Dendritic Cell-Regulated T Cell Immunity and Tolerance against Acute Myeloid Leukemia

Blastic plasmacytoid dendritic cell neoplasm is a rare entity grouped with the acute myeloid leukemia–related precursor neoplasms in the 2008 World Health Organization classification. It was previously postulated to originate from natural killer cells, T cells, or monocytes but is now believed to arise from the plasmacytoid dendritic cell. The pathogenesis of blastic plasmacytoid dendritic cell neoplasm is not well understood, although the neoplasm demonstrates frequent deletion of tumor suppressor genes, including RB1, CDKN1B, CDKN2A, and TP53. Blastic plasmacytoid dendritic cell neoplasm is a clinically aggressive tumor that often initially presents as cutaneous lesions and subsequently progresses to bone marrow involvement and leukemic dissemination. It is characterized by enhanced expression of CD56, CD4, and CD123, which can be detected by flow cytometry/immunohistochemistry. The differential diagnoses include myeloid sarcoma/acute myeloid leukemia, T-cell lymphoblastic leukemia/lymphoma, NK-cell lymphoma/leukemia, and some mature T-cell lymphomas/leukemias. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplant may improve survival.

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Down-Regulation of Signal Transducer and Activator of Transcription 3 Enhances Acute Myeloid Leukemia-Derived Dendritic Cell Function

Blood ◽

10.1182/blood.v116.21.3140.3140 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3140-3140

Author(s):

Michael T Brady ◽

Austin Miller ◽

Sheila Sait ◽

Laurie A Ford ◽

Minderman Hans ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Dendritic Cell ◽

Myeloid Leukemia ◽

Cell Stimulation ◽

T Cell Stimulation ◽

Dc Vaccines ◽

Dc Maturation ◽

Acute Myeloid

Abstract Abstract 3140 Immunotherapies, including stimulating patients' immune system with acute myeloid leukemia (AML)-derived dendritic cell (DC) vaccines, are being sought for the treatment of AML. However, these vaccines have proven to be less successful than anticipated. We have previously shown that STAT3 is constitutively activated in the blasts of approximately half of AML patients and to correlate with poor prognosis. STAT3 regulates a variety of cellular events and has been shown to play a role in immunosuppression by inhibiting DC differentiation, resulting in induction of T cell tolerance rather than T cell activation. We hypothesize that AML-DC with constitutively activated STAT3 are impaired to fully differentiate and to efficiently stimulate T cells. The current study investigated the correlation between STAT3 activity, DC maturation and the ability to stimulate allogeneic T cells in primary AML-derived DCs. AML blasts differentiated to DCs regardless of the level of activated STAT3, however AML-DC with high levels of activated STAT3 elicited less T cell response than AML-DC with low levels of activated STAT3. Knock-down of STAT3 protein with inhibitory shRNAmirs in 4/4 patient AML-DCs increased stimulation of allogeneic T cells compared to control DCs without affecting the immunophenotype or endocytotic activity. Treatment of AML-DC with the STAT3 inhibitors AG490, arsenic trioxide (ATO), JSI-124 and NSC-74859 during early differentiation did not significantly enhance T cell stimulation. Treatment with ATO, but not the remaining inhibitors, during the last 24 hours of maturation led to more mature phenotype and enhanced T cell stimulation in 2/2 AML cell lines and 8/9 patient samples (p=0.0001) while having minimal effect on normal cord blood-derived DC. ATO-treated AML-DCs had an increased expression of the co-stimulatory markers CD80 and CD86, the mature DC marker CD83 and increased HLA-DR expression indicating more mature DCs. Four of six ATO-treated AML-DCs secreted higher amounts of the T cell stimulating cytokine interleukin (IL)-12p40 (average increase 2.5 fold); exogenous administration of IL-12 recapitulated ATO's effect. These data demonstrate that AML-DCs have improved immunogenicity after reducing STAT3 protein levels during differentiation. The observation that treatment with ATO is superior to the more targeted JAK/STAT inhibitors suggests that DC maturation is regulated by other pathways in addition to STAT3. We propose to use ATO-treated AML-DC vaccines in future clinical trials. ATO treatment would not only lead to more immunogenic vaccines, but would also increase the number of mature AML-DCs that could be differentiated from each patient, solving two of the major obstacles for the use of AML-DC vaccines. Disclosures: No relevant conflicts of interest to declare.

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Study of CAR T-cell Therapy in Acute Myeloid Leukemia and Multiple Myeloma

Case Medical Research ◽

10.31525/ct1-nct04097301 ◽

2019 ◽

Author(s):

Keyword(s):

Multiple Myeloma ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

T Cell Therapy ◽

Car T Cell ◽

Car T Cell Therapy ◽

Car T ◽

Acute Myeloid

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Single Injection of CD34+ Progenitor-Derived Dendritic Cell Vaccine Can Lead to Induction of T-Cell Immunity in Patients With Stage IV Melanoma

Journal of Immunotherapy ◽

10.1097/00002371-200309000-00006 ◽

2003 ◽

Vol 26 (5) ◽

pp. 432-439 ◽

Cited By ~ 46

Author(s):

A. Karolina Palucka ◽

Madhav V. Dhodapkar ◽

Sophie Paczesny ◽

Susan Burkeholder ◽

Knut M. Wittkowski ◽

...

