Chimeric antigen receptor T-cell (CAR-T) therapy is a novel cell immunotherapy technology that has been developing very rapidly in recent years. By the end of 2021, the U.S. Food and Drug Administration (FDA) had approved five CAR-T therapies, bringing hope to a number of patients. And research into CAR-T technology continues, with scientists from all over the world still exploring the sustained potential of this technology. This article will present the latest research focused on improving CAR-T therapies.
Nature: A Genome-scale Screen Engineers More Effective Immunotherapy
A research team describes the discovery of synthetic gene programs that profoundly rewire a specific kind of immune cell called T cells, making them more effective at finding and fighting cancer cells.
The research team profiled the impact of nearly 12,000 different genes in multiple T cell subsets from human donors to identify a range of genes that enable T cells to proliferate, and to understand how these genes impact other aspects of immune cell function relevant to fighting cancer.
By combining modifier genes identified in the screen with existing CARs, the researchers were able to engineer T cells that were more effective at eliminating tumor cells. One particular modifier gene, lymphotoxin beta receptor (LTBR), acts to boost T cell and stem cell-like cell multiplication. Adding LTBR also caused T cells to secrete more cytokines, which are vital for the anti-tumor activity of T cells.
The research was published in March 2022 in Nature titled A Genome-scale Screen for Synthetic Drivers of T cell Proliferation. It is an important step forward towards the development of next-generation CAR-T cell therapy.
Nature Biomedical Engineering: New Method Reduces Time to Make CAR-T Cells from 3 days to 24 hours
In a new preclinical study, researchers from the University of Pennsylvania have developed a new method that promises to greatly reduce the time it takes to make CAR-T cells for treating cancer patients.
A key to this new manufacturing method is a lentiviral vector that delivers the CAR gene to the T cells. Lentiviral vectors derived from human immunodeficiency virus (HIV) are able to transfer genes such as CAR into cells without an initial step of activation.
Using this approach, they were able to create functional CAR-T cells with enhanced anti-tumor efficacy in just 24 hours. These results suggest that the time, materials, and labor required to make CAR-T cells could potentially be significantly reduced, which would be particularly beneficial for patients with rapidly progressing disease and in resource-poor medical settings.
Related findings were published in March 2022 in the journal Nature Biomedical Engineering under the title Rapid Manufacturing of Non-activated Potent CAR-T Cells.
Science Advances: Using Hydrogel Delivery of CAR-T cells May Improve Treatment of Solid Tumors
Currently, intravenous infusion (IV) is the primary mode of CAR-T cell delivery. However, this approach is not ideal for treating solid tumors, which are often dense, exist in specific locations, and have defenses that evade and resist immune cells.
A team of scientists has developed a hydrogel that temporarily houses cytokines and CAR-T cells near the tumor. These cells grow and proliferate in the hydrogel injected into the body and are continuously released to attack cancer cell growth. The hydrogel consists of water, dodecyl-modified hydroxypropyl methylcellulose, HPMC-C12, and nanoparticles, and is thus also known as Polymer-Nanoparticle hydrogel, PNP hydrogel.
The authors tested the hydrogel on tumor-bearing mice and found that all experimental mice injected with the hydrogel containing CAR-T cells and cytokines became cancer-free after 12 days, with better results than CAR-T cells injected via IV or injection with CAR-T cells mixed with normal saline. In addition, this hydrogel did not induce an adverse inflammatory response in the mice, and it completely degraded in vivo within a few weeks.
The findings were published in the April 2022 issue of Science Advances in a paper titled Delivery of CAR-T Cells in A Transient Injectable Stimulatory Hydrogel Niche Improves Treatment of Solid Tumors.
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