Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy.

Regulatory T cells (T) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3CD25CD4 T during immunotherapy and to determine the potential impact of T on relapse risk and survival. We observed a pronounced increase in T counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating T resembled thymic-derived natural T (nT), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by T counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of T induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of T in later treatment cycles and a short T telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive T that may be targeted for improved anti-leukemic efficiency.