The In some animals, the residual tumors were devoid ofcancer cells.This treatment efficacy appears in part due to a "bystander effect" in which phosphorylated ganciclovir could be transferred from cell to cell and to an active local immune reaction evidenced by massive infiltration of the tumors by macrophages and both CD4+ and CD8+ lymphocytes. This efficient therapeutic approach might be an ultimate treatment for disseminated liver metass in hums and could also be applied to treatment of a large variety of solid tumors.
Recombinant adenoviral mediated delivery of suicide and cytokine genes has been investigated as a treatment for hepatic metastases of colon carcinoma in mice. Liver tumors were established by intrahepatic implantation of a poorly immunogenic colon carcinoma cell line (MCA-26), which is syngeneic in BALB/c mice. Intratumoral transfer of the herpes simplex virus type 1 thymidine kinase (HSV-tk) and the murine interleukin (mIL)-2 genes resulted in substantial hepatic tumor regression, induced an effective systemic antitumoral immunity in the host and prolonged the median survival time of the treated animals from 22 to 35 days. The antitumoral immunity declined gradually, which led to tumor recurrence over time. A recombinant adenovirus expressing the mIL-12 gene was constructed and tested in the MCA-26 tumor model. Intratumoral administration of this cytokine vector alone increased significantly survival time of the animals with 25% of the treated animals still living over 70 days. These data indicate that local expression ofIL-12 may also be an attractive treatment strategy for metastatic colon carcinoma.Metastatic colon carcinoma is the second leading cause of death from malignancy in the United States. Eighty percent of the patients who die of colon cancer have metastases in the liver (1). Once hepatic metastases occur, surgery and chemotherapy are the only currently available treatment modalities, and the mean survival time is only 37 months (2). Therefore, the development of alternative treatments for metastases of colon cancer is needed to improve the clinical outcome of patients.Cancer immunotherapy is an approach that has been widely investigated in different types of tumor, the goal. of which is to stimulate host immune response against the cancer cells. Because of its well established immunomodulating activities in stimulating the growth and the activation of T cells as well as natural killer (NK) cells, recombinant interleukin (IL)-2 was first tested in patients for this purpose. A severe limitation of such treatment in patients is the toxicity associated with high doses of systemic recombinant IL-2 administration. Cytokine secretion in the vicinity of the tumor can potentially minimize the toxicity associated with systemic cytokine administration, which could be achieved by the transfer and expression of various cytokine genes directly in the tumor cells (3).In the ex vivo gene therapy or "cancer vaccine" approach, cancer cells are isolated from patients, transduced with various gene vectors and expanded in vitro. After irradiation, the cells are transplanted autologously to enhance the patient's immune response against the tumor. This strategy is not only laborious, but the treatment is also individualized as cancer cells need to be cultured and expanded from each patient for therapeutic purposes. A more attractive strategy is to deliver the cytokine genes in vivo. The retroviral vector is commonly used for the ex vivo approach, but its low titer limits its application by in vivo delivery. The ...
Retroviral vectors derived from the Moloney murine leukemia virus have been used in successful and promising gene therapy clinical trials. However, platforms for their large-scale production must be further developed. As a proof of principle, we reported the generation of a packaging cell line that produces amphotropic retroviral vectors in suspension and serum-free medium (SFM). In the present study, we have constructed and characterized two retroviral packaging cell lines designed for gene transfer in hematopoietic cells. These cell lines grow in suspension and SFM, and produce high-titer RD114- and gibbon ape leukemia virus (GALV)-pseudotyped vectors for a 3-month culture period. Viral particles released are as robust during repeated freeze-thaw cycles and on thermal inactivation at 37 degrees C as their counterparts produced in cells cultured adherently with serum. We also show that RD114- and GALV-pseudotyped vectors produced in suspension and SFM efficiently transduce human lymphocytes and hematopoietic stem cells. As these retroviral packaging cell lines distinctively maintain high vector titers while growing in suspension and SFM, we conclude that these cell lines are uniquely suitable for large-scale clinical-grade vector production for late-phase clinical trials involving gene transfer into hematopoietic cells.
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