Targeted immunotherapy in acute myeloblastic leukemia: from animals to humans

Robin, Marie; Schlageter, Marie‐Hélène; Chomienne, Christine; Padua, Rose Ann

doi:10.1007/s00262-005-0678-1

Cited by 12 publications

(9 citation statements)

References 100 publications

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“…Antileukaemic T cell reactivity is important after allogeneic stem cell transplantation and therapeutic targeting of autologous T cells is also considered [124,125]. The effects of HDAC inhibitors on human T cells have not been studied in detail but recent studies suggest that these drugs may interfere with intracellular T cell signalling and thereby have immunomodulatory effects [126].…”

Section: Hdac Inhibitors Have Immunosuppressive Effectsmentioning

confidence: 99%

Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML

Bruserud

Stapnes

Tronstad

et al. 2006

Expert Opinion on Therapeutic Targets

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Several new therapeutic strategies are now considered for acute myelogenous leukaemia (AML), including modulation of protein lysine acetylation through inhibition of histone deacetylases (HDACs): a large group of enzymes that alters the acetylation and, thereby, the function of a wide range of nuclear and cytoplasmic proteins. Firstly, HDACs can deacetylate histones as well as transcription factors, and can modulate gene expression through both these mechanisms. Secondly, acetylation is an important post-translational modulation of several proteins involved in the regulation of cell proliferation, differentiation and apoptosis (e.g., p53, tubulin, heat-shock protein 90). The only HDAC inhibitors that have been investigated in clinical studies of AML are butyrate derivatives, valproic acid and depsipeptide. In the first studies, the drugs have usually been used as continuous therapy for several weeks or months, and in most studies the drugs were used alone or in combination with all-trans retinoic acid for treatment of patients with relapsed or primary resistant AML. Neurological toxicity and gastrointestinal side effects seem to be common for all three drugs. Complete haematological remission lasting for several months has been reported for a few patients (< 5% of included patients), whereas increased peripheral blood platelet counts seem more common and have been described both for patients with AML and myelodysplastic syndromes. Taken together, these studies suggest that HDAC inhibition can mediate antileukaemic effects in AML, but for most patients the clinical benefit seems limited and further studies of combination therapy are required.

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Section: Hdac Inhibitors Have Immunosuppressive Effectsmentioning

confidence: 99%

Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML

Bruserud

Stapnes

Tronstad

et al. 2006

Expert Opinion on Therapeutic Targets

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“…[6][7][8][9] To circumvent these limiting factors, various autologous immunotherapeutic strategies using peptide vaccines or whole-cell approaches, with and without dendritic cells (DCs) as antigenpresenting cells, were developed with the goal of eliciting tumor-specific responses. [10][11][12] Telomerase, the ribonucleoprotein that synthesizes telomeric DNA, is substantially upregulated in cancer cells and plays an essential role in extending the proliferative lifespan of tumor cells. [13][14][15][16][17] Telomerase is highly upregulated in patients with AML, especially those with the high-risk cytogenetic subtypes, and therefore is considered an important leukemia-associated antigen candidate.…”

Section: Introductionmentioning

confidence: 99%

Immune responses and long‐term disease recurrence status after telomerase‐based dendritic cell immunotherapy in patients with acute myeloid leukemia

Khoury

Collins

Blum

et al. 2017

Cancer

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“…[18][19][20] More recently, autoantibodies have been shown to be markers of better prognosis in melanoma patients treated by interferon-␣. 21 Our results show that in patients with APL, antibodies to RAR␣ and autoantibodies like ANCA, and especially ANA, are detected.…”

Section: Anti-rar␣ Antibody Production In Patients With Aplmentioning

confidence: 99%

Frequent antibody production against RAR in both APL mice and patients

Robin

Andreu-Gallien

Schlageter

et al. 2006

Blood

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In an acute promyelocytic leukemia (APL)-transplantable mouse model, we previously reported the presence of antibodies recognizing PML-RAR␣ and RAR␣ in the sera of ATRA-treated mice. To evaluate this immune response, we determined the prevalence of anti-RAR␣ antibodies in a cohort of 48 APL mice, treated by ATRA (n ‫؍‬ 24) or by placebo pellets (n ‫؍‬ 24), and in a preliminary subset of 9 patients with APL using a specific enzyme-linked immunosorbent assay (ELISA). In APL mice, significantly higher antibody levels were observed at the latest time points (day 48 to 58 levels superior to day 15 to 18 or day 28 to 38 levels). Antibody levels were higher in ATRA-treated mice than in placebo-treated mice and were also predictive of better survival. In the patients with APL, anti-RAR␣ antibodies were detected at diagnosis and after maintenance therapy, reminiscent of the ATRAtreated APL mice. Antinuclear or antineutrophil cytoplasmic autoantibodies were also detected. These data reveal for the first time that in patients with APL an immune response may be detected at diagnosis and enhanced after maintenance therapy. IntroductionAcute promyelocytic leukemia (APL) is characterized by a differentiation block at the promyelocytic stage and by a reciprocal chromosomal translocation, t(15;17)(q24;q21), fusing the promyelocytic leukemia gene (PML) with the retinoic acid receptor alpha (RARA) gene. 1 Treatment with all-trans retinoic acid (ATRA) and chemotherapy induces complete remissions in 90% of PML-RAR␣-positive patients with APL through ATRA-induced differentiation of the leukemic cells and their subsequent elimination by apoptosis. 2 Apart from their known effects on cell differentiation, retinoids also play an important role in infection and immune functions. 3 In hypovitaminosis A animal models and in vitamin A-deficient children, alterations in antiviral, antibacterial, or antiparasite responses have been shown. [3][4][5] In an APL-transplantable mouse model that shares the promyelocytic features and response to ATRA of human APL, 6 we have previously reported the presence of antibodies in ATRA-treated mouse sera. 7 By Western blot analysis, we showed that these antibodies recognized mouse and human RAR␣ from spleen and HL-60 cells, respectively, as well as PML-RAR␣ from mouse spleen and NB4 leukemic cells. We hypothesized that such adjuvant effects of ATRA might also participate in the efficacy of ATRA in patients with APL, especially during maintenance therapy when the tumor burden is low and immunocompetency restored. 2 The aim of our study was therefore to further characterize anti-RAR␣ antibody production in APL mice as well as in patients with APL. In patients with APL, antibodies to RAR␣ and autoantibodies like antinuclear autoantibodies (ANAs) or antineutrophil cytoplasmic autoantibodies (ANCAs) were analyzed. Study designThe transplantable APL mouse model of mice undergoing APL transplantation and ATRA therapy was set up as already described. 6,7 Data from 3 protocols that did not differ in their response ...

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Targeted immunotherapy in acute myeloblastic leukemia: from animals to humans

Cited by 12 publications

References 100 publications

Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML

Protein lysine acetylation in normal and leukaemic haematopoiesis: HDACs as possible therapeutic targets in adult AML

Immune responses and long‐term disease recurrence status after telomerase‐based dendritic cell immunotherapy in patients with acute myeloid leukemia

Frequent antibody production against RAR in both APL mice and patients

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