Background Immuno-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.

Methods CUE-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.

Results 12 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.

Conclusions CUE-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 observed in doses up to 4 mg/kg as of the data cut-off. Adverse events have been manageable and consistent with the CUE-102 mechanism of action and underlying disease. Early signs of anti-tumor activity are encouraging.

Acknowledgements The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, with support from LG Chem, Ltd., Seoul, South Korea.

Trial Registration Clinicaltrials.gov NCT05360680

Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB names/reference numbers: UH IRB STUDY20221273, BRANY 22–06-326–01, WCG IRB1340057, Advarra MCC# 22112, JHU IRB00349569, MDACC 2022–0761. All participants gave informed consent before taking part.