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mutations of p53, however, and a new peptide must be synthesized for almost every new patient. For this approach to work, clinicians will need to have on the shelf a repertoire of at least the most common peptides.

  • Researchers know the binding motifs for only a handful of human MHC molecules. Preliminary binding studies suggest that there is a match between the mutation and the patient’s HLA allele in about 35 percent of cases. However, even 35 percent of cancer patients is more than can be treated at present.

  • Because different types of cancer will have different biologies and different escape routes (see above), strategies that fail with one cancer may still succeed with others.

  • Phase I trials were aimed at safety rather than efficacy, and there have been clinical remissions to date, but a few patients have unexpected stability.

  • Tumor immunotherapy may prove to be most useful as a “cancer adjuvant,” for patients who have already had the bulk of their disease removed by surgery or other therapy, but remain at high risk of recurrence from micrometastases.

  • More than 100 common mutations of p53 have been observed in lung, breast, and other cancers. The necessary “repertoire” of mutant p53 peptides is the correspondingly large. This may not be, most cost-effective approach, but it is a first step. It may eventually be possible to make a DNA vaccine of these constructs.

  • Patients in clinical studies are immunized with autologous peptide-pulsed PBMCs, a 2-hour process. If researchers move to purified dendritic cells, grown in GM-CSF or IL-4, quality control is better but several days are required for incubation, and the patient must be available for up to a week at a time.

  • The current route of immunization is intravenous. This is not the best way to make antibodies, but experiments in mice have shown that the intravenous route induces CTLs more effectively than either subcutaneous or intraperitoneal when working with either spleen or dendritic cells.

CTL SCREENING FOR TUMOR ANTIGENS24

Researchers attempted to characterize tumor antigens that are recognized by CTLs, in hopes of targeting the immune system for these antigens. Using mixed lymphocyte-tumor cell culture, they obtained CTL clones that lyse autologous /tumor cells. Most of this work has been done with melanoma, which proved to be easier to work with that other tumor types that are now under investigation (e.g., sarcoma, lung, blood, renal, and head and neck carcinoma).

Investigators used a genetic approach to isolate genes coding for the proeins from which tumor antigens are derived. There are three categories of human tumor antigens:

24  

Based on a presentation by Pierre van der Bruggen, M.D.



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