Suppressing regulatory T cells

The presence of increased numbers of regulatory T (T_Reg) cells in cancer patients suppresses an effective anti-tumour immune response. Jens Dannull and colleagues have investigated whether a targeted therapy, aimed at decreasing the numbers of T_Reg cells, can improve the response of patients to tumour-based vaccines. Although the number of patients in this preclinical trial was small, the results were promising.

T_Reg cells are CD4⁺ T cells that normally suppress the development of autoimmunity. They express high levels of the interleukin 2 (IL-2) α-chain receptor, CD25, and previous studies in mouse models have shown that targeting CD25 can lead to depletion of T_Reg cells. In this study, the authors used human IL-2 conjugated to the catalytic and membrane-translocation domain of diphtheria toxin (DAB₃₈₉IL-2) as a means to specifically kill T_Reg cells in patients with advanced renal cell and ovarian carcinoma.

Initially, the authors carried out in vitro experiments on human peripheral blood cells from both healthy donors and cancer patients to determine whether DAB₃₈₉IL-2 would selectively deplete the T_Reg cells. CD4⁺ CD25^high cells were selectively eliminated with no evident effect on other T cells that expressed low or intermediate levels of CD25 (such as memory T cells). However, the presence of active DAB₃₈₉IL-2 also suppressed the effector T-cell response, indicating that DAB₃₈₉IL-2 can only be used in a pre-vaccination setting.

In the clinical study, DAB₃₈₉IL-2 was given to 7 patients 4 days before administering a vaccine that consisted of dendritic cells that were transfected with tumour cell RNA. DAB₃₈₉IL-2 significantly reduced the numbers of circulating T_Reg cells and therefore increased the numbers of circulating cytotoxic anti-tumour T cells when the vaccine was administered compared with four patients who were treated with the vaccine alone.

The authors hope that this study will act as a baseline from which to improve and define the strategy of T_Reg cell depletion in cancer patients, with a view to achieving anti-tumour immunity with clinical impact.