Dynamics of cytotoxic T cell subsets during immunotherapy predicts outcome in acute myeloid leukemia

Abstract

Preventing relapse after chemotherapy remains a challenge in acute myeloid leukemia (AML). Eighty-four non-transplanted AML patients in first complete remission received relapse-preventive immunotherapy with histamine dihydrochloride and low-dose interleukin-2 in an international phase IV trial (ClinicalTrials.gov; NCT01347996). Blood samples were drawn during cycles of immunotherapy and analyzed for CD8+ (cytotoxic) T cell phenotypes in blood. During the first cycle of therapy, a re-distribution of cytotoxic T cells was observed comprising a reduction of T effector memory cells and a concomitant increase of T effector cells. The dynamics of T cell subtypes during immunotherapy prognosticated relapse and survival, in particular among older patients and remained significantly predictive of clinical outcome after correction for potential confounders. Presence of CD8+ T cells with specificity for leukemia-associated antigens identified patients with low relapse risk. Our results point to novel aspects of T cell-mediated immunosurveillance in AML and provide conceivable biomarkers in relapse-preventive immunotherapy.

Anthracycline-based consolidation may determine outcome of post-consolidation immunotherapy in AML

“…A high frequency of effector memory T cells (T EM ) after consolidation, but prior to HDC/IL-2 immunotherapy, prognosticated LFS, and OS (Figure 3(B)), which is in agreement with an earlier report [17]. The survival benefit of a high frequency of T EM cells at onset of immunotherapy remained significant in multivariable analysis ( Table 3).…”

“…Table 1 provides information about the prior induction and consolidation chemotherapy. Further patient characteristics are accounted for in previous publications [17,18,27]. In this single-armed multicenter phase IV study, patients received 10 consecutive 21-d cycles of HDC and low-dose IL-2 for 18 months or until relapse or death using a regime identical to that employed in a previous phase III trial [28].…”

“…The sensitivity of AML cells to the anti-leukemic activity of cytotoxic lymphocytes such as T cells and NK cells [6][7][8][9][10] along with the purported role of these immune effector cells in the surveillance of leukemic cells [11,12] have inspired the development of strategies to boost cellular immunity in the post-consolidation phase for relapse prevention [13][14][15][16]. The NOX2 inhibitor histamine dihydrochloride (HDC) in conjunction with the T and NK cell activating cytokine interleukin-2 (HDC/IL-2) is approved in AML for relapse prevention in Europe, and recent studies imply that aspects of T and NK cell immunity are relevant to the clinical efficiency of this combinatorial immunotherapy [16][17][18][19].…”

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

“…Despite additional courses of chemotherapy (consolidation), relapse in CR is common and significantly explains why the long-term survival of adult AML patients remains in the range of 30–40% [ 14 ]. A large body of evidence, including the graft-versus-leukemia reaction that mediates relapse prevention after allo-SCT, implicates functions of cytotoxic T cells and NK cells in controlling the malignant clone in AML [ 15 , 39 – 41 ]. The purported role of cell-mediated immunity for the surveillance of leukemic cells in AML has inspired the development of immunotherapeutic strategies, in particular for patients in CR who harbor a minimal yet potentially life-threatening burden of leukemia (reviewed in [ 15 ]).…”

“…The primary endpoints comprised assessment of the quantitative and qualitative pharmacodynamic properties of HDC/IL-2, including monitoring of T and NK cell phenotypes before and after treatment cycles while analyses of aspects of immunity versus outcome (LFS and overall survival; OS) were performed post hoc. Patient characteristics, including details regarding previous induction and consolidation therapy and risk group distribution are accounted for in previous publications [ 39 – 41 ] and in Table 1 . The trial was approved by the Ethical Committees of each participating institution and all patients gave written informed consent before enrollment.…”