A Blood Dendritic Cell Vaccine for Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5221-5221 ◽  
Author(s):  
Jennifer Hsu ◽  
Christian Bryant ◽  
Phillip Fromm ◽  
Michael Papadimitrious ◽  
Daniel Orellana ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Clinical Effects ◽  
Equity Ownership ◽  
Acute Myeloid ◽  
Research Institute

Abstract Many acute myeloid leukemia (AML) patients achieve a complete remission (CR) with chemotherapy but relapse is common. Removal of residual disease remains the greatest challenge. Allogeneic transplantation (alloHCT) addresses this through an immune-mediated graft versus leukemia effect (GVL), but has high morbidity and mortality. Therapeutic dendritic cell (DC) vaccination has the potential to provide immune control with limited toxicity. Previous trials using monocyte-derived DC (Mo-DC) have demonstrated modest clinical effects. This is understandable as Mo-DC have demonstrably poor migration in vivo and relatively inferior antigen processing and presentation compared to blood dendritic cells (BDC). We have developed a more practical, functionally superior vaccine composed of natural blood DC (BDC). This is achieved using the human-mouse chimeric monoclonal antibody CMRF-56 to enrich BDC from patient peripheral blood after a short incubation.We assessed the potential for preparing a CMRF-56+ BDC vaccine from AML patients in CR. We developed an extended flow cytometry panel to distinguish different BDC subsets from blasts in AML, sorted them to confirm morphology, then used TruCount methodology to enumerate them at diagnosis, post-chemotherapy (5-28 weeks) and post alloHCT. We correct previous reports that suggested BDC numbers are normal at AML diagnosis by demonstrating that the Lineage- HLA-DR+ CD11c+ cells commonly classified as myeloid DC contain myeloblasts. Exclusion of myeloblasts, revealed that CD1c and CD141 BDC are grossly depleted at AML diagnosis to 567/mL and 24/mL, 4% and 3% respectively of the the levels of healthy aged-matched controls (HC) (n=9; n=13), but recovered to 7323/mL and 294/mL, representing 57% and 39% HC levels (n=12) during CR1, and to 10282/mL and 299/mL, representing 80% and 40% of HC after alloHCT (n=6). In contrast, plasmacytoid dendritic cells (pDC) levels were 2229/mL and 27% of HC at diagnosis, but failed to recover further remaining at 1453/mL or 18% of HC at CR1 and at 1986/mL and 24% of HC post alloHCT. CD1c BDC from AML patients in CR upregulated the CMRF-56 antigen,. similarly to HC (n=5, p=0.4) but primary AML blasts did not, enabling myeloblast free, CMRF-56+ BDC purifications. CMRF-56+ BDC isolated from AML patients in CR expanded anti-viral and Wilms' Tumour 1-specific autologous CD8+ T cells in vitro. However, patients who failed standard induction chemotherapy and required fludarabine-containing salvage regimens produced good CMRF-56+ BDC preparations but did not expand functional T cells. These data support the feasabillity of preparing a functional BDC vaccine from AML patients in CR using CMRF-56 immune selection and highlight the potential detrimental effects of specific chemotherapeutics on cellular therapy. BDC vaccination may consolidate chemotherapy induced CR in AML, or enhance GVL post alloHCT, by stimulating specific immune responses to control residual disease. Disclosures Hsu: DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Bryant:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Fromm:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Papadimitrious:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Orellana:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Suen:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Yang:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Weatherburn:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Gasiorowski:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Iland:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Brown:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Joshua:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Ho:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Gibson:DendroCyte BioTech Ltd: Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Clark:DendroCyte BioTech Ltd: Equity Ownership, Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd. Hart:DendroCyte BioTech Ltd: Equity Ownership, Other: Laboratory IP contracted via ANZAC Research Institute to DendroCyte BioTech Ltd.

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

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2764-2771 ◽  
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.

Interleukin-12 Gene Expression into Acute Myeloid Leukemia-Derived Dendritic Cells Overcomes T-Cell Functional Impairment Induced by Leukemic Microenvironment.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1816-1816
Author(s):  
Antonio Curti ◽  
Simona Pandolfi ◽  
Michela Aluigi ◽  
Alessandro Isidori ◽  
Isabella Alessandrini ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
T Cell ◽  
Myeloid Leukemia ◽  
Interleukin 12 ◽  
Functional Features ◽  
Ifn Γ ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) cells are poorly immunogenic and release soluble factors inhibiting T-cell function. AML-derived dendritic cells (AML-DCs) have better antigen presentation capacity than leukemic blasts but share with AML cells some immunosuppressive features. In this study, we show that AML-DCs generated from CD14− AML samples (which represent 80% of total AML patients) are defective in IL-12 production. We, then, transfected CD14−-derived AML-DCs with IL-12 gene through the novel non-viral method nucleofection. IL-12 gene-nucleofected AML-DCs produce significant amount of IL-12 while maintain leukemia-specific karyotype, DC-like phenotype and function. In presence of the supernatant from the human leukemic cell line K562, allogeneic T-cell proliferation and interferon (IFN)-γ production induced by mock-transduced AML-DCs are significantly reduced. This effect is mainly directed on T cells, since AML-DC phenotype and cytokine production are not affected by leukemic supernatant. However, when stimulated by IL-12-producing AML-DCs, T cells produce higher concentrations of IFN-γ, thus maintaining a Th1 cytokine profile. In conclusion, IL-12 gene can be expressed into AML-DCs defective in endogenous IL-12 production by using a novel non-viral method which does not modify their phenotypical, cytogenetic and functional features. IL-12 gene expression into AML-DC counteracts the inhibitory effect of leukemic microenvironment on T lymphocytes

