DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance

The interleukin-3 receptor α subunit, CD123, is expressed in many hematologic malignancies including acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Tagraxofusp (SL-401) is a CD123-targeted therapy consisting of interleukin-3 fused to a truncated diphtheria toxin payload. Factors influencing response to tagraxofusp other than CD123 expression are largely unknown. We interrogated tagraxofusp resistance in patients and experimental models and found that it was not associated with CD123 loss. Rather, resistant AML and BPDCN cells frequently acquired deficiencies in the diphthamide synthesis pathway, impairing tagraxofusp’s ability to ADP-ribosylate cellular targets. Expression of DPH1, encoding a diphthamide pathway enzyme, was reduced by DNA CpG methylation in resistant cells. Treatment with the DNA methyltransferase inhibitor azacitidine restored DPH1 expression and tagraxofusp sensitivity. We also developed a drug-dependent ADP-ribosylation assay in primary cells that correlated with tagraxofusp activity and may represent an additional novel biomarker. As predicted by these results and our observation that resistance also increased mitochondrial apoptotic priming, we found that the combination of tagraxofusp and azacitidine was effective in patient-derived xenografts treated in vivo. These data have important implications for clinical use of tagraxofusp and led to a phase 1 study combining tagraxofusp and azacitidine in myelo...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research

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Authors: Kopmar NE, Estey EH Abstract We are witnessing an unprecedented paradigm shift in the treatment of acute myeloid leukemia (AML). For nearly 4 decades-since the introduction of cytarabine- and anthracycline-based induction chemotherapy in the 1970s-treatment options for patients with AML have remained limited, and outcomes remain poor for the majority of patients, particularly the elderly. Over the past 10 to 15 years, we have better elucidated the genetic and molecular basis of AML, which has led to our current understanding of disease heterogeneity. We now appreciate that numerous distinct disease subtype...
Source: Clinical Advances in Hematology and Oncology - Category: Cancer & Oncology Tags: Clin Adv Hematol Oncol Source Type: research
Authors: Ivan I, Climent F, Mercadal S PMID: 31722786 [PubMed - as supplied by publisher]
Source: Medicina Clinica - Category: General Medicine Tags: Med Clin (Barc) Source Type: research
In this study, we investigated the association between polymorphisms in MEG3 (rs11160608, rs7158663, rs3087918) and WTI (rs16754) and risk of AML in Iranian population. A total of 100 AML cases and 100 healthy controls from the North West of Iran were enrolled in our work. The polymorphisms rs7158663 and rs3087918 were genotyped by PCR-restriction fragment length polymorphism (RFLP) method. The amplification-refractory mutation system (ARMS)-PCR method was used for identification of MEG3 rs11160608 and WT1 rs16754 polymorphisms. The rs7158663 and rs3087918 were shown to increase the risk of AML. In summary, our findings in...
Source: Meta Gene - Category: Genetics & Stem Cells Source Type: research
In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
Conclusion and Perspective With in-depth understandings of antibodies, linkers, and payloads, ADCs have also achieved great development. The linkage strategy and target diversity have already improved the delivery of the payloads to tumor tissues and reduced exposure to normal tissues. With the development of payloads, some novel potent payloads are used by ADCs, which allows researchers to exploit novel linkers to attach the antibody and payloads without disturbing their potency (Dragovich et al., 2018). Furthermore, some irrelevant antigen-target ADCs also may exert toxicity to tumor cells due to the vascular gap of tum...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Nicolaas G. van der Maas, Dagmar Berghuis, Mirjam van der Burg and Arjan C. Lankester* Willem-Alexander Children's Hospital, Department of Pediatrics and Laboratory for Pediatric Immunology, Leiden University Medical Center, Leiden, Netherlands B cell reconstitution after hematopoietic stem cell transplantation (HSCT) is variable and influenced by different patient, donor, and treatment related factors. In this review we describe B cell reconstitution after pediatric allogeneic HST, including the kinetics of reconstitution of the different B cell subsets and the development of the B cell repertoire, and d...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is characterized by cytopenias, organomegaly, constitutional symptoms, autoimmune phenomena, and ultimately progression to acute myeloid leukemia (AML). The only known cure for CMML remains allogeneic stem cell transplant. Aside from stem cell transplant, currently utilized therapeutic modalities include hydroxyurea, erythropoietin stimulating agents (ESAs) and hypomethylating agents (HMAs). Azacitidine (AZA) and Decitabine (DAC) have been utilized to treat CMML patients, particularly those with cytopenias, with variable ef...
Source: Blood - Category: Hematology Authors: Tags: 636. Myelodysplastic Syndromes-Basic and Translational Studies: Poster I Source Type: research
We report here indiscriminate killing of CD123+ normal and acute myeloid leukemia / myelodysplastic syndrome cells by SL-401, a diphtheria toxin interleukin-3 fusion protein. SL-401 induced cytotoxicity of CD123+ primary cells/blasts from acute myeloid leukemia and myelodysplastic syndrome patients but not CD123- lymphoid cells. Importantly, SL-401 was highly active even in cells expressing low levels of CD123, with minimal effect on modulation of the CD123 target in acute myeloid leukemia. SL-401 significantly prolonged survival of leukemic mice in acute myeloid leukemia patient-derived xenograft mouse models. In addition...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research
This article will also review different generations of immunotoxins with special focus on immunotoxins which are under clinical trials or approved for clinical use. Finally, current deimmunization strategies for development of new less-immunogenic recombinant immunotoxins will be discussed. ABBREVIATIONS: mAbs: Monoclonal antibodies; EF2: elongation factor 2; ITs: Immunotoxins; DT: Diphtheria toxin; PE: Pseudomonas exotoxin; dgA: de-glycosylated A-chain of ricin; rGel: recombinant de-glycosylated form of gelonin; NKC: natural killer cells; HTR: human transferrin receptor; EGF: epidermal growth factor; GM-CSF: granulocy...
Source: International Reviews of Immunology - Category: Allergy & Immunology Tags: Int Rev Immunol Source Type: research
Authors: Sullivan JM, Rizzieri DA Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy with no defined standard of care. BPDCN presents most commonly with skin lesions with or without extramedullary organ involvement before leukemic dissemination. As a result of its clinical ambiguity, differentiating BPDCN from benign skin lesions or those of acute myeloid leukemia with leukemia cutis is challenging. BPDCN is most easily defined by the phenotype CD4(+)CD56(+)CD123(+)lineage(-)MPO(-), although many patients will present with variable expression of CD4, CD56, or alternate plasma...
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
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