TORONTO, June 4 — In a surprise discovery, American and Canadian researchers found that the first-line diabetes drug metformin boosts long-term immune memory, at least in mice.

• Explain to interested patients that part of the normal immune response is a pool of T cells that remain long after an infection is resolved and are available to react rapidly to reinfection.
• Note that this study found that such cells can be amplifed by the use of the drug metformin, usually used as a treatment for diabetes.

The finding implies that drugs aimed at manipulating energy metabolism may be useful in boosting the immune response to vaccines, according to Yongwon Choi, Ph.D., of the University of Pennsylvania, and colleagues at McGill University in Montreal.

The drug (sold under various trade names) causes an increase in CD8-positive “memory” T cells that maintain the long-term immune response, Dr. Choi and colleagues reported in the June 4 Nature.

Indeed, in one experiment, the increase in so-called CD8 T_M cells translated to a survival advantage when mice were challenged with an experimental tumor cell line, Dr. Choi and colleagues reported.

“Our findings were unanticipated, but are potentially extremely important and could revolutionize current strategies for both therapeutic and protective vaccines,” Dr. Choi said in a statement.

The finding was the unexpected outcome of experiments involving the evolution of the immune response, which begins with an expansion of a set of antigen-specific T cells that specifically attack the invading organism.

That set of “effector” T cells vanishes in time, leaving long-lived CD8 T_M cells that can spring into action if the same pathogen attacks again.

But exactly how that happens remains unclear, so Dr. Choi and colleagues were trying to pin down the process by studying mice deficient in their ability to produce a protein (dubbed TRAF6) involved in that initial response.

The animals were able to mount a normal effector-cell response to bacterial infection, they found, but when the researchers measured T_M cells 60 days later, there were significantly fewer (at P=0.0005) than in control animals.

Further study showed that T cells missing the TRAF6 protein also had defects in fatty acid metabolism, the researchers said.

Specifically, the T cells couldn’t make the switch from burning glucose — a characteristic of proliferating cells — to other methods of generating energy, such as fatty acid oxidation.

Since metformin promotes the activation of a protein involved in regulating fatty acid activation — AMP-activated kinase, or AMPK — the researchers tested the effect of the drug.

They found that injections of the drug promoted survival of T cells after bacterial infection and throughout the contraction phase, leaving a pool of T_M cells able to respond to reinfection.

“We serendipitously discovered that the metabolizing, or burning, of fatty acids by T cells following the peak of infection is critical to establishing immunological memory,” according to lead author Erika Pearce, Ph.D., of the University of Pennsylvania.

“We used metformin, which is known to operate on fatty-acid metabolism, to enhance this process, and have shown experimentally in mice that metformin increases T-cell memory.”

In addition, Dr. Pearce said, the drug increased the animals’ response to an experimental vaccine against a tumor cell line.

The wild-type mice were immunized against the tumor cells, and then given injections of either saline or metformin after the peak of the effector cell response.

Three weeks later, the drug treatment was stopped and the animals were given injections of tumor cells.

Six of the nine metformin-treated mice survived for more than 33 days compared with only one of the eight mice treated with saline.

While the exact mechanism remains unclear, the researchers said, “our work indicates that metabolism-altering drugs hold promise as immunotherapeutics.”

The study was supported by the Canadian Institutes for Health Research, the NIH, and the National Cancer Institute. The researchers reported no conflicts.

Primary source: Nature

Source reference:

Pearce EL, et al “Enhancing CD8 T-cell memory by modulating fatty acid metabolism” Nature 2009; DOI:10.1038/nature08097.

CHICAGO, June 4 — It may be feasible to screen for all cancers of the gastrointestinal tract with a stool DNA test, a researcher said here.

• Explain to interested patients that the researcher said any stool DNA test for screening all GI cancers is likely about five years away.
• Note that this study was published as an abstract and presented as a poster at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.

Such a test detected mutations from the tumors of 68% of patients who had known GI cancers, located from the oropharynx to the colon, David Ahlquist, M.D., of the Mayo Clinic in Rochester, Minn., reported at Digestive Disease Week.

There were no false-positives in a control group of patients who were free from GI symptoms and had a normal colonoscopy.

Dr. Ahlquist said he and his colleagues went into the study with the expectation that a 50% detection rate would be a success.

“So we’re very encouraged by this as a feasible approach to screening multiple cancers with a single test,” he said.

The technology already exists to screen for colon cancer with a stool DNA test, he said, but other GI cancers account for twice as many deaths and are not currently screened for.

Because high cure rates can be achieved when these cancers are discovered in the early, presymptomatic stages, reliable screening is a priority, he said.

To assess the feasibility of a stool DNA test for all GI cancers, Dr. Ahlquist and his colleagues collected samples from 70 patients with proven GI cancers and 70 healthy controls matched by age and sex (median age 65; 65% male).

They identified mutations in tissue biopsies to serve as markers for each patient’s tumor and searched for the mutations in the stool of the patients and a matched control.

The mutations showed up in 68% of the stool samples from the patients with cancer and none of the control samples.

