The recent FDA-approval of a modified, replicating herpes simplex virus (HSV), talimogene laherparepvec (T- VEC), encoding GM-CSF for the treatment of melanoma, was a breakthrough in the field of oncolytic virotherapy. Although the approval of T-VEC was revolutionary, there are still several areas for improvement. First, the live virus cannot be safely administered to immunocompromised patients, including those receiving steroids, without risk of disseminated herpes infection. Second, GM-CSF can induce immune-suppressive myeloid cells and is likely not the optimal insert. Third, the choice of only one cytokine payload is limiting. To this end, our lab has made use of a non-replicating HSV virus, termed d106S, that can serve as a safe viral vector for the treatment of cancers because it is non-replicating. HSV-1 d106S was originally designed as a vaccine vector for transient expression of cargoes, which we have repurposed as a non-lytic vector for local delivery of IL-12, a potent cytokine capable of organizing a Th1 response against tumors. However, due to the pleiotropic effects of IL-12, dose-limiting toxicities often become a barrier to effective treatment. Our replication-defective d106S virus releases a large burst of IL-12 locally within the tumor environment, which synergizes with a type I IFN response induced by the virus. We have shown that d106S-IL12 induces regression of tumors and long-term stable immune equilibrium in murine B16 melanoma. These results are promising and show that the d106S vector can deliver immunotherapeutic cargo and induce shrinkage of established tumors. Intriguingly, the majority of mice do not fully clear their tumors but establish an equilibrium phase. Withdrawal of therapy eventually leads to tumor outgrowth. We have profiled the immune response induced by d106S-IL12 at several time points, and have identified several key nodes of potential intervention, including blockade of innate inflammatory cytokines IL-1?, TNF? and IL-6. We have also demonstrated increased CD8+ T cell infiltration from a d106S vector encoding the chemokine CXCL13. Based on the high potency of d106S-IL12, and we propose that addition of cytokine blockade or chemokine secretion within a non-replicating polycistronic vector will allow for tandem expression, regression of local tumors and priming of an even more robust CD8+ T cell response. This non-replicating, polycistronic HSV-1 would be one of the first of its kind, and our study will give new insight into synergy between different negative and positive regulators of IL-12 and how these cytokines/chemokines affect anti-tumor immune memory formation.
Our lab has developed a non-replicating herpes simplex virus (HSV) that can express proteins to enhance an immune response against tumors. In this proposal, we will use this virus to secrete multiple proteins at once to promote an immune response and clearance of melanoma. The goal of this study is to identify any synergy and characterize the immune responses of these multi-cargo viruses.
