NOT gated T cells that selectively target EGFR and other widely expressed tumor antigens

Oh J, Kirsh C, Hsin JP, Radecki KC, Zampieri A, Manry D, Ando Y, Miller S, Chan J, McLeod E, Cunningham KM, Wong LM, Xu H, Kamb A. NOT gated T cells that selectively target EGFR and other widely expressed tumor antigens. iScience. 2024 May 7;27(6):109913. doi: 10.1016/j.isci.2024.109913.

Key Takeaways

• Tumor-associated antigens (TAAs) are key targets for cancer cell and immunotherapies but risk causing cytotoxic effects on healthy tissues.
• Tmod cell therapy uses a dual-receptor approach for selective targeting: one receptor targets tumor antigens, while another blocks effects on healthy cells.
• EGFR and HLA-E, though broadly expressed in normal cells, can serve as activators in Tmod systems.
• Monoclonal antibody sequencing facilitated the engineering of Tmod constructs by deriving amino acid sequences from commercial antibodies targeting common antigens.

Summary

Distinguishing between tumor and normal tissue is a challenge in cancer drug discovery. Tumor-associated (TAAs) and tumor-specific antigens (TSAs) are essential markers, but TSAs are rare, and TAAs are often present in healthy tissue, which can lead to unwanted cytotoxic effects. 

The goal is to create therapies that selectively target cancer cells while sparing healthy ones. The Tmod (tumor-modulating) system offers a precise cell therapy approach, using a dual-receptor mechanism: an activator targets tumor antigens, while an inhibitory receptor blocks action on healthy cells.

In 2024, researchers at A2 Biotherapeutics developed a potent Tmod cell therapy using epidermal growth factor receptor (EGFR) or human leukocyte antigen-E (HLA-E) as activators, with HLA-A as a blocker to protect normal tissues. They used REmAb® monoclonal antibody sequencing to derive the anti-HLA-E antibody sequence, engineering it into a 3rd generation CAR construct co-expressed with HLA-A as a blocker.

In vitro and in vivo murine models showed that Tmod systems with EGFR or HLA-E as activators achieved selective cytotoxicity. Despite EGFR and HLA-E being widely expressed in both healthy and cancerous tissues, the Tmod system offers a promising solution for tumor selectivity—even with broadly expressed antigens.