JOURNAL EMBARGO: October 21, 2002
UCSD Cancer Researchers Develop
New Anti-Leukemia Strategy
Cancer researchers at the University of California, San Diego (UCSD) have developed a 3-step process in which human leukemia cells and neighboring immune-system T cells are manipulated together in the laboratory to create a powerful and specific cancer-killing cocktail. (T cells represent a family of closely related cells of the immune system that circulate in the blood and orchestrate the immune response to infected or malignant cells.)
The details of this approach, generally known as adoptive immunotherapy or cellular therapy, are reported in the October issue of the journal Biology of Blood and Marrow Transplantation.
Edward D. Ball, M.D.
"For reasons that are not yet entirely clear, leukemia cells fail to trigger immune responses," said the paper's senior author, Edward D. Ball, M.D., of the Rebecca and John Moores UCSD Cancer Center. "We have developed a method in which we induce the leukemia cell to change its behavior and stimulate the immune system. At the same time, we persuade the immune system to wake up and attack only the leukemia cells."
A team led by Ball, who is also professor of medicine at UCSD School of Medicine and director of the UCSD Blood and Marrow Transplantation Program, and the study's first author, project scientist Rui-Kun Zhong, M.D., obtained blood samples from 12 patients with acute myeloid leukemia (AML) at the time of diagnosis or relapse. The researchers simply separated out the white cells, which include the AML cells and the T lymphocytes.
"Our goal was to do a minimal amount of manipulation in order to reproduce in the laboratory, as closely as possible, the situation that is occurring in the patient," Ball said.
Then the researchers added certain growth factors, called GM-CSF (granulocyte-monocyte colony-stimulating factor) and IL-4 (interleukin-4), to the cell mix, turning the AML cells into strong antigen-presenting cells, called dendritic cells. These surface antigens are like red flags to T cells, stimulating them to attack.
On day 8, the researchers discontinued the GM-CSF and IL-4, and began a 10-day course of IL-2, which is the main T cell growth factor, making them actively proliferate. Following that they added anti-CD3/anti-CD28 monoclonal antibodies, which are known to amplify the proliferation of T cells.
"By day 42, we saw that the T cells had more than tripled in volume and had killed significant numbers of the patient's leukemia cells," Ball said. "We also tested this 3-step process against cell lines for AML and other types of cancer such as breast and lung cancer. There was a strong killing effect in the AML cell line, but not in the others. This is a very specific action."
Acute myeloid leukemia is often difficult to diagnose. The early signs may be similar to the flu or other common diseases. The primary treatment of AML is chemotherapy. Radiation therapy may be used in certain cases. Bone marrow transplantation and biological therapy are being studied in clinical trials.
The researchers say that the advantages of this approach are that it was developed in a way that will make it easily transferable to clinical application; that it was shown to be effective against any antigen that a patient's AML cells expressed, making it potentially applicable to a large number of patients; and that no cell separation or purification is needed, which translates into safety for the patient.
"With this approach, it may be possible to transfer these potent, AML-killing cells back into the patient as a way of eradicating residual disease following chemotherapy," Ball said. "If our promising laboratory findings prove as effective in clinical studies, it may open up an important new option for patients who are not eligible for bone marrow transplant, or who do not wish to undergo that procedure."
A next step, he said, will be to move this work into clinical trials.
Founded in 1979, the Rebecca and John Moores UCSD Cancer Center is one of just 40 centers in the United States to hold a National Cancer Institute (NCI) designation as a Comprehensive Cancer Center. As such, it ranks among the top centers in the nation conducting basic and clinical cancer research, providing advanced patient care and serving the community through outreach and education programs.
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