Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1999-09-22
2003-01-21
Salimi, Ali R. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S199100, C424S205100, C435S005000, C435S320100, C435S173300, C435S069100, C536S023720
Reexamination Certificate
active
06509020
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to recombinant virus strains capable of killing tumor cells. More specifically, the present invention relates to a mutated replication-competent viruses which contains mutations in two genes, is hypersensitive to antiviral agents such as ganciclovir, is not neurovirulent and does not replicate in non-dividing cells, yet can kill nervous system tumor cells. The present invention also relates to recombinant herpesvirus strains, vital vaccines incorporating such strains, methods for making such strains and vaccines, and methods for immunizing a human host against herpes simplex virus using the vaccines.
DESCRIPTION OF THE RELATED ART
Malignant tumors of the nervous system are generally fatal, despite many recent advances in neurosurgical techniques, chemotherapy and radiotherapy. In particular, there is no standard therapeutic modality that has substantially changed the prognosis for patients diagnosed with malignant brain tumors. For example, high mortality rates persist in malignant medulloblastomas, malignant meningiomas and neurofibrosarcomas, as well as in malignant gliomas.
Gliomas are the most common primary tumors arising in the human brain. The most malignant glioma, the glioblastoma, represents 29% of all primary brain tumors, some 5,000 new cases per year in the United States alone. Glioblastomas are almost always fatal, with a median survival of less than a year and a 5-year survival of 5.5% or less. Mahaley et al., J. Neurosurg. 71: 826 (1989); Shapiro, et al., J. Neurosurg. 71: 1 (1989): Kim et al., J. Neurosurg. 74: 27 (1991). After glioblastomas are treated with radiotherapy, recurrent disease usually occurs locally; systemic metastases are rare. Hochberg et al., Neurology 30: 907 (1980). Neurologic dysfunction and death in an individual with glioblastoma is due to the local growth of the tumor.
Efforts to cure primary and metastatic brain tumors have focused on new approaches that make use of genetically modified viruses either to deliver cytotoxic genes to tumor cells or to directly infect and destroy tumor cells in a selective fashion. Treatment strategies employing replication-competent HSV-1 mutants may be particularly promising (Hum. Gene Ther. 5, 183-191; Cancer Res. 54, 5745-5751.; J Neuro-Oncol, 19, 137-147: J. Neurosurg, 77, 590-594: Neurosurg. 32, 597-602; Science 252, 854-856; Stereotact. Funct. Neurosurg. 59, 92-99; Nature Med. 1, 938-943; Virol. 211, 94-101.) Such mutants, like wild-type HSV-1 strains, establish a lytic infection in dividing tumor cells, leading to tumor cell destruction, but establish only a latent infection of the surrounding nondividing brain cells, including neurons. These mutants are attenuated human pathogens and thus, must be examined fully for their safety and utility prior to clinical use.
The first HSV-1 mutant studied, dlsptk, carried a single mutation in the thymidine kinase (TK) gene. Mutant strain dlsptk was found to have significant antineoplastic efficacy with a minimal level of toxicity in human tumor xenografts in immunodeficient mice (Neurosurg. 32, 597-602; Science 252, 854-856). These effects demonstrated the potential of HSV-1 as a tumor therapy, but at least two concerns regarding the safety of dlsptk limited its potential for human use. Because it lacks a functional TK gene, strain dlsptk cannot be controlled by the antiherpetic drugs acyclovir or ganciclovir. Second, infection with TK mutant strains causes neurovirulence in animal models when used at doses that would be employed for cancer therapy (N. Engl. J. Med. 320, 293-296). For these reasons, investigators have tested the usefulness of other mutations that severely reduce the ability of the virus to replicate in nondividing cells but do not prevent viral replication in actively dividing cells (Cancer Res. 54, 5745-5751: J Neuro-Oncol. 19, 137-147; J. Neurosurg. 77, 590-594; Neurosurg. 32, 597-602; Virol. 211, 94-101). One such mutation, introduced in both copies of the diploid ICP34.5 gene, has been shown in at least two parental HSV-1 backgrounds to result in viral vectors that have the tumor kill efficiency of dlsptk but minimal to no detectable toxicity (J. Neurosurg. 77, 590-594: Neurosurg. 32, 597-602; Virol. 211, 94-101. J. Gen. Virol. 75, 2059-2063.). Importantly, the HSV-1 strains with mutation of only the ICP34.5 genes retain TK activity, allowing for control by antiherpetic drugs that are activated by HSV-encoded TK. In U.S. Pat. No. 5,328,688. Roizman. issued Jul. 12, 1994, there is disclosed an HSV-1 strain that is reported to be rendered avirulent by the prevention of expression of an active product of a gene, designated gamma 34.5. that maps to the inverted repeats, flanking the long unique sequence of herpes simplex virus DNA. this gene is not essential for viral growth in cell culture. Viruses from which 34.5 was deleted or which carried premature stop codons in the 34.5 gene are avirulent following intracerebral inoculation of mice.
