Subcutaneous biodegradable scaffolds for restimulating the antitumour activity of pre-administered CAR-T cells.

in Nature biomedical engineering by David K Y Zhang, Joshua M Brockman, Kwasi Adu-Berchie, Yutong Liu, Yoav Binenbaum, Irene de Lázaro, Miguel C Sobral, Rea Tresa, David J Mooney

TLDR

  • The study investigates how a special scaffold can help CAR-T cells fight cancer better. The scaffold helps the CAR-T cells find and attack cancer cells more effectively. The study shows that the scaffold can make the CAR-T cells work better and last longer. The study also suggests ways to improve the scaffold and make it even better at fighting cancer.

Abstract

The efficacy of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) is limited by the poor proliferation and persistence of the engineered T cells. Here we show that a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, which forms a microenvironment mimicking features of physiological T-cell activation, enhances the antitumour activity of pre-administered CAR-T cells. CAR-T-cell expansion, differentiation and cytotoxicity were driven by the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules, and depended on the types of co-stimulatory molecules and the context in which they were presented. In mice with aggressive lymphoma, a single, local injection of the scaffold following non-curative CAR-T-cell dosing led to more persistent memory-like T cells and extended animal survival. Injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies.

Overview

  • The study investigates the limitations of adoptive T-cell therapies based on chimaeric antigen receptors (CARs) due to poor proliferation and persistence of engineered T cells. The study proposes a subcutaneously injected biodegradable scaffold that facilitates the infiltration and egress of specific T-cell subpopulations, forming a microenvironment mimicking features of physiological T-cell activation. The primary objective of the study is to enhance the antitumor activity of pre-administered CAR-T cells by optimizing ligand presentation in the scaffold.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, specifically the antitumor activity of CAR-T cells with and without the biodegradable scaffold. The results show that the scaffold enhances the antitumor activity of CAR-T cells by promoting T-cell expansion, differentiation, and cytotoxicity. The study identifies that the scaffold's incorporation of co-stimulatory bound ligands and soluble molecules drives these effects and that the types of co-stimulatory molecules and the context in which they are presented affect the outcomes. The study also shows that a single, local injection of the scaffold following non-curative CAR-T-cell dosing leads to more persistent memory-like T cells and extended animal survival.

Implications and Future Directions

  • The study's findings suggest that injectable biomaterials with optimized ligand presentation may boost the therapeutic performance of CAR-T-cell therapies. The study identifies limitations, such as the need for further optimization of the scaffold's design and the need to investigate the long-term effects of the scaffold on the immune system. Future research directions could include the development of scaffolds with different ligand combinations and the investigation of the scaffold's effects on other types of T cells, such as regulatory T cells. The study highlights the potential of biomaterials to enhance the efficacy of CAR-T-cell therapies and improve patient outcomes.
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