Among novel therapies being explored for malignant glioma, oncolytic viruses possess relative tumorselectivity and are being tested in clinical trials. In prior years of funding, we have constructed herpessimplex viruses genetically engineered to replicate in tumor cells. Published phase I clinical trials for braintumors have reported the safety of herpes viral vectors but offered little data concerning efficacy in humans.We have found that herpes viral replication can be enhanced by the drug, cyclophosphamide. In publishedand pilot experiments, the effect of cyclophosphamide (CPA) is rapid and does not require the presence ofpre-existing immunity to the oncolytic virus. CPA leads to increased viral liters in multiple types of glialtumors (human, mice or rat) and results in increased survival. The effect appears to also occur with anoncolytic adenovirus. We hypothesize that normal host responses impede the process of oncolytic viralinfection. In pilot data, macrophages appear to be a major determinant of such host responses. We havealso dentified molecular markers (including IFNy, iNOS, VEGFR2, APN and versican) of the host (andpossibly macrophage-mediated) response to oncolytic viral infection and have preliminary data that CPAacts as a sensitizer of viral oncolysis by limiting such responses. The CPA effect is relatively pleiotropic andthere is a need to identify specific pathways that underlie the host processes that impede viral oncolysis andpharmacologic means to limit such responses. We thus propose the following aims:
AIM 1 -Validate changesin the molecular markers that are associated with viral oncolysis;
AIM2 - Determine the cellular infiltrates intumor that are associated with viral oncolysis;
AIM 3 -Determine if CD68+ cells (macrophages/microglia)and their gene products limit viral oncolysis:
AIM 4 -Determine if CD56+ (NK cells) and their geneproduct, IFNY, limit viral oncolysis. We will employ quantitative RT-PCR, FACS, molecular imaging(Project 3, immunohistochemistry (Pathology Core) and genetic and pharmacologic analyses to prove orrefute the stated hypotheses, using GLP- and GMP-grade oncolyic HSV (Vector Core B). If successful, thisproject will begin to elucidate at a molecular level how the host responds to a viral infection of its brain tumorand how this can be modulated to increase anticancer effects. This should be of significance for current andfuture clinical trials of cancer that employ this modality.
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