Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma.
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.
Kaufman
Howard L
HL
Department of Surgery, Columbia University, New York, NY 10032, USA. hlk2003@columbia.edu
Deraffele
Gail
G
Mitcham
Josephine
J
Moroziewicz
Dorota
D
Cohen
Seth M
SM
Hurst-Wicker
Karl S
KS
Cheung
Ken
K
Lee
David S
DS
Divito
Joseph
J
Voulo
Magalese
M
Donovan
Julie
J
Dolan
Kate
K
Manson
Kelledy
K
Panicali
Dennis
D
Wang
Ena
E
Hörig
Heidi
H
Marincola
Francesco M
FM
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm; D018122:B7-1 Antigen / Q000235:genetics* / Q000627:therapeutic use; D016827:CD8 Antigens / Q000235:genetics; D005260:Female; D015870:Gene Expression; D015316:Genetic Therapy; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D006801:Humans; D007167:Immunotherapy; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology / Q000556:secondary / Q000628:therapy*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology*
D000951:Antigens, Neoplasm; D018122:B7-1 Antigen; D016827:CD8 Antigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; D016753:Interleukin-10; D007371:Interferon-gamma