Session: 653. Myeloma/Amyloidosis: Therapy, excluding Transplantation: Poster II
Hematology Disease Topics & Pathways:
Biological, antibodies, Diseases, Combinations, Therapies, Biological Processes, immune cells, Technology and Procedures, Cell Lineage, Clinically relevant, flow cytometry, microenvironment, molecular interactions, pathways, proteomics
Materials and Methods Tagraxofusp is a bioengineered therapeutic protein developed by fusing human IL-3 to the catalytic translocation domain of truncated diphtheria toxin (DT) via a Met-His linker (Stemline Therapeutics, NY). pDCs and patient MM cells were purified from BM/PB samples after informed consent, and quantified using FACS, as described (Ray et al, Leukemia, 2018). A novel high-throughput seroproteomics platform SOMAscan was utilized to analyze 1,310 protein analytes in serum samples from MM patients (n = 9). SOMAscan data were subjected to meta-analysis to generate heatmaps, followed by hierarchical cluster analysis. SOMAscan results were validated with ELISA using supernatants from MM patient pDCs cultured with or without tagraxofusp.
Results Analysis of BM/PB samples from MM patients receiving tagraxofusp therapy showed a marked reduction in the frequency of viable pDCs [average 2% at screening vs 0.75% post-tagraxofusp; n = 6; p = 0.036]. pDCs isolated from tagraxofusp-treated patients showed decreased ability to trigger MM cell growth. Seroproteomics analysis of MM patient serum before and after tagraxofusp therapy showed alterations in the levels of 100 proteins [Median Fold Change in expression: 0.39 to 4.5; n = 6; 3 each; p < 0.05]. Importantly, tagraxofusp treatment reduced pDC-related soluble proteins including IFN-α (fold change: 0.8, treated vs untreated; p < 0.05). Our earlier study showed that pDC-MM interactions triggered secretion of IL-3, which in turn promotes both pDC survival and MM cell growth. Importantly, tagraxofusp decreased serum IL-3 (fold change 0.75, treated vs untreated; p < 0.05), consistent with tagraxofusp decreasing survival of tumor-promoting pDCs.
Conclusions Our current correlative science studies validate target specificity of tagraxofusp against MM pDCs in relapsed and refractory MM patients enrolled in a phase 1 clinical trial and support further evaluation for this novel therapeutic to improve the clinical outcome of patients with MM. Further combination studies are planned.
Disclosures: Mo: Celgene/BMS: Membership on an entity's Board of Directors or advisory committees. Olguin: Stemline Therapeutics: Current Employment. Chen: Stemline Therapeutics: Current Employment. Brooks: Stemline: Current Employment. Mughal: Stemline: Current Employment. Richardson: Celgene/BMS, Oncopeptides, Takeda, Karyopharm: Research Funding. Chauhan: consultant to Stemline Therapeutics, Inc., and Equity owner in C4 Therapeutics.: Consultancy, Other: Equity owner in C4 Therapeutics.; Oncopeptide AB: Consultancy. Anderson: Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopep and C4 Therapeutics.: Other: Scientific Founder of Oncopep and C4 Therapeutics.; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium-Takeda: Membership on an entity's Board of Directors or advisory committees.
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