Towards Superior Engineered T Cells
Both cancer and aging impair the activity of T cells of the adaptive immune system, forcing these cells into exhaustion and senescence. The state of exhaustion is incompletely understood, but appears as an issue in immunotherapies making use of engineered T cells, as well as in the natural population of the aged body. Since researchers are already altering the T cells used in cancer therapies, why not alter them further to make them more able to resist the effects of aging cancer on T cell populations in the body? This is an interesting and plausible goal, but one that requires a greater understanding of T cell exhaustion than presently exists.
Cellular immunotherapy is revolutionizing oncology by harnessing T cells' unique ability to specifically target and potentially cure metastatic cancer, a feat not achievable with traditional treatments. Living T cells have proven they can eradicate even the most stubborn metastatic cells. However, challenges persist, as these therapies sometimes fail when T cells do not endure, often succumbing to exhaustion or senescence. This issue is being addressed by researchers who are exploring methods to enhance T cell resilience and functionality.
Evolution has shaped T cells to occasionally dampen their function in chronic viral infections to prevent autoimmunity and mitigate potential harm from an overly aggressive immune response. For example, the immune system's complete elimination of a hepatitis virus could cause significant liver damage. Chronic activation can also drive T cells toward senescence and exhaustion, weakening the immune response to cancer. To address these challenges, researchers have developed checkpoint inhibitors and engineered T cells to create synthetic T cells that can reverse or bypass these evolutionary constraints with great success in some indications.
Researchers have developed a synthetic T cell state they call TIF (T cells with an immortal-like and functional state). TIF cells are the product of disrupting the BCOR and ZC3H12A genes, a result that is surprising because these genes are typically expressed at low levels in T cells and lack dynamic regulation. This approach is aimed at addressing the traditional trade-off in T cell therapies between longevity and potency, offering cells that not only persist longer but also retain robust anti-tumor capabilities. TIF cells demonstrate enhanced survival and can enter a reversible dormant state, like memory cells, providing long-term immunity. Without BCOR, and in combination with ZC3H12A deficiency, genes that are usually repressed might become active, enhancing both stemness- and cytotoxicity-associated genes. This could potentially remove brakes on the T cell stemness and cytotoxic programs, enhancing therapeutic efficacy.