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From our perspective a great deal has changed in the past few years. We now appreciate that tumor-specific T cells have at least a triad of properties (perforin, IFN-γ, and TNF) that they can utilize to mediate tumor regression. We also have a basic understanding of in vitro methods to polarize primed T cells towards a “therapeutic” type 1 cytokine profile (IFN-γ and TNF). Additionally, combining vaccination at a time when host T cells are undergoing homeostasis-driven proliferation has been shown to dramatically increase the frequency of tumor-specific T cells generated by the host. The discovery of CD25+CD4+ regulatory T cells at tumor sites and the success of combining adoptive transfer of CD4 and CD8+ TIL with a non myeloablative conditioning regimen that includes fludarabine, a drug that that preferentially decimates CD4+ T cells, are likely to be related. The availability of antibodies or ligands that block negative signals (CTLA4) or provide costimulatory signals (4-1BB, OX40) will be extended or initiated soon. The next several years should prove particularly informative as trials incorporating combinations of strategies make their way to the clinic.

What is the appropriate end point for a therapeutic vaccine? Althoughwe have begun to see objective tumor responses in some patients, response rates of 10 to 20% are not generally adequate to use as end points in phase 2 trials. In order to see reliable differences in survival in a phase 2 trial, a very striking treatment effect in a wellcontrolled setting is probably required. As a practical matter, to show benefit, most phase 3 studies of therapeutic vaccines have used overall survival in advanced disease or time to recurrence either in the adjuvant setting or following complete resection with a high risk of recurrence. It is important to understand some of the reasons phase 3 vaccine trials have consistently failed to meet expectations following promising phase 2 trials. Phase 2 trial results may be strongly influenced by patient selection and retrospective analysis of subgroups, which may contribute to inadequate phase 3 trials even when based on positive phase 2 data. However, even with well designed trials, rational vaccine development beyond the empiric evaluation of individual products will require a deeper understanding of human tumor immunobiology.

A wide array of immunologic tests are available for immune monitoring in cancer vaccine trials, and the number of novel assays and technical modifications continues to burgeon. Because only a small fraction of all proposed vaccine trials tested in phase I-II trials, for practical reasons, will ultimately move forward to be tested in phase III trials, there must be a system of establishing the most promising immunization strategies. This evaluation of cancer vaccine will require standardization of the immune assays and statistical methods used in immunologic monitoring. Furthermore, the use of a systematic approach to evaluating and adopting novel technologies for immunologic assessment would likely lead to timely implementation of more reliable, practical and cost-effective methods of immune. It should be the goal and expectation that this rational approach to immune monitoring will allow the critical appraisal of the most promising vaccine candidates in the context of pivotal, multi-center trials.