Virally delivered cytokine therapy drives immune equilibrium in melanoma

Abstract

Abstract Although a modified, replicating herpes simplex virus (HSV) encoding GM-CSF was FDA-approved for the treatment of melanoma (T-VEC), which was revolutionary for the field of oncolytic virotherapy, there are several areas for improvement. First, the live virus cannot be safely administered to immunocompromised patients. Second, GM-CSF induces immune-suppressive myeloid cells and is likely not the optimal insert. To this end, our lab has used a non-replicating HSV virus, termed d106S, to serve as a safe viral vector for the treatment of cancers. We have repurposed the non-lytic HSV-1 d106S vaccine vector for local delivery of IL-12. Our replication-defective d106S virus releases a large burst of IL-12 locally within the tumor environment, synergizing with a type I IFN response induced by the virus. We have shown that d106S-IL12 induces regression and long-term stable immune equilibrium in murine B16 melanoma. These results are promising, demonstrating that the d106S vector can deliver immunotherapeutic cargo and induce shrinkage of established tumors. Intriguingly, most mice do not fully clear their tumors but establish an equilibrium phase and withdrawal of therapy eventually leads to tumor outgrowth. We have profiled the immune response induced by d106S-IL12 at separate time points, identifying several points of possible intervention, including blockade of innate inflammatory cytokines IL-1β, TNFα and IL-6. Indeed, blockade of each of these inflammatory cytokines provides a boost to the response initiated by d106S-IL12, which we have further profiled with single-cell RNA-sequencing.