Acute Differentiated Dendritic Cell Leukemia: A New Form of Pediatric Acute Myeloid Leukemia (AML) with MLL Translocations.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3263-3263
Author(s):  
Luca Lo Nigro ◽  
Laura Sainati ◽  
Anna Leszl ◽  
Elena Mirabile ◽  
Monica Spinelli ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
Fusion Transcript ◽  
Fish Analysis ◽  
Rt Pcr ◽  
Pediatric Acute Myeloid Leukemia ◽  
Pediatric Aml ◽  
Acute Myeloid

Abstract Background: Myelomonocytic precursors from acute or chronic leukemias can differentiate to dendritic cells in vitro, but leukemias with a dendritic cell immunophenotype are rare, have been reported mainly in adults, and their molecular pathogenesis is unknown. Dendritic cells are classified as Langherans, myeloid and lymphoid/plasmacytoid cells, but leukemias arising from dendritic cells are unclassified in the FAB system. We identified a new entity of pediatric acute myeloid leukemia (AML) presenting with morphologic and immunophenotypic features of mature dendritic cells, which is characterized by MLL gene translocation. Methods and Results: Standard methods were used to characterize the morphology, immunophenotype, karyotype and MLL translocations in 3 cases of pediatric AML. The patients included two boys and one girl diagnosed with AML between 1–6 years old. Their clinical histories and findings included fever, pallor, abdominal and joint pain, adenopathy, hepatosplenomegaly, normal WBC counts but anemia and thrombocytopenia. and no evidence of CNS disease. The bone marrow aspirates were hypocellular and replaced completely by large blasts with irregular nuclei, slightly basophilic cytoplasm, and prominent cytoplasmic projections. There were no cytoplasmatic granules or phagocytosis. Myeloperoxidase and alpha napthyl esterase reactions were negative, excluding FAB M5 AML, and the morphology was not consistent with any standard FAB morphologic diagnosis. The leukemic blasts in all three cases were CD83+, CD86+, CD116+, consistent with differentiated myeloid dendritic cells, and did not express CD34, CD56 or CD117. MLL translocations were identified in all 3 cases. In the first case FISH analysis showed t(10;11)(p12;q23) and RT-PCR identified and a ‘5-MLL-AF10-3’ fusion transcript. In the second case FISH analysis showed t(9;11)(p22;q23) and RT-PCR identified and a ‘5-MLL-AF9-3’ fusion transcript. In the remaining case, the MLL gene rearrangement was identified by Southern blot analysis and RT-PCR showed an MLL-AF9 fusion transcript. The fusion transcripts in all 3 cases were in-frame. Remission induction was achieved with intensive chemotherapy, and all three patients have remained in durable remission for 30–60 months after hematopoietic stem cell transplantation. Conclusions. We have characterized a new pediatric AML entity with features of mature dendritic cells, MLL translocation and an apparently favorable prognosis. The in-frame MLL fusion transcripts suggest that chimeric MLL oncoproteins underlie its pathogenesis. The partner genes in all 3 cases were known partner genes of MLL that encode transcription factors. This study increases the spectrum of leukemias with MLL translocations. Comprehensive morphological, immunophenotypic, cytogenetic and molecular analyses are critical for this diagnosis, and will reveal its frequency and spectrum as additional cases are uncovered.

scholarly journals Chimeric Antigen Receptor-Modified T Cells for the Treatment of Acute Myeloid Leukemia Expressing CD33

