A phase 1 dose-escalation and expansion study of CUE-101, a novel HPV16 E7-pHLA-IL2-Fc fusion protein, given alone and in combination with pembrolizumab in patients with recurrent/metastatic HPV16+ head and neck cancer.
Authors: Christine H. Chung, A. Dimitrios Colevas, Douglas Adkins, Michael K. Gibson, Cristina P. Rodriguez, Ammar Sukari, Julie E. Bauman, Lori J. Wirth, Faye M. Johnson, Nabil F. Saba, Barbara Burtness, Lara Dunn, Tanguy Y. Seiwert, Francis P. Worden, Jameel Muzaffar, Steven Margossian, Raymond Moniz, Steven N Quayle, Matteo Levisetti, Sara I. Pai
Journal: Journal of Clinical Oncology (2022)

6045 Background: Immuno-STATs are novel, modular fusion proteins designed to locally deliver cytokines for the selective activation of 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) that is 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 or in combination with pembrolizumab was evaluated, followed by expanded enrollment at the recommended phase 2 dose (RP2D). Patients with R/M HNSCC refractory to ≥ 1 platinum- or pembrolizumab-based systemic therapies received CUE-101 monotherapy. Patients with previously untreated PD-L1+ R/M HNSCC received CUE-101 and pembrolizumab 200 mg as first-line treatment. Therapy was administered every 3 weeks until disease progression or toxicity. Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results: As of January 20, 2022, 53 patients received CUE-101 ranging from 0.06 to 8 mg/kg/dose. The most common adverse events included grade ≤ 2 fatigue (40%), anemia (28%), lymphopenia (23%), chills (23%), and hyponatremia (21%). In the monotherapy dose escalation cohort, a MTD was not identified. A RP2D of 4 mg/kg/dose was chosen based on PK, PD, and clinical data in the absence of an MTD. Dose escalation of CUE-101 from 1 to 4 mg/kg in combination with pembrolizumab is ongoing with no DLTs identified as of data cut-off. CUE-101 PK data demonstrated dose-dependent increases in drug exposure that were sustained upon repeat dosing. PD data demonstrated selected expansion of HPV-16 E7 11-20 -specific CD8+ T cells, sustained increase in NK cells and transient increase in Treg cells. Of the 14 evaluable patients treated with CUE-101 monotherapy at the RP2D, there was 1 PR and 6 with SD for ≥ 12 weeks. Of the 7 evaluable patients treated with CUE-101 plus pembrolizumab, there were 2 PR (1 confirmed) and 2 with SD for ≥ 12 weeks. Conclusions: CUE-101 is a novel immunotherapeutic that facilitates the targeted delivery of high concentrations of IL-2 to relevant tumor-specific CD8+ T cells. We demonstrate safety and tolerability with encouraging PD signals and antitumor activity. Enrollment continues in the combination cohort. Other novel Immuno-STATs, targeting local delivery of IL-2 for selective expansion and activation of additional tumor-antigen specific T cells, are in development. Clinical trial information: NCT03978689.