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- Title
PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model.
- Authors
Peng, Shiwen; Tan, Marietta; Li, Yen-Der; Cheng, Max A.; Farmer, Emily; Ferrall, Louise; Gaillard, Stephanie; Roden, Richard B. S.; Hung, Chien-Fu; Wu, T.-C.
- Abstract
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.
- Subjects
GENITAL warts; PROGRAMMED cell death 1 receptors; HUMAN papillomavirus vaccines; ANIMAL models in research; CHIMERIC proteins; T cells
- Publication
Cancer Immunology, Immunotherapy, 2021, Vol 70, Issue 4, p1049
- ISSN
0340-7004
- Publication type
Article
- DOI
10.1007/s00262-020-02754-x