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

Cancer Immunol Immunother. 2021 Apr;70(4):1049-1062. doi: 10.1007/s00262-020-02754-x. Epub 2020 Oct 27.

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.

Keywords: HPV-associated cancers; Human papillomavirus; Intratumoral; PD-1; Therapeutic vaccine.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / pharmacology*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology
  • Female
  • Immunity, Cellular / drug effects
  • Immunity, Cellular / immunology*
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Mice, Inbred C57BL
  • Papillomavirus E7 Proteins / administration & dosage*
  • Papillomavirus E7 Proteins / genetics
  • Papillomavirus E7 Proteins / immunology
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors*
  • Programmed Cell Death 1 Receptor / immunology
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / immunology
  • Uterine Cervical Neoplasms / immunology
  • Uterine Cervical Neoplasms / metabolism
  • Uterine Cervical Neoplasms / prevention & control*
  • Vaccination

Substances

  • Antibodies, Monoclonal
  • Cancer Vaccines
  • PDCD1 protein, human
  • Papillomavirus E7 Proteins
  • Programmed Cell Death 1 Receptor
  • Recombinant Fusion Proteins
  • oncogene protein E7, Human papillomavirus type 16