Cytokine Immuno-Gene Therapy for Treatment of Brain Tumors

摘要

The prognosis for patients with an intracerebral (i.c.) neoplasm is poor. Conventional treatments such as surgery, radiation therapy and chemotherapy have done little to affect long-term survival, and new methods of treatment are urgently needed. In this report approaches involving cytokine gene therapy in treatment of malignant brain tumors are reviewed and contrasted to a strategy developed in this laboratory involving the use of allogeneic cells genetically modified to secrete cytokines. In our studies, mice with an i.c. glioma, melanoma or breast carcinoma treated solely by intratumoral injections with allogeneic cells genetically modified to secrete interleukin-2 (IL-2) were found to survive significantly longer than mice in various control groups. The anti-tumor response was mediated predominantly by T-cell subsets (CD8+ and NK/LAK cells). The injections resulted in the killing of only the neoplastic cells; non-neoplastic cells were unaffected. Experiments involving treatment of animals with i.c. tumor using subcutaneous injections of cytokine-secreting allogeneic cells in the presence of tumor antigens demonstrated no effect in prolonging survival in spite of the development of a vigorous systemic anti-tumor immune response. Of special interest, mice injected intracerebrally with the cytokine-secreting allogeneic cells alone exhibited no neurologic defect and there were no adverse effects on survival. The injection of cytokine-secreting allogeneic cells into the microenvironment of an i.c. tumor is hypothesized to induce an anti-tumor immune response capable of prolonging survival. This pre-clinical animal data directly translates into clinical treatments for patients with a malignant i.c. tumor.