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peptides corresponding to the fusion break point results in generation of specific CTL responses. Immunized animals have reduced tumor burden following tumor challenge, compared with controls. Adoptive transfer of bulk spleen cells from immunized animals mediated partial reduction in tumor burden in animals with established disease. These preliminary results need to be repeated with additional controls, and that work is in progress. Researchers are now planning a clinical trial in patients with these pediatric sarcomas.

Tumor Immunogenicity. These strategies would be unnecessary if the tumor itself were more immunogenic. At least five possible explanations have been offered for the failure of the tumor to elicit a CTL immune response:

  1. Failure of the mutant epitope in the oncogene product or fusion protein to be presented by an individual’s MHC alleles. Research cannot overcome this problem, but it is not the only way to induce an immune response.

  2. The tumor down-regulates the MHC allele responsible for presentation. Research has shown that it takes a much higher density of MHC-peptide complexes to induce an immune response than it does to be the target of a CTL immune response. In this case, even if MHC is expressed at a level insufficient to induce an immune response, it is still possible to induce an immune response on professional APCs that will induce CTLs to kill the tumor.

  3. The tumor processes antigen inefficiently, and hence at insufficient levels to induce immune response.

  4. Loss of costimulatory molecules. Several groups have shown that tumor cells transfected for the B7 costimulatory molecule become immunogenic and induce CD8 CTLs that will kill the tumor. That is, costimulation is necessary for the afferent (inducing) but not the efferent (killing) limb of the immune response.

  5. Tumor cells may be tolerogenic. They present signal 1 without signal 2, and so instead of prolonging memory they kill the CTLs induced by immunization. Evidence for this is seen in the need to immunize repeatedly to suppress the tumor. Even this may have a beneficial effect in terms of the longevity of the patient.

In response to questions from the audience, Dr. Berzofsky added the following:

  • Investigators have intentionally avoided the nonmutated portions of p53, etc., because they don’t want to induce autoimmune responses. Because mutant p53 is overexpressed (due to prolonged survival rather than increased synthesis), this risk is particularly great.

  • Tumor genotype will become an important component of designing specific tumor vaccines. In the case of ras, there is a handful of common mutations, and the peptide is probably already synthesized. There are hundreds of different



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