Author: Kristi Rosa

The FDA has granted a fast track designation to CUE-101 for use as a monotherapy and in combination with pembrolizumab (Keytruda) in patients with human papillomavirus (HPV16+) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).1

CUE-101 is an off-the-shelf therapy that was designed to trigger and expand HPV16 tumor-specific T cells by exhibiting 2 cues to T cells. The first signal includes the HPV E7 protein, which is harbored by HPV-induced cancer cells and interacts with the HPV-specific T-cell receptor to offer selectivity. The second signal is comprised of an engineered interleukin-2 variant that fuels T cell activity.

“We are very pleased to have received fast track designation from the FDA for CUE-101. This designation not only underscores the large unmet need for patients with recurrent/metastatic head and neck cancer who currently rely on available non-targeted therapies, but also highlights the potential of CUE-101 to provide a significant clinical benefit,” Matteo Levisetti, MD, senior vice president of Clinical Development at Cue Biopharma, Inc., stated in a press release.

Previously, investigators evaluated the potential of CUE-101 to selectively activate and expand HPV16 E7–specific CD8-positive T cells in patients with HPV-driven cancers, including HNSCC, cervical cancer, and anal cancer.2 To showcase the activity of the product, human E7-specific T cells and peripheral blood mononuclear cells (PMBCs) were tested. To evaluate the in vivo activity of CUE-101, investigators evaluated the product in HLA-A2 transgenic mice.

The agent was found to selectively bind, activate, and expand HPV16 E7–specific CD8-positive T cells from PBMCs relative to non-target cells. Moreover, when the agent was administered intravenously, it was found to elicit selective expansion of those T cells in the mice. When given to TC-1 tumor-bearing mice, CUE-101 showcased anticancer activity and immunologic memory. The efficacy achieved with the agent was found to be stronger when paired with PD-1 checkpoint blockade.

CUE-101 is currently under investigation in a phase 1 trial (NCT03978689).3 The multicenter, open-label, dose-escalation and -expansion trial is enrolling patients with recurrent or metastatic HNSCC that has progressed after at least 1 previous systemic treatment.

To be eligible for enrollment, patients are required to be at least 18 years of age, have an ECOG performance status of 0 or 1, measurable disease by RECIST v1.1 criteria, have an HLA A*0201 genotype, histologically or cytologically confirmed HPV16 positivity, and a life expectancy of at least 12 weeks. Those with central nervous system metastases must have received treatment or be asymptomatic to participate.

The first-in-human trial is comprised of 4 parts; in parts A and B, investigators are examining CUE-101 as a single agent in dose-escalation and -expansion cohorts, respectively. The primary objectives for this portion of the research are to evaluate the safety and tolerability of the agent in the second-line treatment of those with recurrent or metastatic HNSCC and to determine the maximum tolerated dose or recommended phase 2 dose (RP2D). Other end points of interest include pharmacokinetics, preliminary antitumor activity, and immune response, as well as the potential for immunogenicity.

Part C of the trial is dose-escalation with the agent in combination with pembrolizumab at 200 mg every 3 weeks, and part D will evaluate the doublet at the selected RP2D. In this portion of the research, investigators will focus on characterizing the safety, tolerability, and biological effects of CUE-101 plus pembrolizumab utilized as a frontline treatment in patients with recurrent or metastatic HNSCC.

“To date, in its phase 1b clinical trials, CUE-101 has demonstrated a favorable tolerability profile and single-agent antitumor activity…as well as encouraging antitumor clinical activity in combination with pembrolizumab, supporting the potential to improve overall survival for these patients,” Levisetti added. “We look forward to providing periodic updates and remain committed to advancing the development of CUE-101 to provide patients with a potentially more effective and better tolerated treatment option.”

A registrational trial examining CUE-101 monotherapy is anticipated to initiate in mid-2023.

1. Cue Biopharma granted FDA fast track designation for CUE-101 for the treatment of recurrent/metastatic head and neck squamous cell carcinoma. News release. Cue Biopharma, Inc. October 4, 2022. Accessed October 5, 2022.
2. Quayle SN, Girgis N, Thapa DR, et al. CUE-101, a novel E7-pHLA-IL2-Fc fusion protein, enhances tumor antigen-specific T-cell activation for the treatment of HPV16-driven malignancies. Clin Cancer Res. 2020;26(8):1953-1964. doi:10.1158/1078-0432.CCR-19-3354
3. A phase 1 study in patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma. Updated August 4, 2022. Accessed October 5, 2022.