Immuno-stat Platform: Tcr-selective Engagers for Selective Targeting of IL-2 to Tumor-specific T Cells

Abstract Text: IL-2 immunotherapy is severely hampered by safety and tolerability concerns. Selective targeting of IL-2 to tumor-specific T cells provides an opportunity to create a therapeutic index, hence maximizing potential benefit while limiting safety risks. The CUE-100 series of Immuno-STATs (ISTs) are rationally engineered Fc fusion proteins containing bivalent peptide-HLA complexes and four attenuated IL-2 molecules to preferentially activate tumor-specific T cells. This scaffold bypasses the need for antigen-presenting cells and stimulates T cells directly, including in the tumor microenvironment. CUE-101, the lead clinical candidate, incorporates an immunodominant peptide from the HPV E7 oncoprotein to activate T cells targeting HPV+ cancers. As monotherapy, CUE-101 has been safely dosed up to 8 mg/kg in 2L+ recurrent/metastatic head and neck cancer with favorable pharmacodynamics and evidence of anti-tumor activity. Parallel dose escalation of CUE-101 in combination with pembrolizumab supports further enhancement of anti-cancer efficacy. These clinical data provide proof of concept for selective modulation of the tumor-specific T cell compartment.

Harnessing modularity of the IST platform has enabled rapid generation of additional clinical candidates targeting other tumor antigens. CUE-102 is 99% sequence identical to CUE-101 but targets a Wilms’ Tumor 1 (WT1) peptide for WT1-positive malignances. Preclinically, CUE-102 selectively expands polyfunctional and cytotoxic WT1-specific CD8+ T cells in vitro and in vivo. Future ISTs targeting shared T cell cancer epitopes, such as mutated KRAS, are also under development and will be discussed. Taken together, the clinical de-risking achieved with CUE-101 supports broad applications of this platform to target diverse cancers.