A dual-tumor-recognition trispecific T-cell nano-engager enhances effector-target conjugation and antitumor activity

Area of Science:

• Immunology
• Nanotechnology
• Oncology

Background:

• T-cell engagers show promise against cancer but struggle with solid tumors due to variable antigen expression and poor effector-target cell interaction.
• Current strategies face challenges in achieving efficient T-cell redirection and sustained anti-tumor activity in heterogeneous solid tumor environments.

Purpose of the Study:

• To develop and evaluate a modular dual-tumor-recognition trispecific T-cell nano-engager (Tri-NanoTCE) for enhanced solid tumor therapy.
• To investigate the efficacy of Tri-NanoTCE in improving effector-target cell conjugation and T-cell-mediated cytotoxicity against antigen-heterogeneous solid tumors.

Main Methods:

• Constructed Tri-NanoTCE via Fc-mediated assembly of anti-PD-L1, anti-EGFR, and anti-CD3 antibodies on an FcγR1-HSA/PLLA nano-adaptor.
• Assessed antibody binding, loading efficiency, tumor-cell association, and in vitro T-cell activation and cytotoxicity.
• Evaluated in vivo anti-tumor efficacy, intratumoral T-cell infiltration, and systemic toxicity in PBMC-reconstituted xenograft models.

Main Results:

• Tri-NanoTCE demonstrated retained binding activity, efficient loading, and increased tumor-cell association compared to single-target engagers.
• The dual-recognition design significantly enhanced effector-target conjugation, CD69 expression, cytotoxic mediator release, and PBMC-mediated tumor cell killing.
• In vivo studies showed prolonged intratumoral retention, increased T-cell infiltration, and suppressed tumor growth with no significant short-term systemic toxicity.

Conclusions:

• Modular nanoassembly provides a viable strategy for creating advanced trispecific T-cell engagers.
• Tri-NanoTCE effectively addresses challenges of antigen heterogeneity and poor effector contact in solid tumors.
• This approach holds potential for developing novel immunotherapies for challenging solid tumor indications.