Evaluation of poxviruses targeting the tumor microenvironment for cancer therapy.

Abstract

2600 Background: The tumor microenvironment plays a critical role in mediating anti-tumor immunity following immunotherapy. To overcome the suppressive influence of the microenvironment, recombinant vaccinia and fowlpox viruses were designed to express B7.1 alone or a triad of costimulatory molecules, including B7.1, ICAM-1 and LFA-3 (TRICOM) for direct intra-lesional injection into tumors. The safety profile, immune response and therapeutic efficacy of the four poxviruses are reported herein. Methods: A series of phase I clinical trials were conducted in metastatic cancer patients who have measurable, superficial metastatic lesions (2 colorectal, 35 melanoma). Index tumors were injected with vaccinia virus expressing B7.1 (rV-B7.1, n = 12) or TRICOM (rV-TRICOM, n = 13) or fowlpox virus expressing B7.1 (rF-B7.1, n = 6) or TRICOM (rF-TRICOM, n = 6). Patients were evaluated for toxicity using NCI CTC and clinical response by standard RECIST criteria. Blood and tumor biopsies were collected for analysis of systemic and local immune response of vaccines. Results: There were no serious adverse events in any patient. The three most common adverse events were grade I fever (n = 13), grade I fatigue (n = 13) and grade I injection site pain (n = 16). All viruses induced significant anti-viral antibody titers following intra-tumoral injection, although rV- B7.1 induced the strongest response (2.9 fold increase) and rF-TRICOM the weakest (1.8 fold increase). Although all four viruses induced viral-specific T cell responses, both vaccinia vectors showed the strongest tumor-antigen specific T-cell responses. Objective clinical responses were observed in 3 of 12 (25%) patients treated with rV-B7.1, 5 of 13 (38%) with rV-TRICOM, 0 of 6 with rF-B7.1 and 0 of 6 with rF-TRICOM. Conclusions: Intratumoral injection of recombinant poxviruses is safe and capable of generating tumor-specific immunity in metastatic cancer patients. Vaccinia virus demonstrated better antigen-specific T-cell responses and therapeutic effectiveness in Phase I trials. Further studies using vaccinia vectors in combination with other agents or in prime-boost strategies with fowlpox virus might be considered for targeting the tumor microenvironment. No significant financial relationships to disclose.