Correlates of immune and clinical activity of novel cancer vaccines.

Cancer vaccines are solely meant to amplify the pool of type 1 cytokine oriented CD4+ and CD8+ T cells that recognize tumor antigen and ultimately foster control and destruction of a growing tumor. They are not designed to deal with all aspects of immune ignorance, exclusion, suppression and escape that are generally in place in patients with cancer and may prevent the T cells to enter the tumor or to exert their effector function. This simple fact prompted for a reappraisal of the many recent trials in which therapeutic cancer vaccines have been examined as monotherapy. In this review, I focus on trials examining therapeutic cancer vaccines at different stages of existing disease. The analysis of vaccine-induced immune responses and clinical activity of therapeutic cancer vaccines revealed four levels of evidence for vaccine efficacy. The lowest levels, reflect the many trials in which the strength of the tumor-reactive T cell response of vaccinated patients is associated with better clinical outcome or change in tumor marker. The highest levels indicate occasional regressions of tumors and metastases after vaccination or reflect a stronger clinical impact of vaccine in a randomized trial. A whole series of trials in which vaccine-induced tumor immunity correlates with the clinical impact of cancer vaccines in premalignant diseases, settings of low tumor burden or tumor regressions in patients with cancer, form an attest to the fact that cancer vaccines work. While the current number of true clinical responders in each cancer trial is too low for firm conclusions on immune correlates of clinical reactivity in cancer, extrapolation of the results from vaccinated patients with pre-cancers suggest a requirement of broad type 1 T cell reactivity.