tolerance of extracellular domain is more stringent because it is a shed protein that is more available to the thymus for induction of tolerance—or it may be because researchers merely picked the wrong peptides to work with.
Sequencing shows that the peptides to which rats were immunized are identical in the human protein (rat neu and human HER-2/neu are about 89 percent homologous at the amino acid level). Hence, the antibodies that will immunoprecipitate the rat protein will also immunoprecipitate the human protein. These are also peptides to which at least some human patients have responded.
Researchers now plan to go forward with a vaccine trial in which humans patients will be immunized with peptides identified as immunogenic in rats. The adjuvant used in the rat studies was complete Freund’s, which is too toxic for standard use in humans, so they plan to use GM-CSF as an adjuvant. Instead of growing dendritic cells in vitro with GM-CSF, the cytokine is injected intradermally with the peptide. Animal tests have shown that it is possible to generate immune response to intra- and extracellular domain peptides with GM-CSF as the adjuvant, and indeed that the DTH assay is much stronger that when using complete Freund’s adjuvant. Researchers have submitted to an IRB a protocol to immunize patients with breast and ovarian cancers with peptides. FDA has signed off, and the protocol should begin within months. Data should be available before 2000 on whether these peptides are toxic and/or efficacious in vivo.
Autoimmune Cancer Therapy. Generating an immune response to self-protein does not resolve the issue of whether it is possible to induce an aggressive autoimmune response as a form of cancer therapy. To answer this question, researchers focused on the prostate—once the prostate becomes malignant, it is often removed, at which point any prostate tissue left in the body is by definition malignant. If it were possible to induce a rapidly destructive, aggressive autoimmune prostatitis, it would have therapeutic benefit.
There are several problems in this use of autoimmune prostatitis; not the least is immunological tolerance to self-proteins. There is no information available on which prostate-specific proteins are immunogenic; nor have experiments confirmed that autoimmunity can destroy normal prostate tissue. In addition, most autoimmune disease is relapsing and often resolves spontaneously, while this strategy requires a rapid and aggressive autoimmunity that can eradicate the organ. (Parenthetically, there is a general lack of attention to CTLs in the field of autoimmunity, possibly because autoimmunity isn’t mediated by CTLs, or possibly because CTLs are too difficult to deal with.)
Researchers first tried to immunize to prostatic acid phosphatase (PAP), a common and well-characterized marker for human prostate tumor for which the sequence of a rodent model is also known. PAP is a glycoprotein secreted exclusively by prostate epithelial cells. It is expressed by all normal prostate tissue and by most prostate cancers. And while portions of the molecule are similar to