CUE-101, a Novel E7-pHLA-IL2-Fc Fusion Protein, Enhances Tumor Antigen-Specific T-Cell Activation for the Treatment of HPV16-Driven Malignancies

Abstract

Purpose: To assess the potential for CUE-101, a novel therapeutic fusion protein, to selectively activate and expand HPV16 E7 11-20-specific CD8 þ 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 E7 11-20-specific CD8 þ T cells from PBMCs relative to nontarget cells. Intravenous administration of CUE-101 induced selective expansion of HPV16 E7 11-20-specific CD8 þ 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 E7 11-20-specific population of cytotoxic CD8 þ 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).

Peptide-HLA-based immunotherapeutics platforms for direct modulation of antigen-specific T cells

“…We have described two modular immunotherapeutics platforms, Immuno-STAT and Neo-STAT, for the co-presentation of defined peptide-HLA (pHLA) and co-modulatory ligands to AgS T cells, and engineered an affinity-attenuated variant of IL-2, IL2.FH, for use thereon. IL2.FH-bearing constructs, including an HPV-specific clinical candidate, CUE-101 (NCT03978689), are associated with 110-fold and 3.1-fold decreases in binding to IL2Rα and IL2Rβ, respectively, with minimal Treg and non-AgS T cell responses in vitro and in vivo 14 . While greater AgS selectivity was anticipated for LCMV-IST-IL2.FH 4 over LCMV-IST-IL2 2 due to attenuation of IL-2:IL-2R versus pHLA:TCR binding, this trend was not statistically significant.…”

“…HLA-A*0201, HLA-A*1101 and HLA-A*2402, surveyed here in the context of Immuno-STAT, are collectively expressed by over half the global population and Neo-STAT extends potential pHLAs to include post-translational modifications and low affinity peptides 24 . In preclinical murine studies, CUE-101 and mCUE-101 elicit AgS T cell responses from both naïve and antigen-experienced precursors, with responses to mCUE-101 detectable in blood, spleen, and tumors, suggesting the potential to both invigorate T cell responses within tumors and initiate responses outside of immunosuppressive tumor microenvironments, which are relatively resistant to exhaustion 14 , 25 . Compelling applications of these platforms include enhancing T cell responses against essential antigens in cancer or infectious disease, especially where relevant AgS T cells are limiting or dysfunctional, and more efficiently activating or maintaining ACT cells ex/in vivo.…”

In vivo detection of antigen-specific CD8+ T cells by immuno-positron emission tomography

“…Indeed, a recent report demonstrated that the same synTac scaffold used to image the HPV E7-specific T cells could selectively deliver covalently linked IL-2 (termed ImmunoSTAT) and expand E7-specific CD8 T cells, with antitumor efficacy in the HPV-driven TC-1 tumor model. 38 These capabilities will be expanded for imaging of CD4 T cells by generating synTacs containing class II pMHCs in the future.…”

Frontiers in cancer immunotherapy—a symposium report

“…Preclinical studies showed that CUE‐101 selectively binds to HPV‐specific CD8 + T cells and induces effector function in a dose‐dependent manner. In animal studies, CUE‐101 monotherapy, and combination therapy with an anti‐PD‐1 agent, induced selective expansion of HPV‐E7–specific CD8 + T cells, inhibited tumor growth, and improved survival 85 . CUE‐101 is being tested as a monotherapy in a phase 1 trial in HLA‐A02 patients with HPV‐16 + recurrent or metastatic HNSCC.…”