Cue up a potential answer to fighting tumors

CAMBRIDGE, Mass.—In a “groundbreaking” preclinical study using the healing power of the body’s own immune system to treat human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), biopharmaceutical Cue Biopharma Inc. says it has demonstrated the ability of its lead biologic candidate, CUE-101, to activate tumor antigen specific antitumor immunity right on target. The preclinical study, based on the manuscript by Steven Quayle et al, was published in January 2020 in Clinical Cancer Research, a journal of the American Association for Cancer Research.

“The preclinical and ex-vivo human translational data presented in this paper underscore the promising potential for the current, ongoing clinical study evaluating CUE-101 monotherapy in HPV-driven head and neck cancer,” states Dr. Anish Suri, president and chief scientific officer of Cue Biopharma.

“If successful, treating HPV-driven head and neck cancer with CUE-101 would not only provide a potential treatment option for a patient population with a huge unmet need, but would open the door to treat other HPV-driven cancers, such as cervical, anal, vulvar and penile cancers,” he adds. “The impact of CUE-101, if proven to work, is significant as it lays the foundation for us to expand our biologics platform by changing the tumor antigen peptide, a specific sequence of amino acids within the protein framework, thereby effectively targeting a different T cell subset for a different tumor indication.”

The peer-reviewed journal article reports that, “Human papilloma virus (HPV)-associated head and neck squamous cell carcinoma (HNSCC) is emerging as a global epidemic. Despite recent approvals of immunotherapy drugs for the treatment of HNSCC and the limited clinical success that has been reported with therapeutic vaccines and CAR-T and adoptive cell therapies, metastatic disease remains largely incurable.

“The observation of objective clinical responses in early trials testing adoptive cell therapy with gene-engineered T cells targeting HPV16 E7 supports the concept that a single T cell specificity can lead to antitumor activity in patients with HPV16-driven cancers,” the journal authors conclude.

Oncogenic HPV is responsible for many cervical and anal cancers, as well as HNSCC. Approximately 70 to 80 percent of HPV-driven oropharyngeal cancers in the United States are HPV16/18 driven, and their incidence continues to rise, the article states. Prophylactic HPV vaccines have no therapeutic effect on established disease, thus HPV infections are expected to continue, contributing to the global cancer burden.

Recent studies suggest that HPV+ cancers may be successfully targeted with T cell therapy, wherein adoptive transfer of tumor-infiltrating or genetically engineered T cells was shown to induce responses in HPV-associated cancer patients, providing proof of concept that a therapeutic strategy that increases the frequency of tumor antigen specific T cells may be sufficient to drive clinical benefit in this population, the authors state.

Unlike current autologous approaches such as CAR-T that involve a cumbersome process of ex-vivo manipulation and expansion of T cells, Cue’s injectable biologics can selectively modulate disease-specific T cells within the body on two distinct cues presented by the natural immune response, including recognition of foreign agents and a signal to either stimulate or inhibit the activity of disease-relevant T cells.

This marks the first-time disease relevant T cells have been engaged in vivo to attack cancer, the paper states. These biologics also differ from other IL-2 based therapeutics and bispecific antibodies because the construct is potentially more selective and provides better control over T cell modulation.

According to Cue, the potentially game-changing research highlights the ability of its proprietary Immuno-STAT (Selective Targeting and Alternation of T cells) platform to selectively engage and modulate targeted T cells within the body. CUE-101 is from the company’s IL-2 based CUE-100 series designed to directly engage and activate T cells to target HPV16-driven recurrent/metastatic HNSCC.

The published preclinical results show that CUE-101 demonstrated selective binding, activation and expansion of the disease-relevant human T cell population in vitro—plus predict a favorable safety profile.

A murine surrogate molecule (mCUE-101) administered to HPV16 E7 tumor-bearing mice resulted in selective expansion of disease-relevant T cells, anticancer efficacy and immunologic memory.

CUE-101 is currently being studied in a Phase 1 clinical trial for HPV16-driven HNSCC. The Phase 1 trial is evaluating the safety and tolerability, anti-tumor response, pharmacokinetics and immunogenicity of CUE-101 as a monotherapy in patients with confirmed HPV16-driven recurrent/metastatic HNSCC and HLA-A*02:01 serotype.

Based on results from this trial, including translational pharmacodynamic immunorofiling data, CUE may expand the study to test CUE-101 in the neoadjuvant setting in combination with checkpoint inhibitors in patients with HPV16-driven HNSCC.

“In the future, it is my hope that CUE-101 is found to successfully select and activate HPV16-specific anti-tumor T cells in humans following our Phase 1 study,” Suri remarks. “CUE-101 is injected directly into the patient’s body and is engineered to target and activate T cells against a specific HPV epitope, which eventually should generate a potent anti-tumor T cell response against head and neck cancers and other epithelial cancers driven by HPV.”

HPV-driven cancers account for more than 20,000 deaths each year in the U.S. and Europe. The majority of these cancers are driven by HPV16, which carries the E7 protein targeted by CUE-101. Despite treatment with current standards of care, approximately 50 percent of patients with advanced disease will experience recurrence and significant quality of life impact.