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Collaboration takes killer T-cells to the next level

by Ruth SoRelle, MPH

Cliona Rooney, Ph.D., left, and Helen Heslop, M.D.

The promise of translational medicine – taking new findings directly from the laboratory to the bedside – finds no better example at Baylor College of Medicine than the collaboration of Helen Heslop, M.D., and Cliona Rooney, Ph.D. Their promising experiments using immune system cells called cytotoxic T-lymphocytes or killer T-cells against cancers arising from Epstein-Barr virus provide specific evidence that such work may, in future, provide new tools in the fight against cancer.

Their experiment not only delineated the value and problems involved in such work, it also garnered them one of the 2005 Michael E. DeBakey, M.D., Excellence in Research awards, one of the premier research awards at Baylor College of Medicine.

Quality research

During a convocation to bestow the awards, DeBakey said that rewarding research in this way is among his proudest moments. He pointed out that the six people who received the awards this year contribute not only to the world of science as a whole but also to the standing of Baylor College of Medicine.

"The quality of research activity is the most important activity in assessing the ranking of medical schools," said DeBakey. "The major difference (among medical schools) is the quality of research, and that's one of the reasons that Baylor is listed among the top tier of medical schools in this country."

"This collaboration is notable because it represents what the NIH (National Institutes of Health) is trying to accomplish – a collaboration between basic and clinical scientists," said James Patrick, Ph.D., senior vice president and dean of research at BCM. "This is a perfect example because two individuals with the same interest got together and did the right experiment."

Right place, right experiment

The right experiment meant tailoring these killer T-cells to specifically attack tumor cells carrying proteins or antigens that marked them as related to Epstein-Barr virus. Previously, they had accomplished this against a particular kind of cancer that attacks patients who had undergone bone marrow transplants. These patients had depleted immune systems that made them vulnerable to cancers that would have been seen and actively attacked by a person with normal immunity.

"It was a slightly unusual situation," said Heslop. "It is a very immunogenic tumor that only occurs in patients with an incompetent immune system."

The T-cells were extremely effective in these cases. Building on that, Heslop and Rooney used them against Hodgkin's lymphoma and nasopharyngeal carcinoma (a cancer of nose and pharynx), two cancers that arise from tissue infected with Epstein-Barr virus. This experiment has had some success, even though the cancers were not as easily targeted by the immune system as those that arose after bone marrow transplants.

Some of the patients, whose cancers had recurred after previous treatment, had complete remissions and in some, the cancer responded partially. However, the treatment did not help some patients at all.

The tumor-specific T-cells remained in the body for as long as a year and they tend to accumulate in the tumors – a positive finding, said Heslop.

Future direction

Taking those results back to the laboratory, Rooney and her laboratory are looking at ways to fine-tune the T-cells to attack cancers even more actively. For example, she is identifying new antigens or proteins expressed by tumors for targeting T-cells to them. These specially designed T-cells would look for these antigens – both those associated with viruses and those that are not – and kill tumor cells bearing them.

She is also looking at ways in which tumors evade the immune system and grow as though they were normal tissues in the body. For example, Hodgkin's lymphoma cells inactivate the cells that alert the immune response and present tumor antigens to T-cells. In another instance, these cells can cause the T-cells to enter apoptosis, a form of programmed death. By understanding these immune evasion strategies T-cells can be genetically engineered so that they become resistant to inactivation by tumors.

Therefore, she and Heslop are looking at multi-pronged approaches to overcoming these strategies of evasion, since only by counteracting a number of tumor immune evasion strategies will tumor-specific T-cells fulfill their potential.

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