New Study Committed to Promoting Efficient T Cell Proliferation with Biomaterial Scaffolds

Immunologists and oncologists are using adoptive cell transfer techniques to manipulate the body's immune system against cancer and other diseases. In the normal immune response, one type of leukocyte called T-cell expands its number after being directed by another immune cell called antigen-presenting cell (APC) and remains viable. Adoptive cell transfer programs mimic this process in petri dishes by removing T cells from patients, allowing them to multiply, sometimes genetically modifying them and then transplanting them back into the patient so that they can find and kill cancer cell. However, these procedures typically take weeks to generate large numbers of therapeutic T cells, where the number of these T cells must be large enough and their activity is sufficient to eliminate their target cells.

Recently, in a new study, a research team reported a replacement material-based T-cell expansion method that may help overcome those above-mentioned barriers. These researchers have achieved a better method to promote mouse and human primary T cell proliferation by utilizing a biomaterial scaffold that mimics APC. And they demonstrated the potential of this approach in a mouse lymphoma model treated with T cells expressing the chimeric antigen receptor (CAR-T cells), where these CAR-T cells were genetically engineered to target disrupted lymphoma cell. Relevant research results are published online in the Journal of Nature Biotechnology.

Mooney, one of the professors for this study, said that ‘Our approach closely models how APCs present their stimulatory signals to primary T cells on their outer membrane and how they release soluble factors to increase the survival of these T cells so that we can achieve faster and greater proliferation. By changing the composition of the lipid, the stimulus signal, and the diffusion factor in these biomaterial scaffolds, we have designed a very versatile and flexible platform that can be used to proliferate a specific T-cell population in a blood sample, and It may be deployed in existing treatments such as CAR-T cell therapy.’

In order to design a scaffold that mimics APC, these researchers first placed interleukin 2 (IL-2) that is a factor produced by APC that prolongs the associated T cell survival in tiny mesoporous silica rods (MSRs). They then coated the MSR with lipids that form a supportive lipid bilayer (SLB) of the thin outer membrane similar to APC, followed by functionalization of this supporting lipid bilayer with a pair of antibodies that activate T cells so that these antibodies move in the lipid layer and are able to bind to receptor / co-receptor molecules on the surface of T cells. In the medium, the three-dimensional scaffold spontaneously forms by MSR sedimentation and random packing and creates pores that are large enough to allow T cells to enter, move and aggregate, providing a signal that allows them to proliferate.

In a series of parallel comparisons, the Mooney team demonstrated that scaffolds that mimic APCs performed better than commercially available Dynabeads, which are currently used in clinical adoptive cell transfer methods.

These researchers demonstrated the utility of their T-cell proliferation platform in a therapeutic model based on these findings. Dr. Alexander Cheung, the lead author of the paper, said, "Encouraged by the recent breakthroughs in CAR-T cell therapy, we demonstrate that specific CAR-T cell products that proliferate using APC mimicking scaffolds can facilitate a mouse model to promote the treatment of a human lymphoma cancer.’ APC mock scaffolds engineered to activate specific types of CAR-T cells are capable of producing a greater number of these genetically modified T cells over a longer incubation period than similarly designed proliferating beads and the cells formed are equally effective at killing lymphoma cells in these mice.

After successfully utilizing this material to proliferate all T cells present in the sample, these investigators confirmed that APC mimic scaffolds could also be used to proliferate antigen-specific T cell clones in more complex cell mixtures. These T cell clones are produced stably by the immune system to recognize small molecule-specific peptides contained in foreign proteins. To this end, they incorporated major histocompatibility complex (MHC) proteins presenting small peptides from viral proteins into T cells into these scaffolds.

• Based on our research, we found that the APC mimic scaffolds also have the potential to specifically enrich and amplify rare T-cell subsets in the blood,’ Cheung said, ‘and we are convinced that we have created an effective platform technology that can promote more effective and accurate immunotherapy.’

We believed that these bio-inspired T cell activation scaffolds may speed up the clinical success of many immunotherapy approaches, potentially saving more patients' lives while advancing personalized therapies.

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