Zhang David K Y, Brockman Joshua M, Adu-Berchie Kwasi, Liu Yutong, Binenbaum Yoav, de Lázaro Irene, Sobral Miguel C, Tresa Rea, Mooney David J
John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA.
Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
Nat Biomed Eng. 2025 Feb;9(2):268-278. doi: 10.1038/s41551-024-01216-4. Epub 2024 Jun 3.
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.
基于嵌合抗原受体（CAR）的过继性T细胞疗法的疗效受到工程化T细胞增殖能力差和持久性有限的限制。在此，我们展示了一种皮下注射的可生物降解支架，它能促进特定T细胞亚群的浸润和流出，形成一种模拟生理性T细胞激活特征的微环境，增强预先给药的CAR-T细胞的抗肿瘤活性。CAR-T细胞的扩增、分化和细胞毒性是由支架中掺入的共刺激结合配体和可溶性分子驱动的，并且取决于共刺激分子的类型及其呈现的背景。在患有侵袭性淋巴瘤的小鼠中，在非治愈性CAR-T细胞给药后单次局部注射该支架可导致更持久的记忆样T细胞，并延长动物生存期。具有优化配体呈现的可注射生物材料可能会提高CAR-T细胞疗法的治疗性能。
