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Cancer Immunotherapy Can Use Small Numbers of Stem-Like Immune Cells to Destroy Large Tumors in Mice

A new approach to stimulating immune cells enhances their anticancer activity, resulting in a powerful anti-tumor response in mice, according to a study by researchers at the National Cancer Institute, a part of the National Institutes of Health. This work represents an important advance in the development of immunotherapy for cancer and appears online June 14, 2009 in Nature Medicine.

Researchers found that a subset of immune cells, T lymphocytes called CD8+ memory stem cells, were capable of mediating strong anti-tumor immune response. These potent cells were generated in the laboratory by stimulating anti-tumor T cells in the presence of drugs designed to mimic an important signaling pathway called Wnt, which describes a complex network of proteins whose interactions are essential during development and stem cell maintenance. Under the influence of Wnt, T lymphocytes acquired stem cell-like properties of multipotency and self renewal; that is, they generated differentiating daughter cells while regenerating themselves when transferred back to mice from the lab. These stem cell-like qualities enabled tiny numbers of T cells (about 40,000 cells) to trigger the destruction of large melanoma tumors (containing about one billion malignant cells).

This therapy, in which mice received CD8+ T memory stem cells together with a tumor vaccine and an immune system stimulant known as interleukin 2, improved the survival of treated mice compared with similar treatment using other types of memory T cells.

"This new category of lymphocytes is superior to T cells used in earlier experiments because they have the enhanced ability to renew themselves, to proliferate, to differentiate and ultimately to kill tumor cells," said NCI lead author Nicholas P. Restifo, M.D., an investigator in the Surgery Branch at the Center for Cancer Research.

Current clinical immunotherapies based on the transfer of tumor-specific T cells generated and expanded in the laboratory rely on the use of large numbers of tumor-specific T cells and have had beneficial but sometimes limited success.

If confirmed in humans, the use of tumor-reactive CD8+ memory stem cells could reduce the numbers of tumor-specific T cells needed for successful immunotherapy, thus making this type of therapy easier to develop so that more patients could benefit.

These findings mark the latest advance in the field of cancer immunotherapy using tumor-specific T cells, which is moving from proof-of-concept to a promising treatment for patients with metastatic cancer.

The research was led by Luca Gattinoni, M.D., and Nicholas P. Restifo, M.D., NCI.

For more information on Dr. Gattinoni’s research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=7289. For more information on Dr. Restifo’s research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5762.

NCI leads the National Cancer Program and the NIH effort to dramatically reduce the burden of cancer and improve the lives of cancer patients and their families, through research into prevention and cancer biology, the development of new interventions, and the training and mentoring of new researchers. For more information about cancer, please visit the NCI Web site at http://www.cancer.gov or call NCI's Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

The National Institutes of Health (NIH) — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.
Reference: Gattinoni L, Zhong XS, Palmer DC, Ji Y, Hinrichs CS, Yu Z, Wrzensinski C, Boni, A, Cassard L, Garvin LM, Paulos CM, Muranski P, and Restifo NP. Wnt signaling arrests effector T cell differentiation and generates CD8+ memory stem cells. Nature Medicine. Online June 14, 2009.

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