Immunogene therapy with interleukin-2-secreting fibroblasts for intracerebrally metastasizing breast cancer in mice.
OBJECTIVE
Breast cancer is the second leading cause of cancer-related death in American women. Brain metastases occur in 15 to 30% of patients with breast cancer, and this usually results in death. Despite the availability of surgery, radiotherapy, and chemotherapy, the prognosis for patients with breast cancer that has metastasized to the intracerebral region remains poor. This study was designed to determine if an intracerebrally metastasizing breast tumor could be treated successfully with a cellular vaccine consisting of allogeneic fibroblasts (H-2K) modified to secrete interleukin (IL)-2.


METHODS
The authors used EO771 breast cancer cells, derived from a spontaneously arising breast-cancer tumor in C57BL/6 mice. The authors first determined the length of survival of C57BL/6 mice that had been injected with varying numbers of EO771 cells into the right frontal lobes and found that 100% 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 with a single intratumoral injection of 10(6) allogeneic fibroblasts genetically engineered to secrete IL-2. The allogeneic fibroblasts transfected with the IL-2 gene formed large quantities of IL-2 as measured by an enzyme-linked immunosorbent assay. Control groups of animals were treated with either allogeneic fibroblasts transfected with the retroviral vector, but not the IL-2 gene, or with media. The effects of this treatment on the animal's survival 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 90 days by intracerebral injection of tumor, but no treatment cells, and compared with four naive animals receiving intracerebral tumor. Again, animals that previously had been treated with IL-2-secreting fibroblasts had a markedly prolonged survival (p < 0.05) compared with control animals following a second challenge with tumor cells. Histopathological examination revealed smaller tumors associated with lymphocytic infiltrations in the treated animals.


CONCLUSIONS
This work represents a new treatment for breast cancer that has metastasized to the brain in which a cellular vaccine consisting of allogeneic fibroblasts genetically engineered to secrete cytokines is used as a novel means for delivery of immunogene therapy and demonstrates the induction of long-term immunity against tumor.
Deshmukh
P
P
Department of Neurosurgery, University of Illinois, Peoria, USA.
Glick
R P
RP
Lichtor
T
T
Moser
R
R
Cohen
E P
EP
D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary*; D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D005260:Female; D005347:Fibroblasts / Q000276:immunology*; D015316:Genetic Therapy; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics* / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D007376:Interleukin-2