Broken down by type, the test identified 40% of oropharyngeal, 65% of esophageal, 62% of pancreatic, 75% of biliary/gall bladder, and 100% of stomach and colorectal cancers.

The test also identified 61% of the patients with precancers — 100% of pancreatic intraductular papillary mucinous neoplasia and 56% of colorectal advanced adenoma.

Although the initial results are promising and establish the feasibility of the test, Dr. Ahlquist acknowledged that it would probably take five years to develop a product.

“There’s a lot more work that needs to be done,” he said. “Additional clinical studies need to be done to validate this, to optimize it, and eventually to take it into a multicenter study.”

He envisioned the final test as one that would be used to screen the general population for these cancers.

“If you wait for symptoms for most of these cancers, they’re already late stage,” he said. “So if we’re going to improve outcomes in these patients, it’s going to require intervening with a screening test before symptoms occur, and that’s targeting the population.”

The study was supported by a grant from Charles Oswald Foundation. The study authors have issued and filed patents covering methods used in this study.

Primary source: Digestive Disease Week

Source reference:
Zou H, et al “Pan-detection of gastrointestinal neoplasms by stool DNA test: establishment of feasibility” DDW 2009; Abstract T2036.

TORONTO, June 8 — A majority of the women in a breast cancer study who were questioned during follow-up said they used antioxidants during treatment, researchers said.

• Explain to interested patients that little is known about the risks and benefits of antioxidants during breast cancer treatment.
• Note that this study found that, despite that lack of knowledge, use of such supplements was widespread among participants in a breast cancer study.

The finding suggests that research is needed into how the use of antioxidants such as vitamin C and beta-carotene affects treatment outcomes, Heather Greenlee, N.D., Ph.D., of Columbia University Mailman School of Public Health in New York, and colleagues, reported online in Cancer.

“Given the common use of antioxidant supplements during breast cancer treatment, often at high doses and in conjunction with other complementary therapies, future research should address the effects of antioxidant supplementation on breast cancer outcomes,” they argued.

Their Long Island Breast Cancer Study Project was a case-control endeavor to examine the role of environmental influences on breast cancer among women living in New York’s Nassau and Suffolk counties.

Between Aug. 1, 1996 and July 31, 1997, 1,508 women with a first primary in situ or invasive breast cancer were enrolled in the study. Between 2002 and 2004, the researchers conducted follow-up interviews among case participants.

All told, 764 women completed a full interview and gave information on antioxidant use, Dr. Greenlee said.

The interviews asked about four antioxidants — vitamin C, vitamin E, selenium, and beta-carotene — as well as daily dose.

Intake of each supplement was categorized as none, low, or high, with high doses defined as more than 60 milligrams of vitamin C, more than 30 IU of vitamin E, more than 20 micrograms of selenium, and more than 5,000 IU of beta-carotene.

The researchers created a nine-point “antioxidant index” to summarize total intake, based on scoring the intake of each antioxidant as zero for never, one for low, and two for high.

The antioxidant index itself was divided into three categories — none if the total score was zero, low if the score ranged from one through four, and high if it was five or higher.

Analysis found:

• 663 participants (or 86.8%) reported receiving adjuvant treatment for their cancer and of those, 401 (or 60.5%) reported using antioxidants during adjuvant treatment.
• 120 of 310 women (or 38.7%) used antioxidants during chemotherapy, 196 of 464 women (or 42.2%) used them during radiation, and 286 of 462 women (or 61.9%) used them during tamoxifen therapy.
• 278 women (or 69.3%) used high doses (defined as doses higher than those contained in a Centrum multivitamin).
• Tamoxifen use predicted the highest relative risk for high-dose antioxidant use — 3.66, with a 95% confidence interval from 2.32 to 5.78.
• Higher fruit and vegetable intake at diagnosis was also predictive of high use, with a relative risk of 1.71 with a 95% confidence interval from 1.13 to 2.59.
• Women who had ever used herbal products had a relative risk for high antioxidant use of 3.49, with a 95% confidence interval from 2.26 to 5.38.
• And women who had ever engaged in mind-body practices — such as spirituality or meditation — had a relative risk for high antioxidant use of 1.72, with a 95% confidence interval from 1.13 to 2.64.

The researchers noted that the participants from the original study who agreed to take part in the follow-up were younger, more likely to be white, and of higher socioeconomic status than women who did not respond.

“We believe our results are generalizable to similar populations,” they said, although study participants “may have been heavier users of antioxidants than breast cancer patients in the general population.”

The study was also limited by a relatively low response rate of about 55.4% of the participants who agreed to be contacted again after the end of the original study, they said.

The study was supported by the Lance Armstrong Foundation, the National Cancer Institute, and the National Institutes of Environmental Health and Sciences. The researchers did not report any conflicts.

Primary source: Cancer

Source reference:

Greenlee H, et al “Prevalence and predictors of antioxidant supplement use during breast cancer treatment: The Long Island Breast Cancer Study Project ” Cancer 2009; DOI: 10.1002/cncr.24378.