Amv564, A Bivalent, Bispecific T-Cell Engager, Depletes Myeloid-Derived Suppressor Cells And Activates T Cells In Cancer Patients

Background Myeloid-derived suppressor cells (MDSC) elicit a range of suppressive functions that inhibit normal T cell responses and promote non-responsiveness to immune checkpoint blockade. While CD33 does not appear to play a significant role in differentiated myeloid cells, in immature myeloid cells CD33 signaling via ligand S100A9 is implicated in the expansion of MDSC and production of immune-suppressive factors1. AMV564, a bivalent, bispecific antibody that engages both CD3 and CD33, can selectively deplete MDSC via avid binding to regions of high local CD33 density. Here we report ex vivo and translational clinical data that support the utility of AMV564 as a selective agent to deplete MDSC and activate T cells in AML, MDS and solid tumor patients. Methods Flow cytometry was used to phenotype T cells and MDSC from freshly isolated whole blood samples from Acute Myeloid Leukemia (AML), Myelodsyplastic Syndrome (MDS) and solid tumor patients. MDSC panels were analyzed 24 hours after sample collection. Results In AML and MDS patients treated by continuous intravenous infusion on a 14-day cycle, T cell redistribution from the periphery, consistent with T cell activation, is apparent at lead-in doses of 15-30 ug in the first 1-3 days. In solid tumor patients receiving daily subcutaneous administration of AMV564 (15 ug on a 5 days on/ 2 days off 2-week cycle), marked T cell redistribution is apparent at day 5. Modulation of both monocytic and granulocytic MDSC is apparent in all tumor types, with evidence of MDSC increase and activation in response to T cell activation. MDSC increase in response to T cell activation is controlled by AMV564 in most patients while on therapy. In a subset of cases, where MDSC are not controlled on therapy, substantial increases in regulatory T cells are observed at day 15, unlike patients where MDSC are controlled, for whom regulatory T cells remain low. In solid tumor patients, dynamic T cell profile changes consistent with CD8 and Th1 T cell activation are apparent. Conclusions Treatment with AMV564 selectively depletes MDSC in a dose-dependent fashion in patients and promotes activation of effector T cells. The ability of AMV564 to deplete MDSC while activating T cells may lower the threshold necessary for response to immunotherapy. These results indicate potential for benefit in solid tumor indications, particularly in combination with checkpoint blockade, where elevated MDSC are associated with poor outcomes including inadequate response. 1. Chen et. al. J. Clin. Inv. (2013) 123: 4595-4611 Citation Format: Victoria Smith, Sterling Eckard, Michael P. Rettig, Leah N. Gehrs, Jeanmarie Guenot, Sheng Wei, John F. DiPersio. AMV564, a bivalent, bispecific T-cell engager, depletes myeloid-derived suppressor cells and activates T cells in cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5699.