Cancer Immunotherapy
We are also investigating the role tissue resident macrophages play in regulated immune responses to tumors in mucosal tissues such as the lung and skin. The use of cancer vaccines to induce anti-tumor immunity has largely failed in clinical settings. However, we recently reported the development of a cytomegalovirus (CMV) based cancer vaccine (MCMV-gp100KGP) that elicited a robust anti-tumor CD8 T cell response and tumor rejection. We showed that certain unique properties of CMV made it an excellent vaccine candidate against melanoma and potentially other cancers. In our studies funded by the grant, we used recombinant murine CMV (MCMV) strains as prophylactic and therapeutic vaccines in an aggressive B16 lung metastatic melanoma model. Immunization with MCMV-expressing ovalbumin (OVA) induced a potent OVA-specific CD8 T-cell response and was effective in protecting mice from OVA expressing B16 melanoma in an antigen-dependent manner. We engineered MCMV to express a modified native B16 melanoma antigen gp100 (MCMV-gp100KGP). Immunization with MCMV-gp100KGP was highly effective in overcoming immune tolerance to self-antigen and induced a strong, long-lasting gp100-specific CD8 T-cell response even in the presence of preexisting anti-CMV immunity. Furthermore, both prophylactic and therapeutic vaccinations of mice with MCMV-gp100KGP effectively protected mice from highly aggressive lung B16-F10 melanoma, and gp100-specific CD8 T cells mediated the protection. Our studies showed that MCMV is a superior vaccine vector compared with a commonly used vesicular stomatitis virus vector. Collectively, our studies demonstrated that CMV is a promising vaccine vector to prevent and treat tumors. Although, therapeutic immunization with our CMV based vaccine resulted in significant tumor regression and increased life span; the animals eventually succumbed to the aggressive form of melanoma. Interestingly, none of the check-point blockers (anti-PD-1 or anti-CTLA4) further improved vaccine efficacy. During the course of these studies, we have made several new and interesting observations regarding melanoma. When we imaged the tumors, we observed the influx of specific macrophage populations within the B16 melanoma tumors, and we believe that these tumors associated macrophages (TAMs) may be playing an essential role in regulating anti-tumor immune responses. Thus, currently we are investigating the role of these macrophage and myeloid cell populations in the tumors following vaccination. We are currently determining the following: (i) which subset of TAMs in the lungs and skin are most anti-inflammatory and promote tumor growth, (ii) what are the mechanisms utilized by TAM subsets that suppress anti-tumoral immunity in general and following immunotherapy (CMV based vaccines or CMV + anti-checkpoint blocker combination therapy), (iii) if targeting TAMs would serve as an effective way to improve tumor regression singularly or in combination with CMV vaccine, or in combination with CMV vaccines and checkpoint blockers.