPV peptide vaccine and a4-1BB and aCTLA-4 antibodies produced curative efficacy and a better safety profile against orally implanted mEER tumors. Correlates of protective immunity included enhanced intratumoral levels of CD8 T cells relative to immunosuppressive regulatory T cells and myeloid-derived suppressor cells. Overall, our results demonstrate combination vaccine-immunotherapy modalities as novel treatment options for HPV þ SCCOP. Significance: Combinations of vaccine and checkpoint modulation are effective and safe treatment options for HPV þ oral cancers.
AB - High-risk human papillomavirus (HPV)–associated squamous cell carcinomas of the oropharynx (SCCOP) are among the fastest growing cancers. After standard-of-care treatment, however, patients with HPV þ SCCOP have better overall and disease-specific survival than patients with HPV SCCOP, suggesting the importance of HPV-specific immunity. We reasoned that therapeutic vaccination targeting the HPV-16 E6 and E7 oncogenes could elicit high-affinity, high-frequency tumor antigen–specific T-cell responses, which could then be augmented and shielded from suppression in the tumor microenvironment by immune checkpoint modulation. In this study, we used a preclinical syngeneic mouse model of oral cancer comprised of mouse tonsil-derived epithelial cells stably expressing HPV-16 E6 and E7 genes along with H-ras oncogene (mEER) to identify combinations of vaccination and checkpoint antibodies capable of promoting tumor regression. Intranasal HPV E6/E7 peptide vaccination and single checkpoint antibodies failed to elicit responses in more than half of animals; however, 4-1BB agonist antibody along with either CD40 agonist antibody or CTLA-4 blockade eliminated the majority of established mEER tumors. The combination of intranasal HPV peptide vaccine and a4-1BB and aCTLA-4 antibodies produced curative efficacy and a better safety profile against orally implanted mEER tumors. Correlates of protective immunity included enhanced intratumoral levels of CD8 T cells relative to immunosuppressive regulatory T cells and myeloid-derived suppressor cells. Overall, our results demonstrate combination vaccine-immunotherapy modalities as novel treatment options for HPV þ SCCOP. Significance: Combinations of vaccine and checkpoint modulation are effective and safe treatment options for HPV þ oral cancers.
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U2 - 10.1158/0008-5472.CAN-18-0892
DO - 10.1158/0008-5472.CAN-18-0892
M3 - Article
C2 - 30054333
AN - SCOPUS:85053183460
SN - 0008-5472
VL - 78
SP - 5327
EP - 5339
JO - Cancer Research
JF - Cancer Research
IS - 18
ER -