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Evaluation of Genetically Engineered Herpes Simplex Viruses as Oncolytic Agents for Human Malignant Brain Tumors¹

Brain Tumor Research Laboratories, Division of Neurosurgery, Department of Surgery [L. S., E. R. F., J. M. M., G. Y. G.], Division of Clinical Virology, Department of Pediatrics [S. A., R. J. W.], Department of Microbiology [S. A., G. Y. G., R. J. W.] and Medicine [R. J. W.], University of Alabama at Birmingham School of Medicine, Birmingham, Alabama 35294-0006, and The Marjorie B. Kovler Virology Oncology Laboratory, University of Chicago, Chicago, Illinois 60630 [J. C., B. R.]

Earlier studies have shown that genetically engineered herpes simplex viruses (e.g., HSV-1) are effective in killing malignant tumor cells both in vitro and in various murine tumor models. This report focuses on a panel of five genetically engineered viral mutants of the ₁34.5 gene, which was shown previously to cause reduction in viral replication and associated neurovirulence of HSV. These include R3616, which has both copies of ₁34.5 deleted, R4009, which has a stop codon inserted after codon 28 in both copies of the ₁34.5 gene, R849, which contains a lacZ gene inserted in place of the ₁34.5, R908, which lacks 41 codons in frame after codon 72 of the ₁34.5, and R939, which carries a stop codon precluding the translation of the COOH-terminal domain of the ₁34.5 gene. We report the following: (a) all five mutant HSVs were avirulent in experimental animals but were cytotoxic for human tumor cells in vitro and in vivo; (b) the ₁34.5^- HSV replicated in human glioma cells almost as efficiently as wild-type HSV-1(F) based on replication assays, in situ hybridization for viral DNA, and expression of infected cell protein 27; (c) capacity of mutant HSVs to kill human cells derived from glioblastoma multiforme (CH-235MG, D-37MG, D-54MG, D-65MG, U-251MG, U-373MG, and SK-MG-1), anaplastic astrocytoma (Hs-683), anaplastic glioma (U-87MG and U-138MG), gliosarcoma (D-32GS), or normal human astrocytes demonstrated that glioma cells varied in their susceptibility to HSV-mediated cytotoxicity and that cultured astrocytes were two to three orders of magnitude less susceptible to killing than were malignant glia; and (d) scid mice, which received 0.5 or 5 x 10⁶ plaque-forming units of R4009, either were coinoculated at the time of intracranial transplantation with 10⁶ U251MG or D-54MG human glioma cells or received the cells intratumorally 5 days after tumor induction and experienced significant increases in median survivals, with no histopathological indication of an infectious encephalitic process. Genetically engineered ₁34.5^- HSV mutants appear to be a potentially safe biotherapeutic agent for experimental treatment of uniformly fatal malignant brain tumors.

¹ The studies at the University of Alabama at Birmingham were aided by a fellowship (to E. R. F.) from the American Brain Tumor Association and by funds from the USPHS NIH Grants T35-HL07473, P20-NS31096 (to G. Y. G.), AI-24009 (to R. J. W.), unrestricted Infectious Disease grants from Bristol-Myers Squibb (to R. J. W. and B. R.), and Grant DE-FG05-93ER61654 from the Department of Energy (to G. Y. G.). Studies at the University of Chicago were aided by grants from the USPHS, National Cancer Institute Grant CA47451 (to B. R.), and Grant AI124009 from the National Institute for Allergy and Infectious Diseases.

² To whom requests for reprints should be addressed, at Brain Tumor Research Laboratories, THT 65, 1900 University Boulevard, University of Alabama at Birmingham, Birmingham, AL 35294-0006.

Received 9/ 6/96. Accepted 2/22/97.

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