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IMMUNITY TO ONCOGENIC SELF-PROTEINS25

Immunity to Mutated Ras. Researchers asked whether or not oncogenic proteins can be targeted for vaccine and T-cell therapy. They first examine mutated ras as a prototype. Ras is activated by point mutations that are common in diverse tumors. Ras is present in about 15 percent of all human tumors, including 50 percent of colon cancer and 95 percent of pancreas cancer.

Animal experiments demonstrated that ras can function as a tumor-specific antigen, eliciting both helper T-cell and CTL responses that can decrease the growth of tumor in vitro and in vivo. Researchers have also found existent immune responses in a few patients with pancreatic and colon cancers. Most are antibody responses to normal ras, but a small number have a very restricted antibody response to the mutated protein. Other patients have a very specific T-cell response to the mutated segment of ras, but there is a problem in trying to focus immune attack against a single epitope. More importantly, oncogenic proteins that are activated by mutation have increased function, and proteins that have increased function don’t have to be present in abundant amounts.

Immunity to HER-2/neu. Rather than looking at immune responses to proteins that weren’t abundant, researchers asked whether or not it was possible to focus an immune attack against an oncogenic protein that is present in large amounts. Their prototype was HER-2/neu, a very large nonmutated protein that is expressed in very low amounts in some normal tissues, but is amplified in about 25 percent of breast cancer patients. When amplified, it is overexpressed and substantially more abundant. The structure of HER-2/neu includes a very large extracellular domain, so large that there are potentially epitopes for every individual.

Initial experiments revealed that 15 percent or 16 percent of breast cancer patients have existent antibody responses to HER-2/neu, including 42 percent of patients with documented overexpression of the protein. In the latter case, the immune response is assumed to be elicited by virtue of the fact that the protein is overexpressed. Unfortunately, some normal patients also have a response, between 2 percent and 5 percent based on screening of blood donors. Experience has shown that by setting the cutoff level high enough—in this case, a titer of less than 1:500—it is possible to exclude virtually all responses in normal individuals while retaining a much more specific response for breast cancer patients.

In many cases, the responses are extremely low, between 1:100 and 1:500, but five patients out of 96 had very substantial antibody responses, with titers of greater than 1:12,000. As it happened, these same five patients also had stage I or stage II breast cancer, as opposed to more advanced disease. In general,

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Based on a presentation by Martin Cheever, M.D.



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