Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma

Howard L. Kaufman, Gail DeRaffele, Josephine Mitcham, Dorota Moroziewicz, Seth M. Cohen, Karl S. Hurst-Wicker, Ken Cheung, David S. Lee, Joseph Divito, Magalese Voulo, Julie Donovan, Kate Dolan, Kelledy Manson, Dennis Panicali, Ena Wang, Heidi Hörig, Francesco M. Marincola

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Abstract

Immunotherapy for the treatment of metastatic melanoma remains a major clinical challenge. The melanoma microenvironment may lead to local T cell tolerance in part through downregulation of costimulatory molecules, such as B7.1 (CD80). We report the results from the first clinical trial, to our knowledge, using a recombinant vaccinia virus expressing B7.1 (rV-B7.1) for monthly intralesional vaccination of accessible melanoma lesions. A standard 2-dose-escalation phase I clinical trial was conducted with 12 patients. The approach was well tolerated with only low-grade fever, myalgias, and fatigue reported and 2 patients experiencing vitiligo. An objective partial response was observed in 1 patient and disease stabilization in 2 patients, 1 of whom is alive without disease 59 months following vaccination. All patients demonstrated an increase in postvaccination antibody and T cell responses against vaccinia virus. Systemic immunity was tested in HLA-A*0201 patients who demonstrated an increased frequency of gp100 and T cells specific to melanoma antigen recognized by T cells 1 (MART-1), also known as Melan-A, by ELISPOT assay following local rV-B7.1 vaccination. Local immunity was evaluated by quantitative real-time RT-PCR, which suggested that tumor regression was associated with increased expression of CDS and IFN-γ. The local delivery of vaccinia virus expressing B7.1 was well tolerated and represents an innovative strategy for altering the local tumor microenvironment in patients with melanoma.

Original languageEnglish
Pages (from-to)1903-1912
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
Publication statusPublished - 1 Jul 2005

ASJC Scopus subject areas

  • Medicine(all)

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    Kaufman, H. L., DeRaffele, G., Mitcham, J., Moroziewicz, D., Cohen, S. M., Hurst-Wicker, K. S., Cheung, K., Lee, D. S., Divito, J., Voulo, M., Donovan, J., Dolan, K., Manson, K., Panicali, D., Wang, E., Hörig, H., & Marincola, F. M. (2005). Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. Journal of Clinical Investigation, 115(7), 1903-1912. https://doi.org/10.1172/JCI24624