More recently, efforts to increase the safety of herpes-based therapy have spurred the development of HSV-1 strains that have mutations in two viral genes and thus are theoretically less likely to be repaired by recombination with a preexisting or subsequent HSV-1 infection. U.S. Pat. No. 5,585,096, Martuza et al., issued Dec. 17, 1996, discloses a method for killing malignant brain tumor cells in vivo by introducing replication-competent herpes simplex virus vectors to tumor cells. A replication-competent herpes simplex virus vector, with defective expression of the gamma 34.5 gene and the ribonucleotide reductase gene, specifically destroys tumor cells and is not neurovirulent.
Initial success with such a strain, designated G207, has been reported for treatment of glioblastoma xenografts established in immunodeficient mice (Nature Med. 1, 938-943). Strain G207 carries a deletion of both copies of the ICP34.5 gene and a mutated ICP6 gene, that encodes the large subunit of the ribonucleotide reductase, an enzyme in the salvage pathway required for efficient DNA synthesis (ROIZMAN, B. and SEARS. A. E., 1990). Herpes simplex viruses and their replication, p. 1795-1841. In B. N. Fields, et al. (ed.), Virology, 2nd ed. Raven Press, New York). In addition to being multiply-mutated, this virus also retains sensitivity to antiherpetic drugs and has minimal toxicity in animal models (Nature Med. 1, 938-943).
It remains of utmost importance to develop a multiple HSV-1 mutant viral strain that has the greatest possible safety and therapeutic value.
SUMMARY OF THE INVENTION
It is therefore an object of this invention to provide a replication-competent viral vector, suitable for use in humans, that is capable of killing human tumor cells in vivo, that exhibits hypersensitivity to anti-viral agents and an inability to revert to wild-type virus, and that is not neurovirulent at a dose required to kill tumor cells.
It is another object of the present invention to provide for the production of a replication-competent herpes simplex virus-derived vector that is effective and safe for use in the treatment of malignant brain tumors in humans.
It is a further object of the invention to provide a safe, mutated HSV-1 vector, incapable of reverting to wild-type form through a spontaneous single mutation, for use in the context of a vaccine or tumor therapy.
Still another object of the present invention is to provide a mutant HSV-1 vector that can selectively replicate in and kill a tumor cell of non-nervous tissue origin.
An additional object of the present invention is the production of a replication-competent viral vector, derived from herpes simplex virus, that can be employed in a genetic therapy against tumors by expressing foreign genes to target an immune response that kills the tumor cells.
Yet another object of the present invention is the production of a mutant herpes simplex virus vector containing a tumor cell-specific promoter so that the vector can be targeted to specific tumor cells.
It is also an object of the present invention to provide for production of a rep
Parysek Linda Marie
Pyles Richard Brent
Warnick Ronald E.
Salimi Ali R.
The University of Cincinnati
Wood Herron & Evans L.L.P.
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