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4058-4058 ◽  
Author(s):  
Degang Song ◽  
Michael H. Swartz ◽  
Steve G. Biesecker ◽  
Fernando Borda ◽  
Rutul R. Shah ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Chimeric Antigen Receptor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Relapsed acute myeloid leukemia (AML) is an aggressive disease with very poor outcomes. Redirection of T-cell specificity via chimeric antigen receptor (CAR) has shown promising anti-tumor activity in clinical trials, particularly for B cell linage malignancies. CD33 is a transmembrane protein expressed on normal and malignant myeloid-derived cells as well (as on subsets of activated T cells and NK cells). Since this protein is commonly expressed on AML cells, we sought to evaluate the efficacy of targeting AML with CD33-specific CAR-T cells. We generated a lentiviral construct to co-express CD33-specific CAR and a kill switch based on a tag derived from the epidermal growth factor receptor. The latter allows for the conditional elimination of CAR-T cells in vivo. Following transduction of primary T cells, we confirmed CAR and kill switch co-expression by flow cytometry and western blot analyses. Elimination of genetically modified T cells was demonstrated using the clinically-available antibody, cetuximab. CD33 CAR-T cells demonstrated specific cytotoxicity to CD33+ target cell lines. CD33 CAR-T cells were also activated to produce IFNg, TNF, and IL-2 cytokines in response to CD33+ target cells. Furthermore, adoptive transfer of CD33 CAR-T in immunocompromised (NSG) mice bearing established CD33+(CD19neg) AML (MOLM-13) tumor resulted in reduction of tumor burden and improvement of overall survival, compared to control mice receiving CD19 CAR-T cells or no immunotherapy (Figure). Sampling of blood demonstrated the persistence of the CD33 CAR-T cells with no detection of AML (MOLM-13) tumor cells. These pre-clinical data demonstrate the effectiveness of CD33 CAR-T cells in targeting CD33+ AML tumor cells and provide a rationale for future clinical evaluation in AML patients with unmet medical need. Disclosures Song: Intrexon Corporation: Employment, Equity Ownership. Swartz:Intrexon Corporation: Employment, Equity Ownership. Biesecker:Intrexon Corporation: Employment, Equity Ownership. Borda:Intrexon Corporation: Employment. Shah:Intrexon Corporation: Employment, Equity Ownership. Wierda:Genentech: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Acerta: Research Funding. Cooper:MD Anderson Cancer Center: Employment; Intrexon: Equity Ownership; Sangamo BioSciences: Patents & Royalties; Targazyme,Inc.,: Equity Ownership; City of Hope: Patents & Royalties; ZIOPHARM Oncology: Employment, Equity Ownership, Patents & Royalties; Miltenyi Biotec: Honoraria; Immatics: Equity Ownership. Chan:Intrexon Corporation: Employment, Equity Ownership.

scholarly journals Plasmacytoid dendritic cell expansion defines a distinct subset of RUNX1 mutated acute myeloid leukemia

Blood ◽  
2020 ◽  
Author(s):  
Wenbin Xiao ◽  
Alexander Chan ◽  
Michael R Waarts ◽  
Tanmay Mishra ◽  
Ying Liu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Myeloid Leukemia ◽  
Plasmacytoid Dendritic Cell ◽  
Xenograft Model ◽  
Antigen Expression ◽  
Type I ◽  
Transcriptional Program ◽  
Acute Myeloid

Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.

Vaccines With Interleukin-12–Transduced Acute Myeloid Leukemia Cells Elicit Very Potent Therapeutic and Long-Lasting Protective Immunity

Blood ◽  
1999 ◽  
Vol 94 (12) ◽  
pp. 4263-4273 ◽  
Author(s):  
Kyriaki Dunussi-Joannopoulos ◽  
Kathlene Runyon ◽  
Jamie Erickson ◽  
Robert G. Schaub ◽  
Robert G. Hawley ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Cytotoxic T Lymphocyte ◽  
Interleukin 12 ◽  
Ifn Γ ◽  
Acute Myeloid

Abstract Interleukin-12 (IL-12) is a heterodimeric cytokine mediating a dynamic interplay between T cells and antigen-presenting cells (APCs). Preclinical studies have demonstrated that recombinant murine IL-12 (rmIL-12) promotes specific antitumor immunity mediated by T cells in several types of tumors. However, the in vivo antitumor properties of IL-12 in acute myeloid leukemia (AML) have not been previously reported. We show here in a murine AML model that systemic administration of rmIL-12 significantly delays tumor growth but is incapable of rescuing mice from lethal leukemia. In contrast, AML cells genetically modified to express IL-12 (IL12-AML) using murine stem cell virus (MSCV) p40 + p35 elicit very potent antileukemic activity. Vaccines with lethally irradiated IL12-AML cells protect naive mice against challenge with wild-type AML cells and, more importantly, can cure mice bearing a considerable leukemic burden. Immunized mice show no signs of systemic IL-12 toxicity and their spleen histology is comparable with naive mice spleen. In vivo depletion of IL-12, interferon-γ (IFN-γ), or CD8+ T cells after injections with live IL12-AML cells abrogates completely the antileukemia immune responses. Studies on the in vitro effects of IFN-γ on AML cells demonstrate enhanced expression of major histocompatibility complex (MHC) and accessory molecules and induction of the costimulatory molecules B7.1 and B7.2, but no significant direct antiproliferative effect. 51Cr release assays show that rejection of live IL12-AML cells supports the development of long-lasting leukemia-specific cytotoxic T lymphocyte (CTL) activity. In conclusion, our results demonstrate that IL12-AML vaccination is a safe and potent immunotherapeutic approach that has a great potential to eliminate minimal residual disease in patients with AML.

Attenuated A20 expression of acute myeloid leukemia-derived dendritic cells increased the anti-leukemia immune response of autologous cytolytic T cells

2014 ◽  
Vol 38 (6) ◽  
pp. 673-681 ◽  
Author(s):  
Xiaoying Zhang ◽  
Yongfeng Su ◽  
Haifeng Song ◽  
Zhiyong Yu ◽  
Bin Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Dendritic Cells ◽  
Myeloid Leukemia ◽  
Acute Myeloid
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