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Nagarkatti earns NIH award for cancer-research achievements

By Jeffrey S. Douglas

Spectrum Volume 19 Issue 30 - May 1, 1997

An Independent Scientist Award from the National Institutes of Health will enable an investigator in the Virginia-Maryland Regional College of Veterinary Medicine to intensify research that has already been credited with several major victories in the battle against cancer.

Mitzi Nagarkatti, an associate professor in the college's Department of Biomedical Sciences and Pathobiology who is exploring the role the immune system plays in oncogenesis, was awarded a five-year $330,000 grant on the basis of her laboratory's past research achievements and the promise it holds for the future.

"There is so much being done in cancer research," said Nagarkatti, who will be able to devote more time to her research as a result of the grant. "But there is so much more to do, and much of this must be done in the field of immunotherapy."

Immunotherapy shows great promise in the war against cancer because it does not involve the generalized cellular destruction associated with conventional chemotherapy, there is no "resistance" developed to the pharmacologic agents, and it is highly specific for the targeted tumor cells.

Immunotherapy has already led to successful new approaches for melanoma and renal-cell carcinoma, Nagarkatti said, and work is under way around the nation which should lead to other important applications in the future. But much remains to be learned about how the body's immune system can be stimulated to contain and destroy cancer cells.

Nagarkatti's pioneering work has examined the role T cells play in the destruction of tumors. While scientists had understood that T-cells used T-cell receptor molecules as part of the process of destroying tumors, Nagarkatti's research demonstrated an alternative mechanism for this process in 1991.

In research published in the Proceedings of the National Academy of Science, Nagarkatti discovered that T cells also use another adhesion molecule called CD44 in the process of attacking cancer cells. Several laboratories around the world have subsequently reported similar findings with other immune cells that kill cancer.

This discovery proved of major significance. Not only did it provide immunotherapists with another protocol for activating T-cells to destroy non-specific tumor targets, it provided information that would prove critical in scientific efforts to understand a troublesome medical problem called vascular-leak syndrome.

Associated with disorders ranging from infections to auto-immune disorders and organ-transplant rejection, vascular-leak syndrome occurs when small blood vessel-walls deteriorate and break down, causing hemorrhage.

In results published in the International Journal of Cancer in 1995, Nagarkatti presented work which suggested that under certain conditions, vascular-leak syndrome could be caused when T-cells bearing the CD44 adhesion molecule destroyed the endothelial cells lining blood-vessel walls.

Nagarkatti and colleagues were looking at ways to mitigate this endothelial cell damage by activating cytotoxic T-cells to up-regulate the CD44 adhesion molecules when they made an astonishing discovery: T-cell lines they had cultured became cancerous.

In a breakthrough which has provided a critically important opportunity to understand how cancer originates, Nagarkatti and her colleagues discovered that the T-cells were producing and responding to their own growth factor, called interleukin-2. This mechanism, termed autocrine growth, was the first demonstration that cancer can occur outside of a living organism.

Published in the Proceedings of the National Academy of Sciences in 1994, this work sounded a major note of caution in clinical care and provided significant new hope for treating cancer.

"First, it suggested that extreme caution should be used when using cultured T cells to treat cancer or viral infections to make sure that such cells do not contain `transformed' or cancer cells," Nagarkatti said. "Second, it showed that T-cell leukemias and lymphomas that originate using autocrine growth mechanisms can be treated using antagonists against growth factors such as interleukin-2."

Subsequent work in her laboratory has demonstrated that complete tumor regression has occurred when tumor-bearing mice are treated with antibodies against interleukin-2 or its receptor.

"Independent Scientist Awards have always been prestigious awards that are very difficult to obtain," said Lud Eng, head of the college's Department of Biomedical Sciences and Pathobiology. "We are very pleased to see Dr. Nagarkatti's success in earning the award, and we are very excited about the work she is doing in her laboratory."

Nagarkatti, who has received about $1.7 million in funding from the National Institutes of Health and the American Cancer Society throughout her career, accepted a post in Virginia Tech's Department of Biology in 1986 after conducting NIH-funded post-doctoral work with noted immunologist Alan Kaplan at the University of Kentucky.

She has conducted much of her work in collaboration with her husband Prakash, an associate professor biology in the university's biology department, and with researchers in the VMRCVM, where she accepted a post in 1994.

Nagarkatti has published more 60 professional papers, and organized the Annual Seminar of Cancer Researchers in Virginia at Virginia Tech in 1994.