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Gemcitabine depletes regulatory T‐cells in human and mice and enhances triggering of vaccine‐specific cytotoxic T‐cells

Particle‐mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen‐specific cytotoxic T‐cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY‐ESO‐1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T‐cells among CD4‐positive cells. The higher relative sensitivity of regulatory T‐cells compared to other CD4‐positive T‐cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4‐compartment in healthy people and cancer patients. Thus, by affecting regulatory T‐cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T‐cell response.