Self-Assembled Trispecific T Cell Nanoengagers for Enhanced Cancer Immunotherapy

Area of Science:

• Immunology
• Nanotechnology
• Biotechnology

Background:

• Trispecific T cell engagers (Tri-TCEs) show promise in cancer immunotherapy.
• Current manufacturing processes for Tri-TCEs are complex and yield low production volumes.
• Targeting specific cancer markers alongside T cell receptors is crucial for effective immunotherapy.

Purpose of the Study:

• To develop a novel, modular platform for creating trispecific T cell nanoengagers (Tri-Nb@FNP).
• To evaluate the efficacy of Tri-Nb@FNP in targeting EGFR-positive triple-negative breast cancer (TNBC) and HER2-positive breast cancer.
• To assess the enhancement of T cell activation, proliferation, and cytotoxicity mediated by Tri-Nb@FNP.

Main Methods:

• Utilized nanobody assembly on ferritin nanoparticles (FNP) via SpyTag/SpyCatcher bioconjugation.
• Engineered nanoengagers to target EGFR and HER2 on cancer cells, and CD3/CD28 on T cells.
• Performed in vitro and in vivo studies to evaluate T cell responses and tumor suppression.

Main Results:

• Demonstrated robust T cell activation, proliferation, and cytotoxicity through synergistic targeting.
• Observed enhanced infiltration of cytotoxic CD8+ T cells into the tumor microenvironment.
• Achieved significant tumor suppression in both in vitro and in vivo models.

Conclusions:

• Introduced Tri-Nb@FNP as a novel class of Tri-TCEs with a simple and efficient self-assembly platform.
• The platform facilitates the integration of multispecific targeting molecules for advanced cancer immunotherapy.
• Tri-Nb@FNP offers a promising strategy for improving the manufacturing and efficacy of T cell engagers in cancer treatment.