CAR T cells as micropharmacies against solid cancers: Combining effector T-cell mediated cell death with vascular...

Area of Science:

• Immunology
• Oncology
• Biotechnology

Background:

• Solid tumors present challenges for chimeric antigen receptor (CAR) T cell therapy due to the tumor microenvironment.
• Enhancing CAR T cell potency requires novel strategies combining immune-mediated killing with additional therapeutic mechanisms.

Purpose of the Study:

• To develop a novel cell-based combination strategy to improve CAR T cell efficacy in solid cancers.
• To engineer CAR T cells as micropharmacies producing a targeted pro-coagulatory fusion protein, truncated tissue factor (tTF)-NGR.

Main Methods:

• One-vector gene modification of human T cells to express a GD2-specific CAR and a CAR-inducible tTF-NGR.
• Utilizing CAR T cells to deliver tTF-NGR to tumor vascular endothelial cells, inducing locoregional tumor vascular infarction.
• Evaluating therapeutic efficacy in murine models with GD2-positive tumor xenografts.

Main Results:

• Engineered CAR T cells exhibited potent GD2-specific effector functions and secreted tTF-NGR in a GD2-dependent manner.
• CAR T cells infiltrated tumors and secreted tTF-NGR, showing a trend towards superior therapeutic activity compared to controls.
• In vitro studies indicated hypoxia-mediated enhancement of T cell cytolytic activity.

Conclusions:

• Combined CAR T cell targeting with an additional antitumor mechanism via one-vector engineering is a promising strategy for solid cancers.
• The approach leverages CAR T cells as micropharmacies to induce vascular infarction and hypoxia, leading to combined immune-mediated and hypoxic tumor cell death.
• Further development is warranted for this novel approach in treating solid tumors.