In vivo transfer of the human interleukin-2 gene: negative tumoricidal results in experimental brain tumors.
The authors have recently shown the feasibility of eradicating brain tumors using in vivo retroviral-mediated transduction of tumors with the herpes simplex thymidine kinase (HStk) gene and ganciclovir therapy. However, thymidine kinase-transduced subcutaneous tumors in immunocompromised (athymic) mice were less responsive to this therapy than in immunocompetent animals, suggesting a role of the immune system in the process of tumor eradication. Broad suppression of humoral and cell-mediated immunity is found in patients with malignant gliomas. Interleukin-2 (IL-2) production and IL-2 receptor expression are decreased in gliomas patients. These findings and the proposed association between lymphocytic infiltration of brain tumors and survival suggest that immune response modifiers may be useful in treating glioma patients. To evaluate the role of local cytokine expression by tumor cells, alone or combined with HStk gene transfer and ganciclovir therapy, the authors investigated the efficacy of tumor (9L gliosarcoma) eradication in Fischer rats by in vitro and in vivo tumor transduction with the IL-2 gene alone or with a combined vector carrying both the HStk and IL-2 genes. Tumors injected with HStk vector-producer cells alone, with or without ganciclovir, and rats inoculated in the brain and subcutaneously with 9L cells that had previously been transduced in vitro served as controls. Murine vector-producer cells (3 x 10(6)/50 microliters) were injected into the brain tumors 7 days after tumor inoculation. Ganciclovir (15 mg/kg) was administered intraperitoneally twice daily for 10 days to animals that received HStk with or without IL-2 vector-producer cells, starting 5 days after producer-cell injection. The experiment was repeated with continuous daily treatment of all rats with oral dexamethasone (0.5 mg/kg). Rats were sacrificed 21 days after tumor inoculation, and the brains were removed for histological and immunohistochemical analysis for IL-2. Within each experimental group, tumors were found in a similar proportion in the dexamethasone-treated and untreated rats. Large brain tumors developed in all 10 rats that had been inoculated with 9L cells which had been pretransduced in vitro with the IL-2 gene, whereas only three of eight rats receiving subcutaneous inoculation of similar cells developed palpable tumors. No enhancement of tumor eradication was observed by adding the IL-2 gene in the HStk vector construct compared to the use of the vector with HStk alone. Lymphocytic infiltration was absent in all dexamethasone-treated rats but was observed in all treatment groups not receiving steroids.(ABSTRACT TRUNCATED AT 400 WORDS)
Ram
Z
Z
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland.
Walbridge
S
S
Heiss
J D
JD
Culver
K W
KW
Blaese
R M
RM
Oldfield
E H
EH
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D003907:Dexamethasone / Q000627:therapeutic use; D015774:Ganciclovir / Q000627:therapeutic use; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D007109:Immunity / Q000235:genetics; D007376:Interleukin-2 / Q000235:genetics*; D051381:Rats; D011916:Rats, Inbred F344; D018139:Simplexvirus / Q000235:genetics; D013937:Thymidine Kinase / Q000235:genetics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D003907:Dexamethasone; D013937:Thymidine Kinase; D015774:Ganciclovir