A First-in-Human Phase 1 Trial of NX-1607, a First-in-Class Oral CBL-B Inhibitor, in Patients with Advanced Malignancies Including DLBCL

Introduction: Recurrent diffuse large B cell lymphoma (DLBCL) remains a high unmet medical need despite advances in treatment such as cell- and immune-mediated therapies. T cell dysfunction and emerging resistance to T cell-mediated therapies such as CAR-T and T cell engagers underscores the need for novel therapies that can enhance T cell function, counteract a suppressive tumor microenvironment (TME) and prevent tumor escape associated with low tumor antigen expression. Casitas B-lineage lymphoma proto-oncogene B (CBL-B) is an E3 ubiquitin ligase expressed in immune cells and is a master regulator of T, NK, and dendritic cell activation, collectively curtailing their anti-tumor functionality. Notably, it has been observed that, in the absence of CBL-B, T cell activation can occur even when antigen expression on tumor cells is low, suggesting a potential strategy for circumventing tumor resistance mechanisms [Stromnes et al. 2010]. NX-1607 is an oral, small molecule inhibitor of CBL-B that has been shown to enhance antigen recall, reduce T cell exhaustion and increase cytokine production upon T cell receptor stimulation, overcoming suppressive signals from the TME [Gosling et al. 2019; Rountree et al. 2021; Gallotta et al. 2022]. Moreover, preclinical studies in mouse lymphoma models have demonstrated that NX-1607 can induce robust, T cell-dependent tumor regression. By bolstering the effectiveness of inherent T- and NK-mediated anti-tumor responses and enhancing antigen recall, NX-1607 offers potential as a supportive and rejuvenating agent for CAR-T or NK cell therapies in patients with hematologic malignancies who have developed resistance.