CAR T cells—that is, T cells that have been taken from patients, engineered to express chimeric antigen receptors (CARs), and returned to patients to fight cancer—don’t always perform like champions. All too often, CAR T cells become winded. In other words, they often show poor proliferation and persistence, which limits their tumor-fighting abilities.
To give CAR T cells a boost, scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and Harvard John A. Paulson School of Engineering and Applied Sciences have developed a CAR-T-cell-stimulating biodegradable scaffold that can be implanted beneath the skin. According to the scientists, who were led by Wyss Founding Core Faculty member, David Mooney, PhD, the scaffold facilitates the infiltration and egress of specific T-cell subpopulations, forming a microenvironment that mimics features of physiological T-cell activation and enhances the antitumor activity of pre-administered CAR T cells.
The scientists detailed their work in Nature Biomedical Engineering, in a paper titled, “Subcutaneous biodegradable scaffolds for restimulating the antitumor 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,” the article’s authors wrote. “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.”
The scientists referred to their biodegradable implants as “T-cell-enhancing scaffolds,” or TESs. According to the scientists, the TESs improved therapeutic efficacy of CAR T cells by increasing the numbers of CAR T cells in the blood circulation, as well as by steering T-cell differentiation toward tumor-killing subtypes.
TESs consist of tiny biodegradable mesoporous silica rods that self-assemble into three-dimensional, cell-permeable scaffold structures when injected under the skin, where they connect themselves to the blood circulation via small blood vessels. TESs are loaded with interleukin-2, which is continuously released and stimulates the multiplication of T cells entering the TESs from the blood circulation.
In addition, the silica rods are coated with a double layer of lipids that mimics the outer cell membrane of an antigen-presenting cell that a T cell would encounter in a lymph node. This lipid layer presents two antibody molecules, anti-CD3 and anti-CD28, to the T-cell receptor on the surface of T cells, emulating how antigen-presenting cells present tumor antigens. Thus stimulated, the CAR T cells increase their numbers and differentiate into tumor-killing subtypes of T cells.
“Although our strategy needs to be translated to human needs and settings, it potentially offers a safe, and simple avenue on which to further improve CAR T-cell therapies in patients with poor responses,” Mooney remarked. “It also could have future potential to simplify the extremely arduous and expensive manufacturing of CAR T cell by transferring part of the process into patients’ bodies.”
