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

Regular and Young Investigator Award Abstracts Pub Date : 2022-11-01 DOI:10.1136/jitc-2022-sitc2022.0824

Marilena Gallotta, J. Gosling, A. Tenn-McClellan, Serena Ranucci, J. Romo, F. Cohen, Gwenn H. Hansen, A. Sands, C. Guiducci, R. Rountree

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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

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824 NX-1607是一种CBL-B E3泛素连接酶的小分子抑制剂，在小鼠淋巴瘤肿瘤模型中促进T和NK细胞活化，增强NK介导的ADCC

E3泛素连接酶Casitas B-lineage lymphoma B (CBL-B)在白细胞中表达，并调节T细胞和NK细胞的信号通路，显著限制其抗肿瘤效应功能。在T细胞中，CBL-B减弱由TCR参与引发的激活，部分原因是通过介导对CD28共刺激的需求，从而设定T细胞激活的阈值。在NK细胞中，CBL-B在TAM受体的下游发挥作用，负向调节细胞因子的产生和细胞毒性。方法本研究描述了口服生物利用的cblb分子内胶抑制剂NX-1607对原发人T细胞和NK细胞的影响，并在小鼠非霍奇金淋巴瘤(NHL)异种移植模型中评估了NX-1607与利妥昔单抗联合使用的效果。结果NX-1607增强TCR刺激后人T细胞IL-2和IFN-g的分泌。细胞通过抑制t细胞的激活而增殖。CD4 +细胞

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Regular and Young Investigator Award Abstracts

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