Background Immuno-STATs^TM are modular fusion proteins designed for the selective delivery of IL-2 to tumor-antigen specific CD8+ T cells. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2) designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers.

Methods CUE-101-01 is a first-in-human study in patients with HLA-A*0201 genotype and HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). R/M HNSCC patients refractory to ≥ 1 platinum- or checkpoint-inhibitor-based systemic therapies received CUE-101 monotherapy. Patients with previously untreated PD-L1+ (CPS ≥ 1) R/M HNSCC received CUE-101 and pembrolizumab 200 mg. Therapy was administered every 3 weeks until disease progression or unacceptable toxicity. Escalating doses of CUE-101 monotherapy or in combination with pembrolizumab were evaluated, followed by expanded enrollment at the recommended phase 2 dose (RP2D). Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity.

Results As of July 25, 2022, 62 patients have received CUE-101 ranging from 0.06 to 8 mg/kg/dose. The most common adverse events included fatigue (46%), anemia (24%), chills (24%), and hyponatremia (22%). In the monotherapy dose escalation portion, a MTD was not identified, and 4 mg/kg was chosen as the RP2D based on PK, PD, and preliminary clinical activity. CUE-101 dose escalation from 1 to 4 mg/kg in combination with pembrolizumab 200 mg has been completed with no DLTs observed and expansion of CUE-101 at 4 mg/kg with pembrolizumab is ongoing. PK data demonstrate dose-dependent increases in drug exposure that are sustained upon repeat dosing. PD data demonstrate selected expansion of HPV-16 E7_11-20-specific CD8+ T cells in the peripheral blood. Of the 19 evaluable patients treated with CUE-101 monotherapy at the RP2D of 4 mg/kg, 1 patient experienced partial response (PR) and 7 stable disease (SD) for ≥ 12 weeks. Of the 10 evaluable patients treated with CUE-101 plus pembrolizumab, 3 patients experienced PR (2 confirmed) and 2 patients SD for ≥ 12 weeks.

Conclusions CUE-101 has a manageable safety profile and demonstrates activity alone and in combination with pembrolizumab.

Acknowledgements The authors would like to thank all the patients who are participating in this study. The study is sponsored by Cue Biopharma, in collaboration with Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA and support from LG Chem, Ltd., Seoul, South Korea.

Trial Registration ClinicalTrials. gov NCT03978689

Ethics Approval This study was approved by Ethics and Institutional Review Boards (IRBs) at all study sites. IRB reference numbers: Advarra Pro00037736 (Moffitt Cancer Center), IRB 52744 (Stanford University School of Medicine), HRPO# 201905108 (Washington University School of Medicine), DF/HCC IRB# 19-374 (Massachusetts General Hospital), WIRB STUDY00008948 (University of Washington, Seattle), IRB 191714 (Vanderbilt University Medical Center Vanderbilt-Ingram Cancer Center),

2019-087 Karmanos Cancer Institute, WIRB 2000026098 (Yale Cancer Center), 2019-0578 (The University of Texas MD Anderson Cancer Center), WIRB 1908869642 (University of Arizona Cancer Center), WIRB IRB00112341(Winship Cancer Institute/Emory University), IRB 20-073 (Memorial Sloan Kettering Cancer Center), IRB00255391 (Johns Hopkins University School of Medicine), IRB(IRBMED) HUM00165746 (University of Michigan Comprehensive Cancer Center), IRB0001113 (US Oncology Inc./Affiliated Oncologists, LLC), WCG IRB00000533 (Gabrail Cancer Center), IRB000001113 (George Washington University Cancer Center).