Multiple vaccinations: friend or foe

Abstract

Few immunotherapists would accept the concept of a single vaccination inducing a therapeutic anticancer immune response in a patient with advanced cancer. But what is the evidence to support the "more-is-better" approach of multiple vaccinations? Because we are unaware of trials comparing the effect of a single vaccine versus multiple vaccinations on patient outcome, we considered that an anticancer immune response might provide a surrogate measure of the effectiveness of vaccination strategies. Because few large trials include immunologic monitoring, the majority of information is gleaned from smaller trials in which an evaluation of immune responses to vaccine or tumor, before and at 1 or more times following the first vaccine, was performed. In some studies, there is convincing evidence that repeated administration of a specific vaccine can augment the immune response to antigens contained in the vaccine. In other settings, multiple vaccinations can significantly reduce the immune response to 1 or more targets. Results from 3 large adjuvant vaccine studies support the potential detrimental effect of multiple vaccinations as clinical outcomes in the control arms were significantly better than that for treatment groups. Recent research has provided insights into mechanisms that are likely responsible for the reduced responses in the studies noted above, but supporting evidence from clinical specimens is generally lacking. Interpretation of these results is further complicated by the possibility that the dominant immune response may evolve to recognize epitopes not present in the vaccine. Nonetheless, the Food and Drug Administration approval of the first therapeutic cancer vaccine and recent developments from preclinical models and clinical trials provide a substantial basis for optimism and a critical evaluation of cancer vaccine strategies.

Figure 1. Proposed model for how immune signature can be used to personalize vaccine strategies and improve patient outcomes

A. An active immune signature identified by phenotypic or genetic analysis of immune components within the tumor signals pre-existing immune response that is easier to augment by booster vaccines. This is the cohort of patients that respond to effective boosting vaccines. B. Tumors that lack an immune signature contain few immune cells, signaling the lack of an anti-tumor immune response. Vaccine strategies need to stress both priming of a de novo anti-tumor immune response as well as boosting of the immune response in order to be effective. C. Immunosuppressive gene signature including Tregs, MDSC, Bregs and/or tolerogenic cytokines will block the immune response to vaccination and may have eliminated tumor-specific T cells. Vaccine strategies need to start with elimination of the suppressive environment/cells and subsequently prime and boost the anti-tumor immune response in order to develop a therapeutic immune response. All three scenarios are expected to benefit from agents that induce immunogenic death.