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Preclinical Evaluation of "Whole" Cell Vaccines for Prophylaxis and Therapy Using a Disabled Infectious Single Cycle-Herpes Simplex Virus Vector to Transduce Cytokine Genes¹

Department of Life Sciences, Nottingham Trent University, Nottingham NG11 8NS, United Kingdom [S. A. A., S. R., R. C. R.]; Cantab Pharmaceuticals Research Limited, Cambridge CB4 4GN, United Kingdom [C. S. M., M. E. G. B., G. M., C. L. H., E. E., D. M. B., J. G. S.]; Imperial Cancer Research Fund Laboratory of Molecular Therapy, Imperial College of Science and Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom [S. T., R. V.]; Division of Immunology, Queens Medical Centre, Nottingham, United Kingdom [R. A. R.]; and Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905 [R. V.]

The development of genetically modified "whole" tumor cell vaccines for cancer therapy relies on the efficient transduction and expression of genes by vectors. In the present study, we have used a disabled infectious single cycle-herpes simplex virus 2 (DISC-HSV-2) vector constructed to express cytokine or marker genes upon infection. DISC-HSV-2 is able to infect a wide range of tumor cells and efficiently express the ß-galactosidase reporter gene, granulocyte-macrophage colony-stimulating factor (GM-CSF), or IL-2 genes. Gene expression occurred rapidly after infection of tumor cells, and the level of production of the gene product (ß-galactosidase, GM-CSF, or IL-2) was shown to be both time-and dose-dependent. Vaccination with irradiated DISC-mGM-CSF or DISC-hIL-2-infected murine tumor cells resulted in greatly enhanced immunity to tumor challenge with live parental tumor cells compared with control vaccines. When used therapeutically to treat existing tumors, vaccination with irradiated DISC-mGM-CSF-infected tumor cells significantly reduced the incidence and growth rates of tumors when administered locally adjacent to the tumor site, providing up to 90% protection. The prophylactic and therapeutic efficacy of DISC-mGM-CSF-infected cells was shown initially using a murine renal cell carcinoma model (RENCA), and the results were confirmed in two additional murine tumor models: the M3 melanoma and 302R sarcoma. Therapy with DISC-infected RENCA "whole" cell vaccines failed to reduce the incidence or growth of tumor in congenitally T-cell deficient (Nu⁺/Nu⁺) mice or mice depleted of CD4⁺ and/or CD8⁺ T-lymphocytes, confirming that both T-helper and T-cytotoxic effector arms of the immune response are required to promote tumor rejection. These preclinical results suggest that this "novel" DISC-HSV vector may prove to be efficacious in developing genetically modified whole-cell vaccines for clinical use.

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