Results of a randomized phase I gene therapy clinical trial of nononcolytic fowlpox viruses encoding T cell costimulatory molecules.
Oncolytic viruses have shown promise as gene delivery vehicles in the treatment of cancer; however, their efficacy may be inhibited by the induction of anti-viral antibody titers. Fowlpox virus is a nonreplicating and nononcolytic vector that has been associated with lesser humoral but greater cell-mediated immunity in animal tumor models. To test whether fowlpox virus gene therapy is safe and can elicit immune responses in patients with cancer, we conducted a randomized phase I clinical trial of two recombinant fowlpox viruses encoding human B7.1 or a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3; TRICOM). Twelve patients (10 with melanoma and 2 with colon adenocarcinoma) enrolled in the trial and were randomized to rF-B7.1 or rF-TRICOM administered in a dose escalation manner (~3.7×10(7) or ~3.7×10(8) plaque-forming units) by intralesional injection every 4 weeks. The therapy was well tolerated, with only four patients experiencing grade 1 fever or injection site pain, and there were no serious adverse events. All patients developed anti-viral antibody titers after vector delivery, and posttreatment anti-carcinoembryonic antigen antibody titers were detected in the two patients with colon cancer. All patients developed CD8(+) T cell responses against fowlpox virus, but few responses against defined tumor-associated antigens were observed. This is the first clinical trial of direct (intratumoral) gene therapy with a nononcolytic fowlpox virus. Treatment was well tolerated in patients with metastatic cancer; all subjects exhibited anti-viral antibody responses, but limited tumor-specific T cell responses were detected. Nononcolytic fowlpox viruses are safe and induce limited T cell responses in patients with cancer. Further development may include prime-boost strategies using oncolytic viruses for initial priming.
1 Rutgers Cancer Institute of New Jersey, Rutgers University , New Brunswick, NJ 08903.
Howard L
HL
Kaufman
Dae Won
DW
Kim
Seunghee
S
Kim-Schulze
Gail
G
DeRaffele
Michael C
MC
Jagoda
Joseph R
JR
Broucek
Andrew
A
Zloza
D000368:Aged; D000369:Aged, 80 and over; D000917:Antibody Formation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D000939:Epitopes / Q000276:immunology; D005260:Female; D005587:Fowlpox virus / Q000502:physiology*; D015316:Genetic Therapy / Q000009:adverse effects; D015789:HLA-A2 Antigen / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D050504:Oncolytic Viruses / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D014614:Vaccines, Synthetic / Q000276:immunology
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D014614:Vaccines, Synthetic; C479601:rF-B7.1 vaccine; C479602:rF-TRICOM vaccine; D007371:Interferon-gamma