Steps made toward overcoming biological obstacles to cell therapy for cancer

Interleukin-15 encourages CD8+ T cells to proliferate and reduces their tolerance to tumor antigens

Certain types of white blood cells assist the body in destroying cancerous tumors. Among these are CD8+ T cells. The T is for thymus, the gland near the base of the throat that both raises up and weeds out blood cells involved in immune responses.

One of the strategies being explored to eradicate established tumors is to increase the number of tumor-reactive T cells through immunization (often called a "cancer vaccine") or by growing large numbers of the patient's tumor-reactive T cells outside the body and giving them back to the patient, a method called adoptive immunotherapy.

CD8+T cells detect proteins called antigens and respond in fighting mode. If such antigens are detected on tumor cells, the CD8+ T cells punch holes in the tumor cells and destroy their contents. However, many tumor antigens are also found in normal body tissues. As a result, the thymus must get rid of most of the tumor-reactive T cells to keep the body from attacking itself.

"Those CD8+ T cells that can recognize such tumor antigens but evade thymic deletion are potentially harmful, and thus are held in check inside the body by mechanisms that make them tolerant of the protein even if it is encountered on a tumor cell," said Dr. Philip Greenberg, University of Washington (UW) professor of medicine and immunology, one of the co-authors of a Feb. 13, 2006, paper in Nature Medicine on new research in adoptive immunotherapy.

However, at times the system operates too well. Because tumor cells express higher levels of many of these antigens than do normal cells, some T cells can recognize the tumor cells and largely ignore the normal cells, but these CD8+ T cells are also held in check inside the body by mechanisms that build up their tolerance to the presence of tumor antigens. They become deficient in sending the signals that lead to tumor-cell killing.

"It is precisely these cells that might be most effective in tumor therapy, albeit with some potential toxicity," the paper said.

The researchers developed a transgenic mouse model in which the CD8+ T cells with receptors for a particular tumor antigen, also found in the mice's normal living tissue. The CD8+ T cells had become tolerant of the antigen. The CD8+ T cells were largely unresponsive, failing to proliferate or to secrete interleukin-2, a cellular product essential for maintaining a response to the tumor antigen.

However, the researchers learned through experimentation that the cells could be rescued from this tolerant state and encouraged to proliferate in laboratory beakers if they were mixed with interleukin-15. The cells are naturally exposed to lower doses of interleukin-15 inside the body, and this probably helps keep the cells alive despite their tolerant state. However, once these cells were induced to proliferate, they could be expanded to large numbers and were no longer tolerant of the tumor antigen.

It's not known precisely how proliferation rescues these cells, but the expanded tumor-reactive T cells were now effective in treating a disseminated form of leukemia in mice without damaging their livers. This suggests that the liver and other normal tissues expressing lower levels of the antigen may have their own protective mechanisms.

The research suggests that high-affinity CD8+ T cells are not necessarily deleted when they encounter the antigen as a normal protein, but rather may be rendered unable to expand under normal conditions, and that these CD8+ T cells can potentially be rescued and expanded for use in tumor immunotherapy.

The authors of the Nature Medicine article, "Interleukin-15 rescues tolerant CD8+ T cells for use in adoptive immunotherapy of established tumors," were Drs. Ryan M. Teague, Blythe D. Sather, Jillian A. Sacks, Maria Z. Haung, Michele I. Dossett, Junko Morimoto, Xiaoxio Tan, Claes Ohlen, and Philip D. Greenberg, all of the UW Department of Immunology; and Drs. Susan E. Sutton and Michael P. Cooke, of the Genomics Institute of the Novartis Research Foundation in San Diego. Teague, Dossett, Morimoto, Tan, Ohlen, and Greenberg also hold appointments in Seattle's Fred Hutchinson Cancer Research Center Program in Immunology. Greenberg's primary appointment is in the UW Department of Medicine.

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Grants from the National Cancer Institute of the National Institutes of Health, and from the Leukemia and Lymphoma Society, supported this research. Teague is also a recipient of a Ruth I. Kirschstein National Research Service Award.

At Fred Hutchinson Cancer Research Center, our interdisciplinary teams of world-renowned scientists and humanitarians work together to prevent, diagnose, and treat cancer, HIV/AIDS, and other diseases. Our researchers, including three Nobel laureates, bring a relentless pursuit and passion for health, knowledge, and hope to their work and to the world. For more information, please visit http://www.fhcrc.org

UW Medicine includes the University of Washington School of Medicine, Harborview Medical Center, UW Medical Center, UW Medicine Neighborhood Clinics, and the UW's involvement in the Seattle Cancer Care Alliance. UW Medicine has major academic and service affiliations with Children's Hospital and Regional Medical Center, the Fred Hutchinson Cancer Research Center, and the Veteran's Affairs Medical Centers in Seattle and Boise. Consistently among the nation's top five recipients of federal funding for biomedical research, the School of Medicine has among its more than 1,700 regular faculty five Nobel Laureates, 39 members of the National Academy of Sciences, and 38 members of the Institute of Medicine. For more information about UW Medicine, please visit http://www.uwmedicine.org/

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