Keyword(s):

T Cell ◽

Dendritic Cell ◽

Single Injection ◽

Stage Iv ◽

Dendritic Cell Vaccine ◽

T Cell Immunity ◽

Cell Vaccine ◽

Cell Immunity ◽

Stage Iv Melanoma

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A modular and controllable T cell therapy platform for acute myeloid leukemia

Leukemia ◽

10.1038/s41375-020-01109-w ◽

2021 ◽

Author(s):

Mohamed-Reda Benmebarek ◽

Bruno L. Cadilha ◽

Monika Herrmann ◽

Stefanie Lesch ◽

Saskia Schmitt ◽

...

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Cell Therapy ◽

Myeloid Leukemia ◽

Tumor Antigens ◽

Adoptive T Cell Therapy ◽

Single Chain ◽

T Cell Therapy ◽

Acute Myeloid

AbstractTargeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.

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A lineage switch from NPM1 ‐mutant acute myeloid leukemia to acute T‐cell lymphoblastic leukemia with KMT2D and ARID2 mutant

International Journal of Laboratory Hematology ◽

10.1111/ijlh.13534 ◽

2021 ◽

Author(s):

Yi Chen ◽

Lixia Wang ◽

Fanggang Ren ◽

Yaofang Zhang ◽

Jianlan Li ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

T Cell ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Lineage Switch ◽

Acute Myeloid

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Immunomodulatory Effect of Green Tea Treatment in Combination with Low-dose Chemotherapy in Elderly Acute Myeloid Leukemia Patients with Myelodysplasia-related Changes

Integrative Cancer Therapies ◽

10.1177/15347354211002647 ◽

2021 ◽

Vol 20 ◽

pp. 153473542110026

Author(s):

Andrana K. Calgarotto ◽

Ana L. Longhini ◽

Fernando V. Pericole de Souza ◽

Adriana S. Santos Duarte ◽

Karla P. Ferro ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

T Cell ◽

Green Tea ◽

Regulatory T Cell ◽

Myeloid Leukemia ◽

Low Dose ◽

Related Factor ◽

Low Dose Chemotherapy ◽

Acute Myeloid

Green tea (GT) treatment was evaluated for its effect on the immune and antineoplastic response of elderly acute myeloid leukemia patients with myelodysplasia-related changes (AML-MRC) who are ineligible for aggressive chemotherapy and bone marrow transplants. The eligible patients enrolled in the study (n = 10) received oral doses of GT extract (1000 mg/day) alone or combined with low-dose cytarabine chemotherapy for at least 6 months and/or until progression. Bone marrow (BM) and peripheral blood (PB) were evaluated monthly. Median survival was increased as compared to the control cohort, though not statistically different. Interestingly, improvements in the immunological profile of patients were found. After 30 days, an activated and cytotoxic phenotype was detected: GT increased total and naïve/effector CD8+ T cells, perforin+/granzyme B+ natural killer cells, monocytes, and classical monocytes with increased reactive oxygen species (ROS) production. A reduction in the immunosuppressive profile was also observed: GT reduced TGF-β and IL-4 expression, and decreased regulatory T cell and CXCR4+ regulatory T cell frequencies. ROS levels and CXCR4 expression were reduced in bone marrow CD34+ cells, as well as nuclear factor erythroid 2–related factor 2 (NRF2) and hypoxia-inducible factor 1α (HIF-1α) expression in biopsies. Immune modulation induced by GT appears to occur, regardless of tumor burden, as soon as 30 days after intake and is maintained for up to 180 days, even in the presence of low-dose chemotherapy. This pilot study highlights that GT extracts are safe and could improve the immune system of elderly AML-MRC patients.

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Stimulation of autologous proliferative and cytotoxic T-cell responses by “leukemic dendritic cells” derived from blast cells in acute myeloid leukemia

Blood ◽

10.1182/blood.v97.9.2764 ◽

2001 ◽

Vol 97 (9) ◽

pp. 2764-2771 ◽

Cited By ~ 77

Author(s):

Beth D. Harrison ◽

Julie A. Adams ◽

Mark Briggs ◽

Michelle L. Brereton ◽

John A. Liu Yin

Keyword(s):

T Cells ◽

Acute Myeloid Leukemia ◽

Dendritic Cells ◽

T Cell ◽

Myeloid Leukemia ◽

T Cell Responses ◽

Cell Responses ◽

Antigen Presenting ◽

Acute Myeloid ◽

Stimulation Of

Abstract Effective presentation of tumor antigens is fundamental to strategies aimed at enrolling the immune system in eradication of residual disease after conventional treatments. Myeloid malignancies provide a unique opportunity to derive dendritic cells (DCs), functioning antigen-presenting cells, from the malignant cells themselves. These may then co-express leukemic antigens together with appropriate secondary signals and be used to generate a specific, antileukemic immune response. In this study, blasts from 40 patients with acute myeloid leukemia (AML) were cultured with combinations of granulocyte-macrophage colony-stimulating factor, interleukin 4, and tumor necrosis factor α, and development to DCs was assessed. After culture, cells from 24 samples exhibited morphological and immunophenotypic features of DCs, including expression of major histocompatibility complex class II, CD1a, CD83, and CD86, and were potent stimulators in an allogeneic mixed lymphocyte reaction (MLR). Stimulation of autologous T-cell responses was assessed by the proliferative response of autologous T cells to the leukemic DCs and by demonstration of the induction of specific, autologous, antileukemic cytotoxicity. Of 17 samples, 11 were effective stimulators in the autologous MLR, and low, but consistent, autologous, antileukemic cytotoxicity was induced in 8 of 11 cases (mean, 27%; range, 17%-37%). This study indicates that cells with enhanced antigen-presenting ability can be generated from AML blasts, that these cells can effectively prime autologous cytotoxic T cells in vitro, and that they may be used as potential vaccines in the immunotherapy of AML.

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