Immunogene therapy with interleukin-2-secreting fibroblasts for intracerebrally metastasizing breast cancer in mice

Object. Breast cancer is the second leading cause of cancer-related death i n American women. Brain metastases occur in 15 to 30% of patients with brea st cancer, and this usually results in death. Despite the availability of s urgery, radiotherapy, and chemotherapy, the prognosis for patients with bre ast cancer that has metastasized to the intracerebral region remains poor. This study was designed to determine if an intracerebrally metastasizing br east tumor could be treated successfully with a cellular vaccine consisting of allogeneic fibroblasts (H-2(K)) modified to secrete interleukin (IL)-2. Methods. The authors used EO771 breast cancer cells, derived from a spontan eously arising breast-cancer tumor in C57BL/6 mice. The authors first deter mined the length of survival of C57BL/6 mice that had been injected with va rying numbers of EO771 cells into the right frontal lobes and found that 10 0% of those animals that received a dose of 10(4) cells died within 41 days , whereas 100% of the group that received 10(3) cells died within 23 days. Based on these results, 5 x 10(4) EO771 cells were injected into the right frontal lobe of C57BL/6 mice and the animals were treated intracerebrally w ith a single intratumoral injection of 10(6) allogeneic fibroblasts genetic ally engineered to secrete IL-2. The allogeneic fibroblasts transfected wit h the IL-2 gene formed large quantities of IL-2 as measured by an enzyme-li nked immunosorbent assay. Control groups of animals were treated with eithe r allogeneic fibroblasts transfected with the retroviral vector, but not th e IL-2 gene, or with media. The effects of this treatment on the animal's s urvival and the tumor's histopathological characteristics were investigated . The results indicate a significant prolongation (p < 0.005) of survival in animals with intracerebrally metastasizing breast cancer treated only with IL-2-secreting allogeneic fibroblasts. Tumor did not develop in four of 10 animals in the IL-2-treated group, and these animals were rechallenged at 9 0 days by intracerebral injection of tumor, but no treatment cells, and com pared with four naive animals receiving intracerebral tumor. Again, animals that previously had been treated with IL-2-secreting fibroblasts had a mar kedly prolonged survival (p < 0.05) compared with control animals following a second challenge with tumor cells. Histopathological examination reveale d smaller tumors associated with lymphocytic infiltrations in the treated a nimals. Conclusions. This work represents a new treatment for breast cancer that ha s metastasized to the brain in which a cellular vaccine consisting of allog eneic fibroblasts genetically engineered to secrete cytokines is used as a novel means for delivery of immunogene therapy and demonstrates the inducti on of long-term immunity against tumor.