First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases

The interleukin-3 receptor alpha chain (IL-3Rα), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 is expressed at both the level of leukemic stem cells (LSCs) and more differentiated leukemic blasts, which makes CD123 an attractive therapeutic target. Various agents have been developed as drugs able to target CD123 on malignant leukemic cells and on the normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed of a truncated diphtheria toxin payload fused to IL-3, was approved for use in patients with BPDCN in December of 2018 and showed some clinical activity in AML. Different monoclonal antibodies directed against CD123 are under evaluation as antileukemic drugs, showing promising results either for the treatment of AML minimal residual disease or of relapsing/refractory AML or BPDCN. Finally, recent studies are exploring T cell expressing CD123 chimeric antigen receptor-modified T-cells (CAR T) as a new immunotherapy for the treatment of refractory/relapsing AML and BPDCN. In December of 2018, MB-102 CD123 CAR T developed by Mustang Bio Inc. received the Orphan Drug Designation for the treatment of BPDCN. 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.

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“…SL-401 was also tested in few pediatric BPDCN patients, providing preliminary evidence of clinical activity [99].…”

Section: Therapeutic Cd123 Targetingmentioning

confidence: 99%

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Testa

Pelosi

Castelli

2019

Cancers

106

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“…Sun et al from the City of Hope reported the first three cases of pediatric patients with this type of malignancy. Overall, the treatment was very well tolerated, with side effects similar to those of CLS and infusion reaction [31]. The number of patients in this report was very small, so a conclusion about the efficacy of this treatment cannot be made, although all patients showed some response.…”

Section: Pediatric Experiencementioning

confidence: 97%

Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies

Alkharabsheh

Frankel

2019

Biomedicines

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Overcoming the leukemia stem cell resistance to intensive chemotherapy has been an area of extensive research over the last two decades. Advances and greater understanding of the molecular biology of leukemia stem cells are in rapid progress. Targeted therapies are currently being used in clinical practice with reasonable response rates, but a cure is being achieved in only a small percentage of patients, most likely due to tumor mutational heterogeneity. A genetically engineered diphtheria toxin fused with interleukin-3 (SL-401 or tagraxofusp) has shown robust activity in blastic plasmacytoid dendritic cell neoplasm and promising response rates in different myeloid malignancies, including eradication of minimal residual disease. Multiple clinical trials are being conducted using this drug and the preliminary results are encouraging. This article reviews the clinical trials for SL-401, its mechanism of action, clinical activity, and the adverse event profile.

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“…Seven of nine evaluable BPDCN patients had major responses, including five CR and two PR after a single course of SL-401 (Frankel et al, 2014). Further clinical and non-clinical evaluations of this immunotoxin (Pemmaraju et al, 2017; Sun et al, 2018) led to its approval by the FDA in 2018 for the treatment of adult and pediatric BPDCN under the name of Tagraxofusp TM (Syed, 2019).…”

Section: Diphtheria Toxin-based Immunotoxinsmentioning

confidence: 99%

Targeted Diphtheria Toxin-Based Therapy: A Review Article

Shafiee¹,

Aucoin²,

Jahanian-Najafabadi³

2019

Front. Microbiol.

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Cancer remains one of the leading causes of death worldwide. Conventional therapeutic strategies usually offer limited specificity, resulting in severe side effects and toxicity to normal tissues. Targeted cancer therapy, on the other hand, can improve the therapeutic potential of anti-cancer agents and decrease unwanted side effects. Targeted applications of cytolethal bacterial toxins have been found to be especially useful for the specific eradication of cancer cells. Targeting is either mediated by peptides or by protein-targeting moieties, such as antibodies, antibody fragments, cell-penetrating peptides (CPPs), growth factors, or cytokines. Together with a toxin domain, these molecules are more commonly referred to as immunotoxins. Targeting can also be achieved through gene delivery and cell-specific expression of a toxin. Of the available cytolethal toxins, diphtheria toxin (DT) is one of the most frequently used for these strategies. Of the many DT-based therapeutic strategies investigated to date, two immunotoxins, OntakTM and TagraxofuspTM, have gained FDA approval for clinical application. Despite some success with immunotoxins, suicide-gene therapy strategies, whereby controlled tumor-specific expression of DT is used for the eradication of malignant cells, are gaining prominence. The first part of this review focuses on DT-based immunotoxins, and it then discusses recent developments in tumor-specific expression of DT.

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First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases

Cited by 43 publications

References 14 publications

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Clinical Activity and Tolerability of SL-401 (Tagraxofusp): Recombinant Diphtheria Toxin and Interleukin-3 in Hematologic Malignancies

Targeted Diphtheria Toxin-Based Therapy: A Review Article

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