Interfering With the Immune Response Against the Virus

For the viral antitumor effect to succeed, viral replication must out-compete tumor proliferation. However, the fact that oncolytic viruses are attenuated in their replication and that they also provoke an intense immunogenic response may hinder efficient tumor spread and lysis. Therefore, one strategy to improve biologic efficacy may involve interfering with the immune response.

The immune response of the body to adenoviruses and HSVs follows a similar pattern consisting of an immediate innate response and a slower adaptive response. The nonspecific early occurring immune response contributes the largest effect to elimination of the viruses (44). This innate response includes the activation of the complement cascade (45) and the recruitment and activation of macrophages, neutrophils, and natural killer cells which kill the infected cells either directly, or indirectly by secreting antiviral cytokines and chemokines (46,47). In addition, the recruitment and activation of antigen-presenting cells (APCs) is essential for the development of an adaptive immune response (48,49). The adaptive immune response is elicited when the viral antigens are presented to the T-helper cells, resulting in activation and secretion of cytokines by the T-helper cells and the maturing of B-cells into plasma cells. Plasma cells produce large amounts of high-affinity antibodies directed against the infected cells and the viral proteins. Together, these responses can result in a rapid inac-tivation of the oncolytic viruses and impede their therapeutic efficacy.

For this reason, several strategies have been developed to circumvent early inactivation of the virus by the immune system. Initially, these studies were performed using replication-deficient vectors in the interest of improving and prolonging transgene expression. Partial immune ablation using cytokines or CTL4A-Ig can lead to persistent adenoviral gene expression in mouse lung and liver (50,51). The anti-cancer drugs etoposide and cyclophosphamide (CPA) were shown to enhance intratumoral transgene expression in immunocompetent mice (52). The production of neutralizing antibodies to Ad and cytotoxic T-lymphocyte-mediated lysis of virally transduced cells were significantly suppressed in these animals. In a study using herpes vectors for gene transfer to neurons in the spinal cord, co-administration of cyclosporin A led to more persistent transgene expression in infected cells (53). The inactivating role of the complement system was underscored by studies of Ikeda et al. (55) who demonstrated that rodent plasma inhibits cell transduction by adenoviral and herpes vectors. In vitro inactivation of complement with mild-heat treatment of the serum restored transduc-tion efficiency. In vivo, complement depletion was achieved by administering cobra venom factor (CVF) prior to intra-arterial delivery of replication-conditional (oncolytic) HSV in a rat model for multiple intracerebral tumors. The complement inactivation led to a strong increase in the initial infection efficiency ofthe tumors (54). In earlier reports, it had been demonstrated that administration of CPA enhanced the propagation of the oncolytic virus (55). Combined treatment of oncolytic HSV with CVF and CPA inhibited both the innate and anti-HSV neutralizing antibody response, and their concerted action prolonged survival of rodents bearing intracerebral tumors (54). More recently, cyclophosphamide was shown to inhibit the production of antiviral cytokines by peripheral blood mononuclear cells (PBMCs) as well as PBMC numbers even in the presence of active viral oncolysis (56). This appears to suggest that PBMC responses may be limiting to viral oncolysis.

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