Malignant brain tumors, both metastatic and primary, occur frequently, and only palliative therapy is available at present. CNS tumors are particularly devastating to the quality of life of patients, as they frequently result in severe and debilitating neurological complications including headache, paralysis, seizures, and impaired cognition. We have performed experiments in a mouse intracranial melanoma model that demonstrate the viability of a tumor therapy approach based on the use of replication competent neuroattenuated Herpes Simplex Virus-1 (HSV-1) mutants. The rationale for this approach, is that these genetically mutant viruses cannot replicate within the generally post mitotic cells of the nervous system, yet do replicate in cancer cells, which are mitotically active. Thus, they can be used to selectively lyse cancer cells within the CNS. We have developed straightforward, reproducible, clinically relevant syngeneic mouse models in which to study brain tumor therapy. The presence, progression, or regression of tumors can be assessed by non-invasive magnetic resonance imaging, histology, immunohistochemistry, RNA in situ hybridization, and viral titration studies, allowing detailed examination of viral induced effects on the tumor and the brain. Outcome experiments indicate that HSV-1 mutant 1716 can slow progression of pre-formed tumors, and even lead to complete regression of tumors in some animals. Successful Phase 1 clinical trials have been performed with HSV-1 strain 1716 in Scotland, and with a similar virus in the US. The experiments outlined in this proposal will critically examine several important aspects of the tumor-virus host relationship. Specifically, we will i) extend our data on the role of the immune response in control of viral replication and tumor recognition by determining the differences in response in the brain and flank; ii) examine the role of innate and adaptive antiviral and ant-tumor immunity in this model; iii) explore strategies to augment the effectiveness of HSV-1 based tumor destruction by engineering HSV-1 mutants that will express biological response modifiers, such as an angiogenesis inhibitor specifically within tumors cells. Other mutants will be engineered with melanoma specific promoters replacing key viral promoters, in order to increase the viral specificity for tumor cells. This project will allow us to use insights gained from molecular virology and cancer biology to develop viable innovative therapies for patients with brain (and other) tumors.
| Thomas, Darby L; Fraser, Nigel W (2003) HSV-1 therapy of primary tumors reduces the number of metastases in an immune-competent model of metastatic breast cancer. Mol Ther 8:543-51 |
| Miller, Cathie G; Fraser, Nigel W (2003) Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model. Mol Ther 7:741-7 |
| Miller, C G; Krummenacher, C; Eisenberg, R J et al. (2001) Development of a syngenic murine B16 cell line-derived melanoma susceptible to destruction by neuroattenuated HSV-1. Mol Ther 3:160-8 |
| Poptani, H; Duvvuri, U; Miller, C G et al. (2001) T1rho imaging of murine brain tumors at 4 T. Acad Radiol 8:42-7 |
