In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 5_suppl ( 2018-02-10), p. 70-70
Abstract:
70 Background: The tyrosine kinase AXL acts as suppressive immune checkpoint of the innate immune system. AXL signalling leads to immunosuppression and tumour immune escape by downregulating dendritic cell activity, modulating efferocytosis as well as favouring an immunosuppressive chemokine profile and M-MDSC expansion. Therefore it represents an interesting novel immune oncology target. Bemcentinib (BGB324) is a first-in-class, highly selective and orally bioavailable small molecule AXL inhibitor in phase II clinical development. In pre-clinical models, inhibition of AXL signalling with bemcentinib reversed multiple established immune suppressive mechanisms leading to increased infiltration of CTLs, NK and NKT cells and decreased infiltration of M-MDSCs (Wnuk-Lipinska, 2017). We explored safety, PK, efficacy and the effects of treatment with bemcentinib on the T- and B cell repertoire in patients with relapsed AML or MDS. Methods: BGBC003 (NCT02488408) is an open-label, dose finding study of bemcentinib in patients with R/R AML or MDS. Three dose levels have been explored and a loading dose of 400 mg on days one to three followed by 200 mg daily thereafter has been established as safe and recommended phase 2 dose. The TCRß repertoire was quantified by NGS of DNA isolated from PBMNCs using an Illumina MiSeq sequencer. TCRß genes and the IGH repertoire were analysed with BIOMED2-TCRß-A and –B and BIOMED2-FR1/-FR3 primer pools, respectively. Using genomic DNA as template, the amplicons were tagged with Illumina adapters and indices in two consecutive PCR reactions. Demultiplexing and FastQ formated data output was generated by the MiSeq reporter. Analysis of TCRß and IGH data was performed on a Microsoft Cloud using our in-house analysis pipeline Pippa. Results: Early evidence of antileukemic activity was seen. Diversification of the TCR and IGH repertoire could be detected in peripheral blood at day 21 of therapy compared to pre-treatment in three and two out of five matched samples, respectively. Conclusions: Bemcentinib shows preliminary evidence of immune modulation in AML. Clinical trial information: NCT02488408.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/JCO.2018.36.5_suppl.70
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2018
detail.hit.zdb_id:
2005181-5
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