A paradigm shift in therapeutic vaccination of cancer patients: the need to apply therapeutic vaccination strategies in the preventive setting.

An extraordinary variety of potential therapeutic vaccine strategies directed against a wide variety of tumor antigens has been explored in clinical trials. To date, none of these cancer immunotherapies have been approved by the Food and Drug Administration for use in humans. A significant problem is that the vast majority of such clinical trials are carried out in patients with advanced or metastatic cancer. The immune systems of these patients are considerably compromised as a result of tumor- and treatment-mediated immunosuppression. Even in cases where patients are immunized in the adjuvant setting, where there is minimal residual disease, vaccines directed against tumor-associated antigens have failed to mediate eradication of tumors in the overwhelming majority of cases. Recently, we and others have experimented with administering therapeutic cancer vaccines in the preventive setting. This is achieved by vaccinating at the earliest possible stage of carcinogenesis. These studies have demonstrated that early vaccination is extremely effective in eliciting an anti-tumor immune response that leads to unprecedented improvements in the survival of mice that spontaneously develop cancer. Certain human cancers, notably prostate adenocarcinoma and cervical cancer, can currently be detected at very early stages of carcinogenesis. Therapeutic vaccines are available for these diseases, opening up the possibility of administering vaccinations early to patients diagnosed with pre-malignant lesions to halt disease progression. In addition, new technologies have become available in the past decade that will soon yield very sensitive and specific diagnostic tests for a plethora of other cancers. Earlier detection of these cancers, combined with existing vaccines directed against them, will soon make them targets for therapeutic vaccination in the preventive setting. The ability to immunize patients at the very earliest stages of carcinogenesis, when they have fully competent immune systems, has the potential to cause a paradigm shift in how therapeutic cancer vaccines are tested and used clinically.