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Cancer Immunol Immunother. 2019 Aug;68(8):1273-1286. doi: 10.1007/s00262-019-02357-1. Epub 2019 Jun 26.

Intratumoral delivery of an HPV vaccine elicits a broad anti-tumor immune response that translates into a potent anti-tumor effect in a preclinical murine HPV model.

Author information

1
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
2
Department of Otolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
3
Department of Immunology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
4
Department of Pathology, University of Washington, Seattle, WA, USA.
5
School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.
6
Harvard University, Cambridge, MA, USA.
7
Oncosec Medical, San Diego, CA, USA.
8
Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
9
Department of Otology and Laryngology, Massachusetts Eye and Ear, Boston, MA, USA.
10
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
11
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. sara.pai@mgh.harvard.edu.
12
Division of Surgical Oncology, Department of Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, 55 Fruit Street, GRJ 9-904G, Boston, MA, 02114, USA. sara.pai@mgh.harvard.edu.

Abstract

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFN╬│) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).

KEYWORDS:

HPV vaccine; Immune checkpoints; Intratumoral vaccination; Lag-3; PD-1; Tim-3

PMID:
31243491
PMCID:
PMC6684362
[Available on 2020-08-01]
DOI:
10.1007/s00262-019-02357-1
[Indexed for MEDLINE]

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