In a new study published in Nature Biotechnology, scientists have developed a material-based T-cell-expansion method using APC-mimetic biomaterial scaffolds, which helps achieve greater expansion of primary mouse and human T cells than existing methods.
In a normal immune response, a type of white blood cell known as T cells are instructed by another kind of immune cell called an antigen-presenting cell (APC) to expand their numbers and stay alive. Adoptive cell transfer procedures are mimicking exactly this process in a culture dish by taking T cells from patients, multiplying them, sometimes genetically modifying them, and then returning them to patients so that they can locate and kill cancer cells.
However, these procedures often take weeks to produce batches of therapeutic T cells that are large and reactive enough to be able to eliminate their target cells. Researchers have reported an alternative material-based T-cell-expansion method that could overcome these obstacles. With an APC-mimetic biomaterial scaffold, the researchers achieved greater expansion of primary mouse and human T cells than with existing methods.
The team demonstrated the approach's potential in a mouse lymphoma model treated with chimeric antigen receptor-expressing T cells (CAR-T cells) that are engineered to home in on and destroy lymphoma cells. The approach closely mimics how APCs present their stimulating cues to primary T cells on their outer membrane and how they release soluble factors that enhance the survival of the T cells. As a result, we achieve much faster and greater expansion.
By varying the compositions of lipids, cues, and diffusible factors in the scaffolds, researchers engineered a very versatile and flexible platform that can be used to amplify specific T cell populations from blood samples, and that could be deployed in existing therapies such as CAR-T cell therapies. To engineer an APC-mimetic scaffold, the team first loaded tiny mesoporous silica rods (MSRs) with Interleukin 2 (IL-2) — an APC-produced factor that prolongs the survival of associated T cells.
The MSRs were then coated with lipids that formed a thinly supported lipid bilayer (SLB), which resembles the outer membrane of APCs and then functionalized with a pair of T cell-stimulating antibodies that remain mobile in the lipid layer and can bind to receptor/co-receptor molecules on the surface of T cells. In culture medium, 3D scaffolds spontaneously formed through the settling and random stacking of the rods, forming pores big enough to allow the entry, movement, and accumulation of T cells, thereby signalling them to multiply.
The team demonstrated that APC-mimetic scaffolds performed better than methods involving commercially available expansion beads (Dynabeads). In a single dose, APC-mimetic scaffolds led to two- to the ten-fold greater expansion of primary mouse and human T cells than Dynabeads. APC-mimetic scaffolds enabled to tune the ratios of subpopulations of T cells with different roles in the desired immune responses, which in the future might increase their functionality.
The bio-inspired T cell-activating scaffolds could accelerate the success of many immunotherapeutic approaches in the clinic, with life-saving impact on a broad range of patients, in addition to advancing personalized medicine, the researchers concluded.