Background Immuno-STATs are modular T cell engagers engineered to selectively activate tumor-antigen specific CD8+ T cells via targeted delivery of cytokines. 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 attenuated 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 an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy (0.06 mg/kg to 8 mg/kg) were evaluated in R/M HNSCC refractory to ≥ 1 platinum-based or checkpoint inhibitor therapy and in combination with pembrolizumab (1 mg/kg to 4 mg/kg + 200 mg pembrolizumab) in the first line treatment of PD-L1+ R/M HNSCCs followed by expanded enrollment at the recommended phase 2 dose (RP2D). Therapy was administered every 3 weeks until disease progression or intolerable toxicity. Safety, PK/PD, and antitumor activity were assessed.

Results As of June 22, 2023, 71 patients have been enrolled. Following monotherapy and combination therapy dose escalation, 4 mg/kg of CUE-101 was chosen as the RP2D for both monotherapy and pembrolizumab combination cohorts. Monotherapy RP2D enrollment is complete and combination RP2D enrollment is ongoing. Adverse events have been manageable and are consistent with the CUE-101 mechanism of action and underlying disease. Grade 3 AEs reported include lymphocyte count decreased (11.3%), anemia (7.0%), decreased appetite and infusion-related reaction (4.2%). PD data demonstrate selective expansion of HPV-16 E7_11–20-specific CD8+ T cells, sustained increase in NK cells with only transient increase in Treg cells. Among 19 evaluable monotherapy RP2D patients, 1 PR and 6 durable SD (SD ≥ 12 weeks) were observed, with mOS of 14 months. Among 16 evaluable RP2D CUE-101 and pembrolizumab combination patients at data cut-off, 1 uCR, 4 PRs, 2 uPR, and 4 durable SDs were observed. Of the 7 patients with objective responses, 5 achieved >99% reduction in HPV16 cfDNA, 4 by week 6, with 2 patients pending analysis at time of data cut-off.

Conclusions CUE-101 demonstrates safety, tolerability and results in clinical benefit. Patients treated with CUE-101 monotherapy in 3L showed a long OS and CUE-101 and pembrolizumab combination resulted in an ORR of 44% with a corresponding decrease in HPV16 cfDNA in the 1L treatment of patients with HPV16+ R/M HNSCC.

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 IRBs at all study sites: Advarra Pro00037736, IRB 52744, HRPO# 201905108, DF/HCC IRB# 19–374, WIRB STUDY00008948, IRB 191714, 2019–087, WIRB 2000026098, 2019–0578, WIRB 1908869642, WIRB IRB00112341, IRB 20–073, IRB00255391, IRBMED HUM00165746, US Oncol IRB00001113, WCG IRB00000533.