September 02, 2006
Gene Therapy On Immune Cells Kills Melanoma Cancer

Gene therapy to convert lymphocyte immune T cells to recognize melanoma cells showed success in some of the patients in a small study.

A team of researchers at the National Cancer Institute (NCI), part of the National Institutes of Health, has demonstrated sustained regression of advanced melanoma in a study of 17 patients by genetically engineering patients' own white blood cells to recognize and attack cancer cells. The study appears in the online edition of the journal Science on August 31, 2006*.

"These results represent the first time gene therapy has been used successfully to treat cancer. Moreover, we hope it will be applicable not only to melanoma, but also for a broad range of common cancers, such as breast and lung cancer," said NIH Director Elias A. Zerhouni, M.D.

Immunotherapies that are specific to cancer cells are much preferred over chemotherapies and radiation therapies that also trash normal cells throughout the body. Gene therapy that programs immune cells to attack only cancer cells will cause far fewer harmful side effects. If scientists can find surface protein features specific to all cancers (and it is not clear to me that this is possible) then genetically engineered immunotherapies will eventually cure all cancers.

Not all patients benefitted but it looks like a cure for 2 of them.

Thus, NCI researchers, led by Steven A. Rosenberg, M.D., Ph.D., sought an effective way to convert normal lymphocytes in the lab into cancer-fighting cells. To do this, they drew a small sample of blood that contained normal lymphocytes from individual patients and infected the cells with a retrovirus in the laboratory. The retrovirus acts like a carrier pigeon to deliver genes that encode specific proteins, called T cell receptors (TCRs), into cells. When the genes are turned on, TCRs are made and these receptor proteins decorate the outer surface of the lymphocytes. The TCRs act as homing devices in that they recognize and bind to certain molecules found on the surface of tumor cells. The TCRs then activate the lymphocytes to destroy the cancer cells.

In this study, newly engineered lymphocytes were infused into 17 patients with advanced metastatic melanoma. There were three groups of patients in this study. The first group consisted of three patients who showed no delay in the progression of their disease. As the study evolved, the researchers improved the treatment of lymphocytes in the lab so that the cells could be administered in their most active growth phase. In the remaining two groups, patients received the improved treatments. Two patients experienced cancer regression, had sustained high levels of genetically altered lymphocytes, and remained disease-free over one year. One month after receiving gene therapy, all patients in the last two groups still had 9 percent to 56 percent of their TCR-expressing lymphocytes. There were no toxic side effects attributed to the genetically modified cells in any patient.

So 2 out of the 14 patients who received better optimized later rounds of therapy are cancer-free over a year later.

This team is trying various ways to enhance the treatment. They are also creating lymphocytes to target breast, lung, and other cancers.

"We are currently treating advanced melanoma patients using adoptive transfer of genetically altered lymphocytes, and we have now expressed other lymphocyte receptors that recognize breast, lung, and other cancers," said Rosenberg.

The researchers rely on a known protein that shows up on the outside of melanoma cancer cells.

Developing the new treatment involved first investigating the chemical markers on the outside of cancer cells that the body's natural immune system recognises. The team honed in on chemical markers unique to melanoma cells, such as one called "MART-1".

As more is learned about various types of cancer and as instrumentation for detecting and measuring proteins on the surfaces of cells become more sensitive the scientists will gain more targets on cancer cells to aim immune cells at.

The researchers think they've since made progress and their current technique will achieve a higher success rate.

The fact that only two out of the seventeen patients in this trial responded is disappointing, says Davis. The researchers suspect the problem was that their technique did not always alter the T cells in the desired way; they say they have improved their technique in the months since this trial was done, so future remission rates should be higher.

This therapy will only get better. Development of better ways to deliver gene therapy will enhance the effectiveness of this therapy by providing scientists with a way to convert a larger fraction of T cells into cancer killers.

Cancer is curable. Most of us are going to live to see it cured.

Update: Patrick Hwu is working on genetically engineered lymphocytes that hone in on chemokines which are released by cancer cells.

Other researchers are working on similar strategies. Hwu, of M.D. Anderson, is engineering lymphocytes that have receptors for substances called chemokines that some tumors put out. This will help the lymphocytes home in on the cancer.

"We need to figure out how to get the T cells to migrate into the tumor more efficiently," he said. "If the T cells are able to recognize the cancer but are circulating in the bloodstream, then they are not on the battlefield where they need to be."

One problem that immunotherapies need to address comes from compounds which some cancer cells secrete that basically discourage immune cells from approaching. These compounds are one reason cancer vaccines have not achieved great success. A combination of immune cells aimed at cancer cells with monoclonal antibodies or other approaches that aim at the immune system damping compounds would be more potent.

Share |      Randall Parker, 2006 September 02 02:35 PM  Biotech Cancer

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