Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus

Feorillo Galivo, Rosa Maria Diaz, Uma Thanarajasingam, Dragan Jevremovic, Phonphimon Wongthida, Jill Thompson, Timothy Kottke, Glen N. Barber, Alan Melcher, Richard Geoffrey Vile

Research output: Contribution to journalArticle

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Abstract

Oncolytic virotherapy can be achieved in two ways: (1) by exploiting an innate ability of certain viruses to selectively replicate in tumor tissues, and (2) by using viruses to deliver toxic or immunostimulatory genes to tumors. Vesicular stomatitis virus (VSV) selectively replicates in tumors lacking adequate type I interferon response. The efficacy of oncolytic virotherapy using VSV against B16 melanomas in C57BL/6 mice is dependent on CD8+ T and natural killer cells. Because immunotherapies that prime specific CD8 + T cells against melanocyte/melanoma antigens can generate significant therapeutic responses, we hypothesized that engineering VSV to express the potent T cell costimulatory molecule CD40 ligand (VSV-CD40L) would enhance virotherapy with concomitant priming of melanoma-specific T cells. However, we observed no difference in antitumor efficacy between the parental VSV-GFP and VSV-CD40L. In contrast, intratumoral injection of a replication-defective adenovirus expressing CD40L (Ad-CD40L) consistently produced significantly greater therapy than either replication-competent VSV-GFP or VSV-CD40L. The Ad-CD40L-mediated tumor regressions were associated with specific T cell responses against tumor-associated antigens (TAAs), which took several days to develop, whereas VSV-CD40L rapidly induced high levels of T cell activation without specificity for TAAs. These data suggest that the high levels of VSV-associated immunogenicity distracted immune responses away from priming of tumor-specific T cells, even in the presence of potent costimulatory signals. In contrast, a replication-defective Ad-CD40L allowed significant priming of T cells directed against TAAs. These observations suggest that an efficiently primed antitumor T cell response can produce similar, if not better, therapy against an established melanoma compared with intratumoral injection of a replication-competent oncolytic virus.

Original languageEnglish (US)
Pages (from-to)439-450
Number of pages12
JournalHuman Gene Therapy
Volume21
Issue number4
DOIs
StatePublished - Apr 1 2010

Fingerprint

CD40 Ligand
Vesicular Stomatitis
Immunotherapy
Viruses
T-Lymphocytes
Neoplasms
Neoplasm Antigens
Oncolytic Virotherapy
Adenoviridae
Melanoma
Oncolytic Viruses
Melanoma-Specific Antigens
Interferon Type I
Experimental Melanomas
Natural Killer T-Cells
Injections
Poisons
Melanocytes
Inbred C57BL Mouse
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. / Galivo, Feorillo; Diaz, Rosa Maria; Thanarajasingam, Uma; Jevremovic, Dragan; Wongthida, Phonphimon; Thompson, Jill; Kottke, Timothy; Barber, Glen N.; Melcher, Alan; Vile, Richard Geoffrey.

In: Human Gene Therapy, Vol. 21, No. 4, 01.04.2010, p. 439-450.

Research output: Contribution to journalArticle

Galivo, Feorillo ; Diaz, Rosa Maria ; Thanarajasingam, Uma ; Jevremovic, Dragan ; Wongthida, Phonphimon ; Thompson, Jill ; Kottke, Timothy ; Barber, Glen N. ; Melcher, Alan ; Vile, Richard Geoffrey. / Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. In: Human Gene Therapy. 2010 ; Vol. 21, No. 4. pp. 439-450.
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