In experiments reported in the Dec. 15 issue of Cancer Research, Chung Lee and colleagues at the Feinberg School of Medicine at Northwestern University applied the gene therapy technique to render immune cells insensitive to transforming growth factor beta (TGF-beta), a powerful, naturally occurring substance in the body called an immunosuppressor that enables cancer cells to evade surveillance by the immune system.
The approach boosted the mice's immune system, which virtually eliminated cancerous tumors in the animals' lungs and prostate gland. "We hypothesized that an immunotherapy strategy that specifically blocks TGF-beta signaling in immune cells, regardless of tumor location or tumor microenvironment, could be highly successful in mediating an antitumor response," said Lee.
Lee is John T. Grayhack, M.D., Professor of Urology at the Feinberg School. Collaborating with Lee and his research group were investigators from the National Cancer Institute, Massachusetts Institute of Technology, the Mayo Clinic and Baylor College of Medicine.
After inserting a mutated gene for the TGF-beta receptor into bone marrow cells, transplanting the cells into mice and subsequently injecting the mice with melanoma cells, the researchers found that 70 percent of the animals survived and showed a virtual absence of metastatic (widely spread) lesions in the lung.
In another group of mice with the mutated TGF-beta gene that were later injected with prostate cancer cells, the gene-targeted approach resulted in 80 percent survival.
All of the control mice in the melanoma and prostate cancer arms of the study that had not received the gene therapy died of metastatic cancer.
Tests showed that in the mice treated with the mutated TGF-beta receptor gene, infection-fighting immune cells had mounted a powerful response to kill cancerous tumors.
Results of the group's studies strongly indicate that a gene therapy approach to inducing TGF-beta insensitivity in transplanted bone marrow cells may be a potent anticancer therapy.
"Our observation in these mice provides a testimony to this possibility," Lee said.
In earlier research studies, Lee and colleagues removed TGF-beta from the prostate cancer of rats. Tumors of half of the animals were eradicated.
While Lee cautions that these results are very preliminary, he also believes that they are extremely encouraging. "We will conduct a few more experiments to further verify these results. It is our hope that we will aggressively pursue a phase I/II clinical trial with cancer patients," Lee said.
"It is possible we may offer mankind an opportunity to eradicate cancer in the future," he said.
Lee's co-authors in this study were Ali H. Shah, William B. Tabayoyong, Shilajit D. Kundu and Victoria Liu, department of urology, Feinberg School of Medicine; Seong-Jin Kim, National Cancer Institute, Bethesda, Md.; Luk Van Parijs, Massachusetts Institute of Technology, Cambridge, Mass.; Eugene Kwon, Mayo Clinic, Rochester, Minn.; and Norman M. Greenberg, Baylor College of Medicine, Houston.
KEYWORDS: cancer, gene therapy, TGF-beta, bone marrow transplantation
Journal
Cancer Research