학술논문
Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma.
Document Type
Journal Article
Author
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; Ena Wang; Hörig, Heidi; Marincola, Francesco M.; Wang, Ena; Hörig, Heidi
Source
Subject
*VACCINIA
*VIRUSES
*MELANOMA
*TUMORS
*VACCINATION
*PATIENTS
*MELANOMA treatment
*ANTIGENS
*CLINICAL trials
*COMPARATIVE studies
*GENE expression
*GENE therapy
*IMMUNOTHERAPY
*INJECTIONS
*INTERFERONS
*INTERLEUKINS
*RESEARCH methodology
*MEDICAL cooperation
*PROTEINS
*RESEARCH
*RESEARCH funding
*T cells
*TUMOR antigens
*HLA-B27 antigen
*EVALUATION research
*THERAPEUTICS
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Language
ISSN
0021-9738
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 CD8 and IFN-gamma. 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. [ABSTRACT FROM AUTHOR]