title: Local delivery of vaccinia virus expressing multiple costimulatory molecules for the treatment of established tumors.
abstract: Successful immunotherapy of established tumors depends on overcoming the suppressive influence of the local tumor microenvironment. The direct injection of vaccinia virus expressing the B7.1 (CD80) costimulatory molecule into melanoma lesions resulted in local and systemic immunity with associated clinical responses. Therefore, we sought to evaluate the effects of a vaccinia virus expressing three costimulatory molecules, B7.1, ICAM-1, and LFA-3 (rV-TRICOM), in patients with metastatic melanoma. A standard dose escalation phase I clinical trial was performed. Thirteen patients were enrolled and 12 were available for follow-up. Local vaccination was feasible, with only low-grade injection site reactions associated with mild fatigue and myalgia reported. There was one occurrence of grade 1 vitiligo. Overall there was a 30.7% objective clinical response, with one patient achieving a complete response for more than 22 months. An inverse association was detected between anti-vaccinia antibody and anti-vaccinia T cell responses. Patients who failed to respond to vaccination but received high-dose interleukin-2 had a trend toward improved survival. Collectively, these results confirm the safety profile and feasibility of direct injection of vaccinia virus expressing multiple costimulatory molecules in patients with established tumors. Further clinical investigation is needed to better define the role of antigen, adjuvant cytokines, costimulation, and cross-presentation in the host immune response to local vaccination with vaccinia viruses expressing immunomodulatory molecules.
authors.affiliation: Tumor Immunology Laboratory, Department of Surgery, Columbia University, New York, NY 10032, USA. hlk2003@columbia.edu
authors.forename: Howard L
authors.initials: HL
authors.lastname: Kaufman
authors.forename: Seth
authors.initials: S
authors.lastname: Cohen
authors.forename: Ken
authors.initials: K
authors.lastname: Cheung
authors.forename: Gail
authors.initials: G
authors.lastname: DeRaffele
authors.forename: Josephine
authors.initials: J
authors.lastname: Mitcham
authors.forename: Dorota
authors.initials: D
authors.lastname: Moroziewicz
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: Charles
authors.initials: C
authors.lastname: Hesdorffer
mesh_terms: D000328:Adult; D000368:Aged; D018122:B7-1 Antigen / Q000008:administration & dosage / Q000235:genetics; D019496:Cancer Vaccines; D005260:Female; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000008:administration & dosage / Q000235:genetics; D007376:Interleukin-2 / Q000627:therapeutic use; D008297:Male; D008545:Melanoma / Q000473:pathology / Q000628:therapy*; D008875:Middle Aged; D013601:T-Lymphocytes / Q000276:immunology; D017211:Treatment Failure; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000235:genetics; D014616:Vaccinia virus / Q000235:genetics* / Q000276:immunology
chemical_list: D018122:B7-1 Antigen; D019496:Cancer Vaccines; D007376:Interleukin-2; D014614:Vaccines, Synthetic; C439566:rV-Tricom; D018799:Intercellular Adhesion Molecule-1