June 13, 2000 PITTSBURGH, June 9 - Agents that starve tumors by cutting off their blood supply have come to the forefront in experimental cancer therapies within recent years. Promising though they are, these anti-angiogenic drugs are no magic bullet. When treatment with them is discontinued in experimental models, tumors rebound because small pockets of viable cancer cells remain. Now, University of Pittsburgh scientists have shown that triggering an anti-tumor immune response significantly potentiates the effects of the anti-angiogenic drug endostatin in animal models, leading to permanent and complete regression in half of treated animals. These results are being presented Sunday, June 11, at the Era of Hope/Department of Defense breast cancer meeting in Atlanta.
"We have the first data suggesting that anti-tumor immunotherapy combined with vascular inhibition is a promising treatment strategy for cancer," said Eli Gorelik, Ph.D., professor of pathology at the University of Pittsburgh School of Medicine and a member of the University of Pittsburgh Cancer Institute (UPCI). "Increasing anti-tumor immunity and combining this approach with anti-angiogenic drugs could provide a highly effective cancer therapy."
This combined therapy uses endostatin to prevent blood flow to the tumor, leading to tumor starvation, and then uses the body's immune system to kill the remaining cancer cells.
In their research, Dr. Gorelik and his colleagues studied endostatin in two groups of mice, one group with lung cancer cells that fail to stimulate the immune system (3LL cells) and in another group with so-called immunogenic lung tumor cells (3LL-C75 cells). Because they carry special markers on their surface, immunogenic cells stimulate the body's own immune cells to recognize and destroy them.
The investigators found that endostatin inhibited tumor growth in 3LL-bearing animals. However, an 18-day course of endostatin eradicated cancers in 40 percent of animals bearing 3LL-C75 tumors, suggesting that tumor immunity is essential for complete eradication of tumor cells remaining after endostatin therapy. To increase the therapeutic efficacy of endostatin against the non-immunogenic 3LL cells, mice either were vaccinated with 3LL-C75 cells or were treated with interleukin-12. These 3LL-bearing animals were then treated with endostatin. Half of the animals became well, with complete and permanent regression of tumors. No regression of 3LL tumors was observed in mice treated separately with either endostatin alone or by tumor vaccination.
More recently, the UPCI investigators have found that endostatin significantly inhibits growth of breast cancer in mice. Future studies are underway to determine whether endostatin together with anti-tumor immunity yields sustained, complete breast tumor regression. The long-term goal is to develop a clinical protocol for breast cancer incorporating both strategies. The research is supported by a Department of Defense research grant.
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