Programming our Immune System to Cure Diseases
Overview of CAR T cell therapy and how it can be improved to better combat diseases.
The immune system makes up an integral part of our bodies, preventing us from getting sick. It is composed of a complex network of organs, cells and proteins that defends the body against infection while also protecting its own cells. Within this complex network of organisms, white blood cells are the key players. White blood cells move through blood and tissue throughout our body, looking for foreign invaders such as bacteria, viruses, parasites and fungi. When they find them, they launch an immune attack to rid them from our body.
Perhaps the most important white blood cell in our immune system is the T cell. T cells are extremely unique because they are a specialist category of immune cells that are capable of adapting to new molecular threats. The ability to adapt means that T cells can respond to numerous types of foreign invaders in our bodies. This adaptation occurs when they are presented with antigens, which are strings of molecules or primary peptides, that are recognized as foreign by our body.
Using this ability to adapt, scientists have found that T cells can be engineered to target specific diseases such as cancer. To do this, scientists remove the T cells from our body, engineer them to express a Chimeric Antigen Receptor (CAR), and then reintroduce these modified cells to circulate throughout our blood, detecting cancer or other cells.
These new cells, called CAR T cells, are engineered to have receptor proteins that enable them to target a specific antigen. These receptors are chimeric meaning that they combine both antigen-binding (cells that are able to bind to antigens) and T cell functions into a single receptor.
CAR T cells have actually been able to cure patients with leukemia and other cancerous diseases.While CAR T cells have been excellent at targeting diseases, they have had trouble efficiently combating solid tumors.
CARs currently in use either possess a 4-1BB or CD28 intracellular costimulatory domain, a specific region within immune cells involved in the recognition and response to antigens. These costimulatory domains allow for enhanced activation and signaling within the immune cells, allowing them to better recognize and kill cells expressing specific antigens. These types of CARs are commonly referred to as second generation CARs due to the fact that they elicit more robust T cell activation than their original CD3ζ-only counterparts.
However, despite the advancements in CAR therapeutics, there is still much more work to be done. The current state of the literature still shows that T cells expressing the CD28 CAR are initially faster at reproducing themselves and killing tumor cells but suffer from reduced quality after long-term use or activation. This lack of long-term persistence means that patients can potentially get sick again years after treatment and suffer from the same conditions.
To address these issues, the Roybal group at UC San Francisco introduced “CAR Pooling,” a method that allows us to quickly and simultaneously identify different designs of CARs that have the potential to be used in clinical settings.
They conducted these pooled assays by combining multiple CAR designs and tested their ability to activate T cells and fight tumor cells. This way, scientists can determine what design for CARs is best for targeting solid tumors or other diseases.
The lab tested forty distinct CARs that possessed different combinations of immune costimulatory parts. The team developed a four-week repetitive stimulation, measuring cytokine production and cellular proliferation; through the stimulation sequence, they continued to find elements that enhance the ability of CAR T cells to fight tumors over a long period.
Through the “CAR Pooling” experiment, the scientists found that some receptors in the TNF receptor family such as CD40, BAFF-R and TACL, enable increased cell growth or cell-killing ability when compared to the aforementioned established standards used in clinics. These receptors also exhibited different characteristics related to memory, cell-killing ability, and metabolism. For example, The CAR T cells with BAFF-R receptors were more likely to have a strong cell-killing ability. The results of this experiment suggest that in the future, engineers will likely be able to separate different signals in cells to improve T cell phenotypes, making custom combinations that work best for certain types of cancers.
Furthermore, the pooled screening of CARs for solid tumors will provide invaluable insights for the development of improved CAR T cell therapies for both solid tumors and other immune-related diseases. Ultimately, this experiment may serve as a blueprint for how to research T cell phenotypes and their development, expanding our knowledge about the immune system and our bodies at large.
Sources:
https://www.science.org/doi/10.1126/scitranslmed.abm1463
https://centuryofbio.substack.com/p/immune-engineering