824 NX-1607, a small molecule inhibitor of the CBL-B E3 ubiquitin ligase, promotes T and NK cell activation and enhances NK-mediated ADCC in a mouse lymphoma tumor model

Abstract

Background The E3 ubiquitin ligase Casitas B-lineage lymphoma B (CBL-B) is expressed in leukocytes and regulates sig-naling pathways in T and NK cells, significantly limiting their antitumor effector function. In T cells CBL-B attenuates activation initiated by TCR engagement, in part by mediating the requirement for CD28 co-stimulation, thus setting the thresh-old for T cell activation. In NK cells, CBL-B functions down-stream of TAM receptors and negatively regulates cytokine production and cytotoxicity. Methods Here we describe the effects of NX-1607, an orally bioavailable intramolecular glue inhibitor of CBL-B, on pri-mary human T and NK cells and assess NX-1607 in combination with Rituximab in a murine xenograft model of Non-Hodgkin ’ s Lymphoma (NHL). Results NX-1607 enhances IL-2 and IFN-g secretion in human T cells following TCR stimulation. cells multiple in the the by suppressing T-cell activation. CD4+ cells