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PD-1 blockade synergizes with intratumoral vaccination of a therapeutic HPV protein vaccine and elicits regression of tumor in a preclinical model.
- Source :
-
Cancer immunology, immunotherapy : CII [Cancer Immunol Immunother] 2021 Apr; Vol. 70 (4), pp. 1049-1062. Date of Electronic Publication: 2020 Oct 27. - Publication Year :
- 2021
-
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.<br />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.<br />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.<br />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 :
- Animals
CD8-Positive T-Lymphocytes drug effects
CD8-Positive T-Lymphocytes immunology
Cancer Vaccines immunology
Female
Immunity, Cellular drug effects
Lymphocytes, Tumor-Infiltrating drug effects
Lymphocytes, Tumor-Infiltrating immunology
Mice
Mice, Inbred C57BL
Papillomavirus E7 Proteins genetics
Papillomavirus E7 Proteins immunology
Programmed Cell Death 1 Receptor immunology
Recombinant Fusion Proteins immunology
Uterine Cervical Neoplasms immunology
Uterine Cervical Neoplasms metabolism
Vaccination
Antibodies, Monoclonal pharmacology
Cancer Vaccines administration & dosage
Immunity, Cellular immunology
Papillomavirus E7 Proteins administration & dosage
Programmed Cell Death 1 Receptor antagonists & inhibitors
Recombinant Fusion Proteins administration & dosage
Uterine Cervical Neoplasms prevention & control
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0851
- Volume :
- 70
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancer immunology, immunotherapy : CII
- Publication Type :
- Academic Journal
- Accession number :
- 33108473
- Full Text :
- https://doi.org/10.1007/s00262-020-02754-x