Clinical translation of peptide-based vaccine trials: The HER-2/neu model

In the development of targeted cancer immunotherapies, the choice of antige n is obviously critical to the design of any therapeutic strategy, but part icularly so for tumor vaccines, which must distinguish malignant cells from normal cells.' Investigations a decade ago focused on mutated tumor antige ns, or viral tumor antigens, with the belief that these foreign or abnormal proteins would be best recognized by the host immune system.(2) Within the last 10 years, however, several tumor antigens have been identified on the basis of recognition by infiltrating T cells in tumor samples. Studies on melanoma, in particular, have revealed that in addition to some mutated tum or antigens, several aberrantly expressed normal proteins, as well as tissu e-specific differentiation factors, are recognized by the host immune syste m.(3) Similar studies in other solid tumors have revealed that certain onco genes overexpressed in malignant cells, such as p53 and HER-2/neu, are also recognized by host T cells.(4-6) Our group has been investigating the HER- 2/neu oncogenic protein as a vaccine target in patients with HER-2/neu-over expressing cancers. However, several issues unique to the design of human c linical trials of cancer vaccines must be addressed when translating precli nical experiments to human clinical trials. First, HER-2/neu protein expres sion can vary depending on the tumor type. How would expression differences impact clinical trial design? Secondly, what are the issues in clinical tr ial design that are critical to the successful execution of a phase I study of a peptide-based vaccine? Thirdly, what types and amounts of clinical ma terial are readily available for immunologic analysis and can be obtained w ith little distress and risk to the patients enrolled in the study? Finally , what steps must be implemented for a laboratory assay to evolve to meet t he validation criteria needed for application as an immunologic monitoring tool?