Immune Responses to Chemotherapy Could Lead to New Treatments

Researchers at NCI's Center for Cancer Research (CCR) have discovered a mechanism by which cancer patients' immune systems respond to chemotherapy. The new finding changes the current understanding of how the immune system responds to chemotherapy and could lead to opportunities for new treatments based on enhancing the body's immune response to the disease. The study findings appear in the November 2005 issue of Nature Medicine.

The researchers examined immune recovery in 26 young cancer patients with pediatric sarcomas who received cyclophosphamide-based chemotherapy, which depleted lymphocytes - creating a condition known as lymphopenia. The patients were then infused with their own lymphocytes, which had been frozen and stored before chemotherapy began. Researchers examined the effect of this treatment on the patients' immune recovery with or without recombinant interleukin-2 (IL-2), an agent that has been considered capable of restoring an immune system weakened by chemotherapy.

The researchers reported that the patients who received IL-2 showed a marked increase in suppressor T cells after chemotherapy. "This is a surprising result, since IL-2 has been considered an immune activator, not a suppressor," comments Dr. Crystal L. Mackall, head of CCR's Pediatric Oncology Branch Immunology Section and study co-author.

They also discovered that the suppressor T cells that appeared following chemotherapy and IL-2 were derived from existing T cells. "If a patient with lymphocyte depletion was also depleted of suppressor cells, the immune system would be predicted to be highly reactive - and responsive to antitumor vaccines - and therefore may be better able to fight cancer," Dr. Mackall explains. CCR is planning a new clinical trial to test this approach.

Mutations in microRNA Genes Found in Leukemia Patients

About 10 percent of patients with chronic lymphocytic leukemia (CLL) have mutations in genes for microRNAs, and some of these mutations may be involved in initiating the disease, according to a study in the October 27 New England Journal of Medicine (NEJM).

microRNA genes produce small molecules that control the levels of some proteins in cells by degrading or repressing the messenger RNA of these proteins. More than 200 human microRNA genes have been identified, and recent studies have indicated that the genes may play a role in some cancers.

In the new study, Dr. Carlo Croce of the Ohio State University Comprehensive Cancer Center and his colleagues identified 13 micro RNA genes that represent a unique genetic "signature" and could potentially be used to distinguish between the two types of CLL. This distinction is critical because it determines the course of therapy.

The researchers then screened the 13 microRNA genes for mutations using DNA from 75 patients with CLL. They identified mutations in 5 of 42 sequenced microRNAs in 11 patients but found no such mutations in 160 individuals without cancer.

One of the mutations affects two microRNAs, miR15 and miR16; without these microRNAs, cells can become cancerous by producing too much of the protein Bcl-2. In the September 27 Proceedings of the National Academy of Sciences, Dr. Croce's team reported that introducing the missing microRNAs into these tumor cells in the laboratory killed the cells, suggesting a possible strategy for treating the disease.

"The experiments were pretty stunning because we could kill the cancer cells just by using miR15 and miR16," says Dr. Croce. "microRNAs are so small that they can get into cells, and we might not be too far from developing microRNA-based therapies."

"The importance of microRNAs in cancer now seems clear," notes Dr. Chang-Zheng Chen of Stanford University School of Medicine, who wrote a commentary accompanying the article in NEJM. "The results of this study demonstrate that it may be necessary to systematically screen for mutations in all microRNA genes for other cancers."

Urine Test for Bladder Cancer Proves Accurate

A new urine test for bladder cancer successfully identifies 90 percent of cases, Italian authors report in a study published in the October 26 Journal of the American Medical Association. The test identifies high levels of the enzyme telomerase, a hallmark of most cancers.

The authors say that the invasiveness and limited sensitivity of current detection techniques, such as cystoscopy, beg the development of a better test. "The test...requires a small amount of urine, is noninvasive, inexpensive, and easy to perform…. Furthermore, it is objective, reproducible, and specific, and is not reliant on the expertise of the cytopathologist," they write. The test also identifies low-grade tumors generally missed by traditional techniques.

The study evaluated the telomerase assay in 134 men with bladder cancer diagnosed with traditional techniques and in 84 healthy men. The technicians performing the telomerase assay did not know the status of each volunteer. The researchers included only men because bladder cancer is three times more prevalent in men than in women. A previous pilot study prompted this larger follow-up.

While detecting 90 percent of cases, the test also correctly identified 88 percent of healthy volunteers. The false-positive rate was 12 percent. The test performed slightly better in men younger than 75 years of age than in older men.

While encouraged by their results, the researchers caution that the test should not be used for routine screening. Instead, they advocate testing for people at high risk - namely smokers and those who report blood in their urine.