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Manipulating the local tumor microenvironment with vaccinia virus expressing costimulatory molecules for the treatment of melanoma.

7504 Background: The local tumor site possesses a number of suppressive factors that may limit therapeutic responses following vaccination. Therefore, we hypothesized that delivery of a vaccinia virus expressing costimulatory molecules directly into the tumor environment would improve local and systemic anti-tumor immunity.


METHODS
We conducted two Phase I clinical trials in 25 patients with metastatic melanoma, one using vaccinia virus expressing B7.1for monthly direct intra-lesional vaccination and one using vaccinia virus expressing three costimulatory molecules: B7.1, ICAM-1, and LFA-3 using a similar design. Patients were evaluated for toxicity and local responses by blood chemistry, measurement of injected lesions, and FNA for tumor antigen expression. Systemic immunity was assessed in all patients against vaccinia virus, and in HLA-A2 patients (9/25) using A2-restricted gp100 and MART-1 epitopes by IFN-γ ELISPOT assay.


RESULTS
25 patients with melanoma were sequentially enrolled in the two clinical trials (mean age 57.1 years). Toxicity was minimal with three reports of vitiligo and several grade I/II local reactions. All patients developed anti-vaccinia antibody titers, and several patients had evidence of vaccinia-specific T-cell responses. Systemic immunity was documented by an increase in gp100- and MART-1-specific T-cells following vaccination. Overall, 12/25 (48%) of the patients exhibited an objective clinical response in the index lesion. Furthermore, 8/25 (32%) of the patients demonstrated responses of distant disease, including two patients with a complete response for 22+ and 43+ months.


CONCLUSIONS
These results demonstrate that local vaccination with vaccinia virus expressing human costimulatory molecules was well tolerated and induced local tumor regression in nearly half of vaccinated patients. The use of poxviruses to deliver costimulatory molecules to the tumor microenvironment appears to be a powerful method for inducing local anti-tumor responses. Further studies are needed to determine the full potential for the translation of local vaccination into systemic immunity. [Table: see text].