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HLA-haploidentical transplantation with regulatory and conventional T-cell adoptive immunotherapy prevents acute leukemia relapse

Massimo F. Martelli, Mauro Di Ianni, Loredana Ruggeri, Franca Falzetti, Alessandra Carotti, Adelmo Terenzi, Antonio Pierini, Maria Speranza Massei, Lucia Amico, Elena Urbani, Beatrice Del Papa, Tiziana Zei, Roberta Iacucci Ostini, Debora Cecchini, Rita Tognellini, Yair Reisner, Franco Aversa, Brunangelo Falini and Andrea Velardi

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  • Accumulation of regulatory T cells during immunotherapy does not increase relapse risk in acute myeloid leukemia
    • Anna Martner, Researcher University of Gothenburg
    • Other Contributors:
      • Anna Rydström, Researcher
      • Frida Ewald, Researcher
      • Rebecca E. Riise, Researcher
      • Johan Aurelius, Researcher
      • Mats Brune, Principal investigator in the Re:Mission Trial
      • Robin Foà, Principal investigator in the Re:Mission Trial
      • Kristoffer Hellstrand, Researcher
      • Fredrik B. Thorén, Researcher

    Martelli et al. 1 highlight the impact of regulatory T cells (Tregs) for the outcome of allogeneic transplantation in acute myeloid leukemia (AML). However, the role of Tregs for relapse risk in non-transplanted AML patients remains largely unknown. In a phase IV trial (Re:Mission Trial, registered at clinicaltrials.gov, identifier: NCT01347996) 79 adult patients (age 18-79) with AML in first complete remission, received histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) for relapse control through ten three-week cycles for 18 months. This immunotherapy aims at pharmacologically mimicking the graft-versus-leukemia reaction to prevent relapse 2,3. A pronounced increase in CD4+/25+/Foxp3+ Treg blood counts was observed during treatment cycles (P=9 x 10-10 and P=1 x 10-6 in cycles 1 and 3, respectively; n = 45 in both cycles; paired t-test), which is likely explained by the interaction between IL-2 and its high-affinity receptor (CD25) expressed by Tregs 4. In preliminary experiments the accumulating Tregs (sorted on CD4+/25high/127low phenotype) suppressed the proliferation of effector T cells in vitro as efficiently as did Tregs from healthy donors.

    In exploratory analyses, we assessed the impact of Tregs in blood on relapse-free survival (RFS). Treg counts (dichotomized by the median) before the onset of therapy did not affect RFS. Also, the magnitude of induction of Tregs during cycle 1 or high Treg counts at the end of cycle 1 did not herald relaps...

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    Conflict of Interest:
    Authors M.B., R.F and K.H. are past or current advisors to the study sponsor (Meda Pharma GmbH & Co, Bad Homburg, Germany). Authors F.B.T., M.B., K.H. and A.M. have received travel grants and/or honoraria from this company. Author K.H. holds patents related to the work described in this study. This study was supported by the Swedish Research Council, BioCARE, the Swedish Society for Medical Research, the Swedish Cancer Society, the Swedish Society of Medicine, the Erna and Victor Hasselblad Foundation, the Torsten and Ragnar Söderberg Foundation, IngaBritt och Arne Lundberg’s Research Foundation and Meda Pharma.