Production of autologous tumor vaccines would be facilitated by the development of a rapid and efficient method for the transfer of genes into freshly isolated cells. To evaluate the potential of replication defective herpes simplex viral (HSV) amplicon vectors as gene transfer vehicles for tumor vaccine generation, a vector that expresses the human interleukin-2 (IL-2) gene (HSV-IL2) and one that expresses Escherichia coli beta-galactosidase (HSVlac) were tested in hepatoma cells of both murine and human origin. Gene transfer into murine hepatoma cells (HEPA 1-6) was both rapid and highly efficient: greater than 50% of cells expressed beta-Gal when infected at a multiplicity of infection (m.o.i.) of 1 with an exposure period of 20 min. Moreover, gene transfer was as efficient in tumor cells after irradiation with 10,000 rads as in nonirradiated tumor cells. Irradiated HEPA 1-6 cells infected with HSV-IL2 for 20 min secreted IL-2 at a rate of 1,200 +/- 160 ng/10(6) cells per day. C57B1/6J mice immunized with irradiated, HSV-IL-2-transduced tumor cells produced in this way demonstrated specific tumor immunity by in vitro splenocyte tumoricidal activity and by in vivo protection against tumor challenge. Human hepatobiliary tumor specimens harvested at the time of operation, irradiated, and infected with HSV-IL-2 also produced nanogram quantities of IL-2/10(6) cells per 24 hr. These results indicate that the HSV amplicon vector is a good candidate vehicle for gene transfer in the production of autologous tumor vaccines. By allowing rapid gene transfer to freshly harvested tumor specimens, these vectors bypass the requirement for cell culture and make feasible reinfusion of genetically modified and irradiated autologous cells within hours of tumor harvest.
Background: Costimulatory and cellular adhesion molecules are thought to be essential components of antigen presentation in the immune response to cancer. The current studies examine gene transfer utilizing herpes viral amplicon vectors (HSV) to direct surface expression of adhesion molecules, and specifically evaluate the potential of a tumor-expressing intercellular adhesion molecule-1 (ICAM-1) to elicit an anti-tumor response. Materials and Methods: The human ICAM-1 (hICAMI) gene was inserted into an HSV amplicon vector and tested in a transplantable rat hepatocellular carcinoma and in a human colorectal cancer cell line. Cell surface ICAM-1 expression was assessed by flow cytometry. Lymphocyte binding to HSV-hICAMI-transduced cells was compared with that to cells transduced with HSV not carrying the ICAM gene. Tumorigenicity of HSV-hICAMI-transduced tumor cells were tested in syngeneic Buffalo rats. Additionally, immunization with irradiated (10,000 rads) HSV-hICAMI-transduced tu-
An increasing number of hepatic resections are being performed as potentially curative surgery for malignant liver neoplasms. Hepatectomy and subsequent liver regeneration produce a local environment that enhances growth of microscopic residual tumor. To determine if pretreatment with murine interferon gamma (IFN-gamma) can protect against such enhanced tumor growth, Buffalo rats were randomized to receive a 3-day treatment of IFN-gamma (50,000 U/qD intraperitoneally) or saline. Groups then underwent intrasplenic injection of 10(6) Morris hepatoma cells, followed 1 hour later by sham (control) or partial hepatectomy (PH) of 70%. PH significantly enhanced tumor growth within the liver (control, 8 +/- 3 nodules per liver; PH, 73 +/- 12 nodules per liver; P < .001). This enhancement was attenuated by prior administration of IFN-gamma IFN-gamma/PH, 16 +/- 3; P < .001 vs. PH). Growth factor release and liver regeneration were not affected significantly by pretreatment with IFN-gamma. The effect of IFN-gamma on tumor growth is associated with a significant enhancement of Kupffer cell (KC)-mediated tumoricidal activity (percentage of specific lysis, 55 +/- 10% control, 78 +/- 11% IFN-gamma, P < .01) but not lymphocyte-mediated tumoricidal activity. Because microscopic residual disease may be present after hepatectomies for cancer, IFN-gamma may be useful agent in retarding growth of residual tumors.
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