PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model.

Journal Article (Journal Article)

INTRODUCTION: The human papillomavirus (HPV) encoded oncoproteins E6 and E7 are constitutively expressed in HPV-associated cancers, making them logical therapeutic targets. Intramuscular immunization of patients with HPV16 L2E7E6 fusion protein vaccine (TA-CIN) is well tolerated and induces HPV-specific cellular immune responses. Efficacy of PD-1 immune checkpoint blockade correlates with the level of tumor-infiltrating CD8 + T cells, yet most patients lack significant tumor infiltration of immune cells making immune checkpoint blockade suboptimal. We hypothesized that intratumoral vaccination with TA-CIN could increase the number of tumor-infiltrating CD8 + T cells, synergize with PD-1 blockade and result in better control of tumors compared with either PD-1 blockade or vaccination alone. METHODS: We examined the immunogenicity and antitumor effects of intratumoral vaccination with TA-CIN alone or in combination with PD-1 blockade in the TC-1 syngeneic murine tumor model expressing HPV16 E6/E7. RESULTS: Intratumoral vaccination with TA-CIN induced stronger antigen-specific CD8 + T cell responses and antitumor effects. Intratumoral TA-CIN vaccination generated a systemic immune response that was able to control distal TC-1 tumors. Furthermore, intratumoral TA-CIN vaccination induced tumor infiltration of antigen-specific CD8 + T cells. Knockout of Batf3 abolished antigen-specific CD8 + T cell responses and antitumor effects of intratumoral TA-CIN vaccination. Finally, PD-1 blockade synergizes with intratumoral TA-CIN vaccination resulting in significantly enhanced antigen-specific CD8 + T cell responses and complete regression of tumors, whereas either alone failed to control established TC-1 tumor. CONCLUSIONS: Our results provide rationale for future clinical testing of intratumoral TA-CIN vaccination in combination with PD-1 blockade for the control of HPV16-associated tumors.

Full Text

Duke Authors

Cited Authors

  • Peng, S; Tan, M; Li, Y-D; Cheng, MA; Farmer, E; Ferrall, L; Gaillard, S; Roden, RBS; Hung, C-F; Wu, T-C

Published Date

  • April 2021

Published In

Volume / Issue

  • 70 / 4

Start / End Page

  • 1049 - 1062

PubMed ID

  • 33108473

Pubmed Central ID

  • 33108473

Electronic International Standard Serial Number (EISSN)

  • 1432-0851

Digital Object Identifier (DOI)

  • 10.1007/s00262-020-02754-x

Language

  • eng

Conference Location

  • Germany