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  • Several strains of rats are used in these studies.

  • Whole prostate homogenate appears to contain fractions that somehow suppress or block the immune response, as well as fractions that induce a response. Researchers use the Western blot test to determine which induce an antibody response, and then select for them.

  • Ras and other oncoproteins still represent a valid approach, but it will apply only to a small subset of patients. The advantage of working on a protein like HER-2/neu is the greater likelihood of getting a response in every individual who has that very common protein.

CYTOKINES AND THEIR LOCAL ENVIRONMENTS26

Potential Energy Model. A certain threshold level of response against a particular tumor antigen is required for rejection of that tumor. The endogenous level of immunity against the antigen is below this threshold; vaccination must enhance existent immunity sufficiently to raise the response above this threshold level. This has implications for the choice of antigen and vaccine strategy:

  • Even if the endogenous level of immunity to antigen A is close to the thre-shold, if the vaccine approach is weak, the response will not reach the threshold, and the vaccine fails.

  • On the other hand, if the endogenous level of immunity to antigen B is much lower, even a strong vaccine may not be able to raise the response to the threshold, and the vaccine still fails.

An extreme example of the latter case is an antigen expressed in the thymus, with tolerance generated by clonal deletion; the endogenous immunity is negative, and no vaccine approach could hope to produce a therapeutic response.

Consequently, the ideal strategy is to identify a good antigen whose endogenous level of immunity is relative close to the threshold, along with a strong vaccine approach. This involves issues of endogenous self-tolerance, repertoire, and vaccine approaches. At the present time, however, there is almost an embarrassment of riches in terms of different approaches to cancer vaccines—peptides, recombinant adenovirus, pox virus, Listeria, BCG, etc. It may well be impossible to test each of them reasonably in patients unless there is first a concerted effort to compare them rigorously, in a head-to-head fashion, in the appropriate animal models.

Role of Cytokines. For many cancers these target antigens still aren’t known, although it is assumed that tumor cells themselves are important—the

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Based on a presentation by Drew Pardoll, M.D.



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