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Fighting Cancers with "T" Cells

Dr. Charles Sentman has combined two different immune cells into a powerful tumor-attacking hybrid cell

Our body's immune system fights foreign invaders, like viruses, by recognizing signals on infected cells. But when normal cells mutate from within, as in cancer, the distress signals are more subtle, and cancers often evade immune detection and grow into deadly tumors.

Focus article photo

Dr. Sentman's research team includes, from left to right: Dr. Amorette Barber, Dr. Sentman, Dr. Tong (Tony) Zhang, Dr. Mitsuhiro Iyori, Paul Spear, Ming-Ru Wu, and Dr. Agnieszka Rynda.

Researchers are trying to outsmart these evasion tactics with novel immunotherapy treatments. Dr. Charles Sentman, an immunology researcher at Dartmouth Medical School and the Director of the Cancer Center's Immunology and Cancer Immunotherapy Research Program, has found a new way to destroy cancer cells by creating a novel, hybrid immune cell that combines two kinds of immune cells—T cells and natural killer (NK) cells.

T cells have receptors that can detect cancer cells based on even a single changed protein on a cell's surface. T cells are powerful and activate other immune system players to sustain an attack on tumor cells. The highly focused receptor is the T cell's strength but also its weakness. Because T cells are so specific, each patient's cancer would need different T cells to recognize its subtle variations, and there are just too few tumor-specific T cells in each patient. Dr. Sentman's research team designed a way to "reprogram" T cells to widen their "field of vision" so they can target many different tumors.

The answer came from another well-known player in the immune system's arsenal—the NK cell. Unlike T cells, NK cells don't target subtle differences in cells. Instead, they have a receptor called NKG2D that recognizes common "stress-induced" proteins that appear on many different cancer cells but not on normal cells. NKs recognize many types of cancer, such as lymphomas, ovarian, colon, myelomas, and melanomas. Armed with their NKG2D receptors, NK cells attack tumor cells, killing them rapidly. However, NKs are tightly regulated and easily inactivated. Sentman and his team believed they could modify the NKG2D receptor to form a new hybrid immune cell having the power of a T cell but the wide tumor recognition of an NK cell.

To make the new designer cells, Dr. Sentman removed T cells from the body and reprogrammed them to include modified NKG2D receptors. The hybrid cells were transfused back into the body to start their work. And work they did!

Over the past five years, Sentman's team has shown that the new hybrid T cells recognize and kill tumors in both mice and humans. In mice, the hybrid T cells eliminated tumors and led to long-term, tumor-free survival. In fact, Sent-man found that infusing the hybrid T cells induced a strong immune response that protected mice from the tumor long after the infused T cells were undetectable.

In humans, T cells taken from patients with myeloma or ovarian cancer and outfitted with the hybrid NKG2D receptors were able to efficiently kill the patient's own cancer cells. Sentman confirmed that the hybrid T cells also produced cytokines—powerful chemicals that promote an inflammatory response and therefore change the tumor environment to sustain the attack. Sent-man believes these new immune cells attack the tumor directly and "activate the immune system to be much more aggressive against the tumor." This induction of immunity may be what leads to long-term survival.

To take this exciting new research directly to the clinic, Dr. Sentman and several clinical colleagues—Drs. Lionel Lewis, Kenneth Meehan, Marc Ernstoff, and Zbigniew Szczepiorkowski—are preparing to file a formal application with the Food and Drug Administration to test this new immune therapy in cancer patients at Norris Cotton Cancer Center.

April 10, 2010