Improving the tumor selectivity of T cell engagers by logic-gated dual tumor-targeting

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Targeting single tumor antigens with T cell engagers (TCEs) often results in poor tumor selectivity and significant toxicity, especially in solid tumors.
• This limitation can lead to treatment failure and necessitates the development of more precise therapeutic strategies.

Purpose of the Study:

• To design and evaluate novel trispecific TCEs (TriTCEs) that employ logic-gated dual tumor-targeting to enhance tumor selectivity.
• To assess the efficacy of TriTCEs in redirecting and activating T cells for targeted tumor cell killing.

Main Methods:

• Development of trispecific TCEs (TriTCEs) engineered for logic-gated dual tumor antigen recognition.
• In vitro assessment of TriTCEs' ability to induce T cell-mediated tumor cell killing, comparing EC50 values to isotype controls.
• In vivo studies to evaluate TriTCE accumulation in tumor tissue, T cell infiltration, tumor growth inhibition, and survival rates in mouse models.

Main Results:

• TriTCEs demonstrated potent T cell-mediated tumor cell killing with an EC50 of approximately 18 pM, significantly outperforming single-antigen targeted controls (70- to 750-fold improvement).
• In vivo experiments confirmed TriTCEs accumulate in tumor tissue and promote T cell infiltration into tumors.
• TriTCEs significantly inhibited tumor growth and prolonged survival in preclinical models.

Conclusions:

• The novel logic-gated dual tumor-targeted TriTCE platform offers improved tumor selectivity and enhanced T cell activity compared to traditional TCEs.
• This approach holds promise for developing safer and more effective T cell engager therapies for solid tumors by enabling precise targeting of multiple tumor antigens.
• The dual-targeting strategy is adaptable for various tumor antigen combinations, broadening its therapeutic potential.