T cell-nanodrug conjugates synchronize vascular normalization and immune activation for solid tumor therapy

Area of Science:

• Immunotherapy
• Nanotechnology
• Oncology

Background:

• Adoptive T cell therapy is crucial for cancer treatment but hindered by abnormal tumor vasculature impeding T cell infiltration and function.
• Current strategies lack parallel vascular normalization and T cell enhancement, limiting therapeutic efficacy in solid tumors.

Purpose of the Study:

• To develop a strategy that simultaneously normalizes tumor vasculature and enhances T cell function for improved adoptive T cell therapy.
• To create pH-responsive T cell-nanodrug conjugates for coordinated drug release and T cell activation within the tumor microenvironment.

Main Methods:

• Utilized lenvatinib (LEN) to induce transient vascular normalization and promote T cell memory differentiation via the PI3K-AKT-mTOR and FOXO1 pathways.
• Developed T cell-nanodrug conjugates by linking LEN-loaded, PD-L1-blocking micelles to T cells using acid-labile click chemistry.
• Coordinated intratumoral release of LEN and a PD-L1 antagonist peptide (OPBP-1) to synchronize vascular normalization, T cell differentiation, and checkpoint blockade.

Main Results:

• Conjugates significantly increased intratumoral CD8+ T cells and splenic memory T cells (over sixfold) in B16-OVA tumor models.
• Achieved complete tumor regression in a subset of MC38-OVA tumors.
• Demonstrated no systemic toxicity, highlighting the safety and efficacy of the approach.

Conclusions:

• The developed T cell-nanodrug conjugates offer a promising strategy for solid tumor immunotherapy by overcoming vascular barriers and enhancing T cell persistence.
• This approach provides a coordinated method for vascular normalization, T cell differentiation, and checkpoint blockade, paving the way for more effective cancer treatments.