oHSV-1 was originally conceived as a local therapy, with cell killing at the site of injection by selective lytic infection of tumor cells and subsequent propagation of viral progeny. As more studies are done in immunocompetent animal models, understanding of the complex relationship between viral oncolysis and immunity is evolving. Postinfection antiviral immunity limits intratumoral viral spread and associated tumor lysis (11
). Accordingly, strategies that oppose elements of innate immunity, such as complement, are associated with enhanced intratumoral viral replication and antitumor effect (11
). Cyclophosphamide has been used to this effect, and in cyclophosphamide-pretreated animals, oHSV replication is enhanced and tumor growth is inhibited (12
). Low-dose cyclophosphamide also reduces the proportion of circulating regulatory T lymphocytes, and it may be that this relative boost in the number of effector T lymphocytes contributes to antitumor activity, raising the possibility that the drug works by enhancing antitumor immunity (13
). Previous data confirm the “vaccination” effect of oHSV infection of tumors, as a systemic antitumor immune response, which is cell-specific and has memory, follows (4
). This antitumor immune response is an important benefit of the therapy, transforming it from a mechanism for local control of cancer into a systemic treatment for multifocal disease, the effect of which may be durable.
Numerous efforts have been undertaken to enhance this antitumor immune effect. Although not definitively proven, dendritic cell subsets likely play central roles in transforming oHSV infection of tumors into systemic antitumor immunity. Viral infection and oncolysis may lead to recruitment and activation of plasmacytoid dendritic cells through toll-like receptors, generating a robust type I IFN response. As immunity responds, iDCs may infiltrate the inflammatory milieu associated with dying tumor, engulf and process cellular debris, and then, having been matured by the “danger signals” associated with the oncolytic environment, migrate to draining lymph nodes where antigen presentation to naive lymphocytes occurs.
Although presentation of tumor-associated antigens by dendritic cells is necessary for antitumor immunity, these cells and other antigen-presenting cells such as macrophages are components of tumor-derived immunosuppressive networks (14
). Many tumors are sources of vascular endothelial growth factor, cyclooxygenase-2, and prostaglandin E2
, all of which suppress dendritic cell differentiation and maturation. Furthermore, tumors, tumor-associated macrophages, and regulatory T lymphocytes express IL-10 and transforming growth factor-β, which suppress dendritic cell maturation and function (14
). Some tumors, including human and murine neuroblastomas, express gangliosides, which are suppressive of dendritic cell maturation and migration (15
). Cytokines associated with dendritic cell differentiation, such as granulocyte-macrophage colony-stimulating factor, IL-4, IL-12, and IFN-γ, are rare in the tumor environment. This cytokine imbalance in the tumor milieu leads to overrepresentation of immature, partially differentiated dendritic cells, which, rather than leading to tumor-specific immunity, is associated with T-cell anergy or with induction of suppressive T lymphocytes (14
However, in the context of cytodestructive and/or inflammatory stimuli, the tumor milieu may be altered to allow iDCs to overcome tumor-associated suppression of function. HSV-1 infection is associated with up-regulated expression of cytokines classically associated with dendritic cell maturation, such as IL-1 and tumor necrosis factor-α (17
Simultaneously, antigen-presenting cells may be exposed to a wider array of tumor-associated antigens and immune adjuvants such as heat shock proteins. Our demonstration that injection of mature dendritic cells into the post-oHSV infection environment does not add to tumor control () suggests that antigen uptake and processing by iDC is a necessary first step before in situ maturation and subsequent migration to regional lymph nodes.
Combination therapy for tumors with G47Δ and iDCs is an attractive and promising clinical strategy. Safety and feasibility have been shown for oHSV-1 injection of tumors and antigen-pulsed dendritic cell vaccination is a commonly studied strategy in patients (18
). We have shown that sequential treatment of established subcutaneous tumors with intratumoral injection of G47Δ and iDCs is curative and should be developed as a feasible clinical strategy for cancer patients.