Phase 2 trial of three schedules of CUE-101 administered before surgery or chemoradiotherapy in HLA-A*0201 positive patients with HPV16+OPSCC

TPS6109 Background: Patients with locally advanced HPV+ OPSCC have a favorable prognosis; however, 10-40% will experience disease recurrence after curative-intent therapy (CIT). 80-90% of cases are caused by HPV genotype 16. HPV16 E7 is a promising HPV target as there is little variation among isolates and high epitope affinities for HLA--A*0201 have been identified. HLA--A*0201 is the most common class I allele in the USA, expressed in 40-50% of people of European descent. We aim to lower the recurrence rate in these patients by activating tumor antigen-specific CD8+ T cells. CUE-101 is a novel fusion protein comprised of HLA--A*0201, an HPV16 E7 epitope (aa residues 11-20), a reduced affinity human IL-2 variant, and an effector attenuated human IgG1 Fc domain. In pre-clinical models, CUE--101 demonstrated selective binding, activation, and expansion of HPV16 E7 11-20 -specific CD8 + T cells. In the murine TC-1 tumor model, a murine surrogate of CUE-101 (mCUE--101) increased the frequency of tumor-infiltrating E7-specific CD8 + T cells and improved survival. Animals that remained tumor-free rejected TC-1 tumors upon re-challenge, demonstrating functional immunologic memory. In an ongoing phase 1 trial (NCT03978689) of HLA--A*0201+ patients with recurrent HPV16+ OPSCC, CUE-101 was well tolerated, resulted in expansion of target HPV16 E7 11-20 -specific CD8+ T cells, and showed durable disease control in some patients. In this Phase 2 trial (NCT04852328), CUE-101 will be administered to HLA--A*0201+ patients with HPV16+ OPSCC before CIT. The aims of the trial are to evaluate the safety, tolerability, and pharmacodynamic and immunologic activity of CUE-101 in these patients. Methods: This is a non-randomized Phase 2 trial of three schedules of CUE-101 administered before CIT to HLA--A*0201+ patients with HPV16+ OPSCC. HPV16 status of tumor will be assessed by PCR. Safety assessments will be performed, and blood and tumor samples collected, at baseline and after CUE-101 administration. Following CUE-101, CIT will be administered. Each schedule will enroll 10 patients. CUE-101 (4 mg/kg IV) will be administered 14 days (Schedule A), 14 and 7 days (Schedule B), or 7 days (Schedule C) before day 1 of CIT. If Schedule A is safe and tolerable, Schedule B and then C will commence. A schedule will be deemed safe and tolerable if ≤2 patients experience grade 3-4 TRAEs and/or treatment-related delays of >7 days from the planned date of CIT. Immunologic activity is defined as measurable observation of or increases in HPV16-specific T cells in post-CUE-101 blood and/or tumor samples, relative to baseline, as assessed by either ELISpot or tetramer staining and flow cytometry. Exploratory measures of immune activity will be assessed by single-cell RNAseq and immunofluorescence in tumor samples. A schedule will be considered active if immunologic activity is observed in ≥3 patients. Clinical trial information: NCT04852328 .