Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster I
Hematology Disease Topics & Pathways:
AML, Acute Myeloid Malignancies, Research, Non-Biological therapies, Translational Research, bioinformatics, Combination therapy, drug development, immune mechanism, Diseases, Therapies, computational biology, Biological Processes, Myeloid Malignancies, Technology and Procedures, omics technologies
Among 32 patients evaluated for efficacy, 8 patients responded to their treatment (objective response rate: 25%). Among patients who received previous therapy (i.e. relapsed/refractory patients), objective response rate was 18.5% (5/27). The median overall survival was 8.0 months, with a notable survival benefit (median overall survival of 24.8 months) in responders. Relapsed/refractory patients exhibited a median overall survival of 7.8 months. These data highlight that bemcentinib-LDAC benefits a considerable subset of AML patients unfit for intensive chemotherapy.
In order to gain mechanistic insights into the efficacy of bemcentinib-LDAC, we profiled cells from bone marrows of 13 participating patients (6 responders, 7 non-responders, according to best response) using single-cell transcriptomics and multi-omics (CITE-seq). Cell type annotation highlighted various immune cell populations next to AML blasts. Successful treatment was associated with stronger TNFα signaling in blasts before treatment. A tight link between TNFα and AXL could subsequently be established in vitro as several AML cell lines up-regulated expression of AXL upon exposure to TNFα. Inhibiting AXL in these cell lines using bemcentinib increased expression of TNFα. This indicates a potential negative feedback loop between these two players. Furthermore, cytotoxic immune cells (CD8+ effector T cells, γδ T cells and natural killer cells) from responders displayed evidence for increased pro-inflammatory signaling upon bemcentinib-LDAC treatment. This included TNFα signaling programs next to IFNα and IFNγ signaling programs. Thus, our data indicate that bemcentinib-LDAC promotes the activity of such cytotoxic cells. In line with this, we observed increasing crosstalk between immune cells upon bemcentinib-LDAC treatment in responders. Importantly, cells from non-responders generally exhibited the opposite trend, highlighting the aforementioned cell types and pathways as factors that distinguish responders from non-responders. Together, our results indicate a potential role of TNFα and cytotoxic immune cells in the successful application of bemcentinib-LDAC.
In conclusion, our findings warrant further clinical development of bemcentinib-LDAC for AML patients unfit for intensive chemotherapy. Additionally, extended research on TNFα and cytotoxic immune cells may lead to a better understanding of what mechanisms cause a treatment response. This may ultimately enable an accurate selection of patients who will benefit from bemcentinib-LDAC.
Disclosures: Heuser: BergenBio: Research Funding; Astellas: Research Funding; Pfizer: Consultancy, Honoraria; Sobi: Honoraria; Certara: Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; PinotBio: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Glycostem: Consultancy, Research Funding; Servier: Consultancy; Karyopharm: Research Funding; Agios: Research Funding; Loxo Oncology: Research Funding; Novartis: Honoraria; Amgen: Consultancy; LabDelbert: Consultancy. Chromik: Alexion: Honoraria. Fiedler: AbbVie: Consultancy, Honoraria, Other: Support in medical writing; Stemline: Consultancy; Servier: Consultancy, Other: Support for meeting attendance; Pfizer: Consultancy; Amgen: Consultancy, Other: Support for meeting attendance, Patents & Royalties; Clinigen: Consultancy; Morphosis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Support for meeting attendance; Apis: Research Funding. Micklem: BerGenBio: Current Employment, Current equity holder in publicly-traded company. Nilsson: BerGenBio: Current Employment. Madeleine: BerGenBio: Current Employment. McCracken: BerGenBio ASA: Current Employment. Oliva: BerGenBio ASA: Current Employment. Gorcea-Carson: BerGenBio ASA: Current Employment. Janning: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gjertsen: Otsuka: Consultancy; Coegin: Consultancy; BerGenBio: Consultancy; InCyte: Consultancy; Immedica: Consultancy; GreinDX: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; KinN Therapeutics AS: Current holder of stock options in a privately-held company; Mendus AB: Consultancy, Research Funding; in Alden Cancer Therapy AS: Current holder of stock options in a privately-held company. Loges: BerGenBio: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Eli Lilly: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Roche Pharma: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Sanofi Aventis: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Boehringer Ingelheim: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Medac: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Amgen: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Bayer: Consultancy, Honoraria, Other: Travel support, Speakers Bureau; Janssen: Consultancy, Honoraria, Other: Travel support; Merck: Consultancy, Honoraria, Other: Travel support, Speakers Bureau.