Intralesional Vaccinia/GM-CSF Recombinant Virus in the Treatment of Metastatic Melanoma
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INTRALESIONAL VACCINIA/GM-CSF RECOMBINANT VIRUS IN THE TREATMENT OF METASTATIC MELANOMA
Michael J. Mastrangelo, Henry C. Maguire, and Edmund C. Lattime*
Jefferson Medical College of Thomas Jefferson University
1025 Walnut Street Philadelphia, Pennsylvania 19107, USA
1. INTRODUCTION Requisite to the development of an immune response is an array of cytokines which provide co-stimulatory signals to facilitate T lymphocyte activation. Approaches to
enrichment of the cytokine milieu have included systemic administration (Maguire, 1995) as well as direct injection at the immunization site (Harris et al., 1998; Russo et al., 1989).
We and others hypothesized that higher, and perhaps more effective, cytokine levels could be achieved at immunization sites by active local production rather than passive transfer. The demonstration by Golumbeck et al. (1991) that immunization with tumor cells
engineered to secrete interleukin-4 could induce regression of an established syngeneic renal cell cancer (RENCA) in mice has led to clinical trials of the methodology. However,
the application of this technique in the clinic is severely limited by the requirements that autologous tumor be removed, grown in tissue culture, successfully transfected and prepared for safe re-introduction into the host. Our over-all goal has been to circumvent this cumbersome procedure by using a recombinant virus to insert genes of interest into tumor cells in vivo so that cytokines will be produced in situ, thus facilitating the generation of a therapeutically effective systemic anti-tumor immune response.
In the present study, vaccinia virus was used as a vector for the transfer and expression of the granulocyte-macrophage colony stimulating factor (GM-CSF) cDNA, as well as the cDNA of the reporter gene (beta glalactosidase), to melanoma cells in vivo by
direct intratumoral injection. Parameters assessed included toxicity, cytokine and passenger gene expression, anti-vaccinia immunity and tumor regression.
*Current Address: The Cancer Institute of New Jersey 195 Little Albany Street New Brunswick, NJ 08901, USA
Cancer Gene Therapy: Past Achievements and Future Challenges, edited by Habib Kluwer Academic/Plenum Publishers, New York, 2000.
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1.1. Gene Transfer Vector Mastrangelo et al. (1996) reviewed the attributes of various viral and non-viral vectors for gene transfer. Vaccinia virus seemed well suited for intralesional therapy (Moss, 1991). It is highly infectious and targets many cell types. Viral lysis of infected tumor cells directly reduces tumor burden. The wild-type virus alone will trigger a cytokine cascade and recruit helper T lymphocytes to the injection site (Schimizu et al., 1988). Vaccinia has been successfully employed for gene insertion in patients at risk for AIDs (Cooney et al., 1991) and in colon cancer patients (Cole et al., 1996). The large size of the virus allows it to serve as a carrier for multiple genes as needed. Encoded genes are delivered into and function in the cytoplasm of th
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