Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity

Dan A. Erkes, Guangwu Xu, Constantine Daskalakis, Katherine A. Zurbach, Nicole A. Wilski, Toktam Moghbeli, Ann Hill, Christopher M. Snyder

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Cytomegalovirus is an attractive cancer vaccine platform because it induces strong, functional CD8 + T-cell responses that accumulate over time and migrate into most tissues. To explore this, we used murine cytomegalovirus expressing a modified gp100 melanoma antigen. Therapeutic vaccination by the intraperitoneal and intradermal routes induced tumor infiltrating gp100-specific CD8 + T-cells, but provided minimal benefit for subcutaneous lesions. In contrast, intratumoral infection of established tumor nodules greatly inhibited tumor growth and improved overall survival in a CD8 + T-cell-dependent manner, even in mice previously infected with murine cytomegalovirus. Although murine cytomegalovirus could infect and kill B16F0s in vitro, infection was restricted to tumor-associated macrophages in vivo. Surprisingly, the presence of a tumor antigen in the virus only slightly increased the efficacy of intratumoral infection and tumor-specific CD8 + T-cells in the tumor remained dysfunctional. Importantly, combining intratumoral murine cytomegalovirus infection with anti-PD-L1 therapy was synergistic, resulting in tumor clearance from over half of the mice and subsequent protection against tumor challenge. Thus, while a murine cytomegalovirus-based vaccine was poorly effective against established subcutaneous tumors, direct infection of tumor nodules unexpectedly delayed tumor growth and synergized with immune checkpoint blockade to promote tumor clearance and long-term protection.

Original languageEnglish (US)
Pages (from-to)1444-1455
Number of pages12
JournalMolecular Therapy
Volume24
Issue number8
DOIs
StatePublished - Aug 1 2016

Fingerprint

Muromegalovirus
Immunity
Melanoma
Infection
Neoplasms
T-Lymphocytes
gp100 Melanoma Antigen
Cytomegalovirus Vaccines
Cancer Vaccines
Cytomegalovirus Infections
Neoplasm Antigens
Growth
Cytomegalovirus

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Erkes, D. A., Xu, G., Daskalakis, C., Zurbach, K. A., Wilski, N. A., Moghbeli, T., ... Snyder, C. M. (2016). Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity. Molecular Therapy, 24(8), 1444-1455. https://doi.org/10.1038/mt.2016.121

Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity. / Erkes, Dan A.; Xu, Guangwu; Daskalakis, Constantine; Zurbach, Katherine A.; Wilski, Nicole A.; Moghbeli, Toktam; Hill, Ann; Snyder, Christopher M.

In: Molecular Therapy, Vol. 24, No. 8, 01.08.2016, p. 1444-1455.

Research output: Contribution to journalArticle

Erkes, Dan A. ; Xu, Guangwu ; Daskalakis, Constantine ; Zurbach, Katherine A. ; Wilski, Nicole A. ; Moghbeli, Toktam ; Hill, Ann ; Snyder, Christopher M. / Intratumoral Infection with Murine Cytomegalovirus Synergizes with PD-L1 Blockade to Clear Melanoma Lesions and Induce Long-term Immunity. In: Molecular Therapy. 2016 ; Vol. 24, No. 8. pp. 1444-1455.
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