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Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse.sup.1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable.sup.3-5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human [alpha]CD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine ((https://clinicaltrials.gov/ct2/show/NCT03030612)). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at A phase 1 dose-escalating trial evaluating CD70 inhibition in combination with hypomethylating therapy results in the elimination of leukemia stem cells and achieves clinical activity in untreated patients with acute myeloid leukemia., Author(s): Carsten Riether [sup.1] [sup.2] , Thomas Pabst [sup.1] , Sabine Höpner [sup.1] [sup.2] , Ulrike Bacher [sup.3] , Magdalena Hinterbrandner [sup.1] [sup.2] [sup.4] , Yara Banz [sup.5] , Rouven [...]

Background: The clinical benefit of cusatuzumab, a CD70‐directed monoclonal antibody with enhanced effector functions, was investigated in patients with relapsed/refractory (R/R) cutaneous T‐cell lymphoma (CTCL). Methods: In this cohort expansion of the ARGX‐110‐1201 study, 27 patients with R/R CTCL received cusatuzumab at 1 (n = 11) or 5 mg/kg (n = 16) once every 3 weeks to investigate its safety, dose, and exploratory efficacy. The pharmacokinetics, immunogenicity, CD70 expression, and CD70/CD27 biology were also assessed. Results: The most common adverse events included infusion‐related reactions, pyrexia, and asthenia. Eighteen serious adverse events (grade 1‐3) were reported in 11 patients; 1 of these (vasculitis) was considered drug‐related. For 8 of the 11 patients receiving 1 mg/kg, anti‐drug antibodies (ADAs) affected the minimal concentration, and this resulted in undetectable cusatuzumab concentrations at the end of treatment and, in some cases, a loss of response. This effect was greatly reduced in the patients receiving 5 mg/kg. The overall response rate was 23%; this included 1 complete response and 5 partial responses (PRs) in 26 of the 27 evaluable patients. In addition, 9 patients achieved stable disease. The mean duration on cusatuzumab was 5.2 months, and the median duration was 2.5 months. Patients with Sézary syndrome (SS) achieved a 60% PR rate with a dosage of 5 mg/kg and a 33% PR rate with a dosage of 1 mg/kg; this resulted in an overall response rate of 50% for patients with SS at both doses. Conclusions: Cusatuzumab was well tolerated, and antitumor activity was observed at both 1 and 5 mg/kg in highly pretreated patients with R/R CTCL. The observed dose‐dependent effect on exposure supports the use of 5 mg/kg for future development. Cusatuzumab, a monoclonal antibody targeting CD70, is well tolerated and shows dose‐dependent evidence of antitumor activity in a heavily pretreated patient population with cutaneous T‐cell lymphoma. The overall response rate was 23% with increased efficacy in patients with Sézary syndrome, warranting further clinical development. [ABSTRACT FROM AUTHOR]

PML and Tif1a are fused to RARA and Braf, respectively, resulting in the production of PML-RARα and Tif1α-B-Raf (T18) oncoproteins. Here we show that PML, Tif1α and RXRα/RARα function together in a transcription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXRα/RARα. PML interacts with Tif1α and CBP. In Pml?/? cells, the RA-dependent induction of genes such as RARB2 and the ability of Tif1α and CBP to act as transcriptional coactivators on RA are impaired. We show that both PML and Tif1α are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RARα, disrupts the RA-dependent activity of this complex in a dominant-negative manner resulting in a growth advantage. Our data define a new pathway for the control of cell growth and tumorigenesis, and provide a new model for the pathogenesis of acute promyelocytic leukaemia (APL). [ABSTRACT FROM AUTHOR]

Examines the mechanism of interferon (IFN) and retinoic acid (RA) in treating acute promyelocytic leukemia (APL). Use of IFN to overcome acquired resistance to all-trans retinoic acid; Role of IFN and RA in differentiating hemopoietic and leukemic cells.