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 - Jul 2005
Externally publishedYes

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Tumor Microenvironment
Vaccinia virus
Melanoma
MART-1 Antigen
Vaccination
T-Lymphocytes
Therapeutics
Immunity
Enzyme-Linked Immunospot Assay
Vitiligo
Clinical Trials, Phase I
Myalgia
Immunotherapy
Fatigue
Real-Time Polymerase Chain Reaction
Fever
Down-Regulation
Clinical Trials
Antibodies
Neoplasms

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Kaufman, H. L., DeRaffele, G., Mitcham, J., Moroziewicz, D., Cohen, S. M., Hurst-Wicker, K. S., ... 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

Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. / Kaufman, Howard L.; DeRaffele, Gail; Mitcham, Josephine; Moroziewicz, Dorota; Cohen, Seth M.; Hurst-Wicker, Karl S.; Cheung, Ken; Lee, David S.; Divito, Joseph; Voulo, Magalese; Donovan, Julie; Dolan, Kate; Manson, Kelledy; Panicali, Dennis; Wang, Ena; Hörig, Heidi; Marincola, Francesco M.

In: Journal of Clinical Investigation, Vol. 115, No. 7, 07.2005, p. 1903-1912.

Research output: Contribution to journalArticle

Kaufman, HL, DeRaffele, G, Mitcham, J, Moroziewicz, D, Cohen, SM, Hurst-Wicker, KS, Cheung, K, Lee, DS, Divito, J, Voulo, M, Donovan, J, Dolan, K, Manson, K, Panicali, D, Wang, E, Hörig, H & Marincola, FM 2005, 'Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma', Journal of Clinical Investigation, vol. 115, no. 7, pp. 1903-1912. https://doi.org/10.1172/JCI24624
Kaufman, Howard L. ; DeRaffele, Gail ; Mitcham, Josephine ; Moroziewicz, Dorota ; Cohen, Seth M. ; Hurst-Wicker, Karl S. ; Cheung, Ken ; Lee, David S. ; Divito, Joseph ; Voulo, Magalese ; Donovan, Julie ; Dolan, Kate ; Manson, Kelledy ; Panicali, Dennis ; Wang, Ena ; Hörig, Heidi ; Marincola, Francesco M. / Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. In: Journal of Clinical Investigation. 2005 ; Vol. 115, No. 7. pp. 1903-1912.
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