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Fighting Tumors with Their Own Kind

When most people think of vaccines, their reference is to doctors giving these agents to prevent illness in the first place. But vaccines can be more than that, since they are simply modified infectious agents, or portions of agents, that stimulate an immune response when administered into a body. Thus a vaccine can be given after a person is sick, with the intention of stimulating an immune response strong enough to enable the patient to heal and then stay well. This approach underlies the idea of cancer vaccines.

The method used to construct most cancer vaccines has entailed introducing genes for cytokines into tumor cells and injecting these into the body. (To ensure safety, they have been treated with high-dose radiation so they cannot proliferate but can still carry out functions such as releasing the cytokines.) Researchers believe that physically bringing together these agents, plus immune cells that are always circulating in the body, approximates what happens during the natural generation of an immune response against cancer. The additional tumor cells should theoretically secrete extra-large doses of cytokines that will in turn activate heightened immune responses. And theoretically, the treatment should work for a long time, since immune responses produce other cells known as memory T cells, which provide long-term immunity.

Experiments introducing cytokine genes into animals’ tumor cells began in the late 1980s, with researchers having now tested more than 10 of some 50 isolated cytokines. Working with mice, scientists have found that 4 cytokine genes-those that produce interleukin-2, interleukin-4, gamma interferon, and GM-CSF-suppress the growth of existing malignancies of various kinds, including melanoma, colon, kidney, breast, and leukemia.

The encouraging results have led to more than 80 human clinical trials. Researchers have treated over 100 people with interleukin-2 vaccines, more than 80 with GM-CSF, and 30-plus with gamma interferon. The investigators are just starting to publish their findings. In the first trial to be described that has had a significant number of patients, for instance, investigators at Somatix of Alameda, Calif., inserted the GM-CSF gene into tumor cells of more than 40 extremely sick patients for whom other treatments for malignant melanoma had failed. The researchers then injected the modified cells into the patients. While because of the stage of their illness many of the patients died during the treatment period, 3 of 13 people have had some tumors partly or completely shrink after therapy. Since ordinarily none of these tumors would have been expected to shrink, that number is encouraging enough to suggest that further trials are warranted.

Still, the general technique is not ideal to use across the board, since it requires genetically engineering each patient’s tumor cells. That’s necessary because an individual will reject another individual’s cells. To avoid this problem, some researchers have come up with the idea of using something other than whole cells: tumor antigens-proteins found on the surface of tumor cells. Antigens, which are not necessarily unique to individuals and therefore not something that bodies reject, lead to an immune response against abnormal entities such as tumors. If investigators can figure out the antigens produced by particular kinds of tumors, the thinking goes, large amounts of such compounds, or better yet, their genes, could be placed, along with cytokine genes, into “vectors.” These are viruses manipulated so that they cannot replicate and therefore cannot cause disease but can still insert themselves into the DNA of host cells. The engineered vectors could be used to infect cells in a person with a particular malignancy. Presumably the resulting antigens would induce an immune response against the cancer.

In 1991, Thierry Boon, director of the Ludwig Institute for Cancer Research branch in Brussels, published a technique for identifying antigens found on the surface of tumor cells. Transferring into mice a gene he discovered using this method-for an antigen associated with a mouse tumor-Boon has generated immune responses that have protected against subsequent injection of tumor cells. Steven Rosenberg’s group at the National Cancer Institute has since started clinical trials to evaluate the effect of transferring genes for that antigen, as well as two others subsequently discovered, into melanoma patients. Results are not yet available.

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Tagged: Biomedicine

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