CUE-101, a Novel HPV16 E7-pHLA-IL-2-Fc Fusion Protein, Enhances Tumor Antigen Specific T Cell Activation for the Treatment of HPV16-Driven Malignancies

Purpose: To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E711-20-specific CD8+T cells as an off-the shelf therapy for the treatment of HPV16-driven tumors, including head and neck squamous cell carcinoma (HNSCC), cervical and anal cancers. Experimental Design: CUE-101 is an Fc fusion protein comprised of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human interleukin-2 (IL-2) molecules, and an effector attenuated human immunoglobulin G (IgG1) Fc domain. Human E7-specific T cells and human peripheral blood mononuclear cells (PBMC) were tested to demonstrate cellular activity and specificity of CUE-101, while in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Anti-tumor efficacy with a murine surrogate (mCUE-101) was tested in the TC-1 syngeneic tumor model. Results: CUE-101 demonstrates selective binding, activation, and expansion of HPV16 E711-20-specific CD8+T cells from PBMCs relative to non-target cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+T cells in HLA-A2 (AAD) transgenic mice, and anti-cancer efficacy and immunologic memory was demonstrated in TC-1 tumor bearing mice treated with mCUE-101. Combination therapy with anti-PD-1 checkpoint blockade further enhanced the observed efficacy. Conclusions: Consistent with its design, CUE-101 demonstrates selective expansion of an HPV16 E711-20-specific population of cytotoxic CD8+T cells, a favorable safety profile, and in vitro and in vivo evidence supporting its potential for clinical efficacy in an ongoing Phase 1 trial (NCT03978689).