Cancer Immunotherapy Uses Small Number of Stem-Like Immune Cells to Kill Large Tumors

A new approach to stimulating immune cells enhances their anticancer activity, resulting in a strong antitumor response in laboratory mice.

This research, conducted by investigators from the U.S. National Cancer Institute (NCI), a part of the U.S. National Institutes of Health (Bethesda, MD, USA), represents an important advance in the development of immunotherapy for cancer, and appears online June 14, 2009, in the journal Nature Medicine.

Researchers discovered that a subset of immune cells, T lymphocytes called CD8+ memory stem cells, were capable of mediating strong antitumor immune response. These powerful cells were generated in the laboratory by stimulating antitumor T cells in the presence of drugs designed to mimic an important signaling pathway called Wnt, which is 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; meaning, they generated differentiating daughter cells while regenerating themselves when transferred back to mice from the lab. These stem-like characteristics enabled tiny numbers of T cells (approximately 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, depend on the use of large numbers of tumor-specific T cells and have had beneficial but sometimes limited effectiveness. 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 development 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 NCI scientists Luca Gattinoni, M.D., and Nicholas P. Restifo, M.D.

Related Links:
[U.S.] National Cancer Institute