750 A phase 1 trial of CUE-102, a novel WT1-pHLA-IL2-Fc fusion protein in HLA-A0201 positive patients with WT1-positive recurrent/metastatic cancers

BackgroundImmuno-STATs are modular fusion proteins designed for the selective activation of tumor antigen specific CD8+ T cells. CUE-102, the second Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the Wilms Tumor 1 (WT1) protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2), and is designed to bind, expand, and activate WT1-specific CD8+ T cells for the treatment of WT1+ cancers. In pre-clinical studies, CUE-102 elicits selective expansion of WT1-specific cytotoxic CD8+ T cells in vitro and in vivo.MethodsCUE-102–01 is a phase 1, 2-part study evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary antitumor activity of CUE-102 monotherapy administered every three weeks in HLA-A*02:01 positive patients with WT1+ recurrent/metastatic colorectal, gastric/gastroesophageal Junction (GEJ), pancreatic or ovarian cancer that has progressed on conventional therapies. Trial eligibility includes HLA-A*02:01 genotype and tumor WT1 protein expression by immunohistochemistry. Part A is a dose escalation phase following 3+3 design rules with a Bayesian Logistic Regression Model (BLRM) overlay. Dose levels that exhibit an immune or tumor response may be expanded to further characterize activity and toxicity as allowed by safety rules. Part B is a dose expansion/confirmation phase in patients with colorectal cancer. Objectives include characterization of safety, PK,PD, recommended phase 2 dose (RP2D), and preliminary anti-tumor activity.Results12 patients have received CUE-102 monotherapy as of June 27, 2023. Doses ranging from 1 mg/kg to 4 mg/kg were determined to be safe and well-tolerated, enabling dose escalation to 8 mg/kg. Preliminary PK data support that anticipated drug exposures are observed in patients. Characterization of post-treatment expansion of WT1-reactive T cells in peripheral blood is ongoing. Stable disease of ≥ 12 weeks, as determined by RECIST 1.1, has been observed in 2 patients (1 with colorectal; 1 with gastric cancer) in the early dose cohorts, allowing for dose expansion of the 2 mg/kg cohort. Data on safety, PK, PD and preliminary anti-tumor activity from additional patients will be presented.ConclusionsCUE-102 is a novel T cell activating agent that to date demonstrates acceptable tolerability, favorable PK, and supportive preliminary PD readouts. No DLTs or drug-related SAEs have been o