Dynamics of myeloid cell populations during relapse-preventive immunotherapy in acute myeloid leukemia

Abstract

Relapse of leukemia in the postchemotherapy phase contributes to the poor prognosis and survival in patients with acute myeloid leukemia (AML). In an international phase IV trial (ClinicalTrials.gov; NCT01347996), 84 patients with AML in first complete remission who had not undergone transplantation received immunotherapy with histamine dihydrochloride (HDC) and low-dose IL-2 with the aim of preventing relapse. The dynamics of myeloid cell counts and expression of activation markers was assessed before and after cycles of immunotherapy and correlated with clinical outcome in terms of relapse risk and survival. During cycles, a pronounced increase in blood eosinophil counts was observed along with a reduction in monocyte and neutrophil counts. A strong reduction of blood monocyte counts during the first HDC/IL-2 treatment cycle predicted leukemia-free survival. The HDC component of the immunotherapy exerts agonist activity at histamine type 2 receptors (H2Rs) that are expressed by myeloid cells. It was observed that the density of H R expression in blood monocytes increased during cycles of immunotherapy and that high monocyte HR expression implied reduced relapse risk and improved overall survival. Several other activation markers, including HLA-DR, CD86, and CD40, were induced in monocytes and dendritic cells during immunotherapy but did not predict clinical outcome. In addition, expression of HLA-ABC increased in all myeloid populations during therapy. A low expression of HLA-ABC was associated with reduced relapse risk. These results suggest that aspects of myeloid cell biology may impact clinical benefit of relapse-preventive immunotherapy in AML.

Histamine receptors and cancer pharmacology: an update

“…Supporting the ability of histamine to modulate the immune system, histamine dihydrochloride inhibits the formation of ROS from monocytes/macrophages by suppressing the activity of NADPH oxidase (NOX2) via H 2 receptors and thus preventing the inactivation of T‐cells and NK cells (Blaya et al ., 2010). In this regard, histamine is being administered in clinical trials as an adjuvant to immunotherapy with IL‐2 for the treatment of metastatic melanoma and acute myeloid leukaemia (AML), and is showing clinical benefits (Perz and Ho, 2008; Rydström et al ., 2017). Treatment of patients with stage IV melanoma with the combination of histamine and IL‐2 increases type 1 T‐cell responses, promoting the induction of melanoma‐specific T‐cells.…”

A skewed distribution and increased PD-1+Vβ+CD4+/CD8+ T cells in patients with acute myeloid leukemia

“…Immunotherapy‐like immune checkpoint blockade, chimeric antigen receptor (CAR)‐ and TCR‐modified T cells have entered main street for both solid tumor and hematologic malignancies . However, unlike B‐cell leukemia and lymphoma, the application of immunotherapy for acute myeloid leukemia (AML) has been limited due to limited understanding of global T cell immune dysfunction in AML . Multiple aspects of T cell dysfunction including lower activation, terminal proliferation, exhaustion, and senescence are functioning in AML at diagnosis, and impairment of T cell function might be mediated by up‐regulating immune checkpoint receptors, such as programmed death‐1 (PD‐1), lymphocyte‐activation gene 3, T‐cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3) .…”

“…Multiple aspects of T cell dysfunction including lower activation, terminal proliferation, exhaustion, and senescence are functioning in AML at diagnosis, and impairment of T cell function might be mediated by up‐regulating immune checkpoint receptors, such as programmed death‐1 (PD‐1), lymphocyte‐activation gene 3, T‐cell immunoglobulin and mucin‐domain containing‐3 (Tim‐3) . For example, CD8+ T cell dysfunction in AML was in part reversible upon PD‐1 blockade in vitro, and PD‐1 blockade could enhance CD33‐CD3 BiTE antibody construct‐mediated cytotoxicity in AML . Thus, it would be interesting to further characterize the complexity of AML‐related T cell immunity, which might support the design of immunotherapies for AML …”

“…[1][2][3][4][5] However, unlike B-cell leukemia and lymphoma, the application of immunotherapy for acute myeloid leukemia (AML) has been limited due to limited understanding of global T cell immune dysfunction in AML. 6,7 Multiple aspects of T cell dysfunction including lower activation, terminal proliferation, exhaustion, and senescence are functioning in AML Abbreviations: AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; CAR, chimeric antigen receptor; CR, complete remission; NCR, non-complete remission; PD-1, programmed death-1,; Tim-3, T cell immunoglobulin and mucin-domain containing-3. at diagnosis, 8,9 and impairment of T cell function might be mediated by up-regulating immune checkpoint receptors, such as programmed death-1 (PD-1), lymphocyte-activation gene 3, T-cell immunoglobulin and mucin-domain containing-3 (Tim-3).…”

Cytomegalovirus Serostatus Affects Autoreactive NK Cells and Outcomes of IL2-Based Immunotherapy in Acute Myeloid Leukemia

“…In this study, we asked whether CMV IgG serostatus, as a reflection of a past CMV infection, correlated with relapse risk and survival in two cohorts of nontransplanted AML patients, one of which received postconsolidation immunotherapy comprising IL2, an activator of T cells and NK cells, and histamine dihydrochloride (HDC), which targets the production of immunosuppressive reactive oxygen species from myeloid cells (34,35). Based on the effect of CMV on NK cell differentiation and education (10), we hypothesized that a skewed NK cell repertoire might affect the outcome for patients receiving immunotherapy dependent on NK cell function (36). Our results show that CMV seropositivity was associated with high relapse risk and poor survival in AML patients receiving HDC/IL2.…”