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 Apr 15;26(8):1953-1964. doi: 10.1158/1078-0432.CCR-19-3354. Epub 2020 Jan 21.


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 composed of a human leukocyte antigen (HLA) complex, an HPV16 E7 peptide epitope, reduced affinity human IL2 molecules, and an effector attenuated human 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, whereas in vivo activity of CUE-101 was assessed in HLA-A2 transgenic mice. Antitumor 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 nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E711-20-specific CD8+ T cells in HLA-A2 (AAD) transgenic mice, and anticancer 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 I trial (NCT03978689).

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • Cells, Cultured
  • Disease Models, Animal
  • Female
  • HLA-A2 Antigen / immunology*
  • Healthy Volunteers
  • Humans
  • Immunoglobulin Fc Fragments / immunology*
  • Interleukin-2 / immunology*
  • Leukocytes, Mononuclear
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neoplasms / immunology
  • Neoplasms / therapy*
  • Neoplasms / virology
  • Papillomavirus E7 Proteins / immunology*
  • Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology*


  • HLA-A2 Antigen
  • Immunoglobulin Fc Fragments
  • Interleukin-2
  • Papillomavirus E7 Proteins
  • Tumor Necrosis Factor Receptor Superfamily, Member 7
  • oncogene protein E7, Human papillomavirus type 16

Associated data