Background VISTA (V-domain Ig suppressor of T cell activation) is a key negative immune checkpoint regulator, locking T cells in a quiescent state, unlike PD1 and CTLA4, which are expressed on activated T cells. Preclinically, VISTA monoclonal antibody treatment increased the number of tumor-specific T cells in the periphery, and enhanced the infiltration, proliferation and effector function of tumor-reactive T cells within the tumor microenvironment (TME). VISTA blockade alters the suppressive feature of the TME by decreasing the presence of monocytic myeloid-derived suppressor cells and increasing the presence of activated dendritic cells (DCs) within the TME leading to enhanced T cell mediated immunity. VISTA monoclonal antibody administration as a monotherapy has been shown to suppress the growth of both transplantable and inducible melanoma in preclinical models. CI-8993 is a first-in-class, fully human immunoglobulin (Ig) G1κ monoclonal antibody (mAb) against the VISTA ligand. Prior human clinical evaluation of CI-8993 demonstrated target-related clinical findings and pharmacodynamic activity at 0.15 mg/kg.
Methods This phase 1 study is being conducted in the USA (NCT04475523) and is designed as a 3+3 dose escalation study beginning at 0.15 mg/kg. Patients with solid tumor malignancy (non-lymphoma) that is metastatic or unresectable and considered relapsed and/or refractory to prior therapy will be included, excluding prior CAR-T therapy or allogenic transplant. Patients will be treated with an initial step-dose of CI-8993 by IV infusion, followed by every 2 weeks of a full dose, until disease progression or toxicity. Efficacy, pharmacokinetics, pharmacodynamic and safety endpoints will be monitored and reported.
Ethics Approval The study was approved by Dartmouth-Hitchcock, Norris Cotton Cancer Center Ethics Board, approval number IRB00012031The study was approved Sarah Cannon Caner Research Institute, approval number IORG0000689
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