The first FDA-approved gene therapies have been revolutionary in optimizing cancer treatment through rewiring immune cells to target tumors. Yet, there had always existed a major problem in that the effects were not very long-lasting in many cases. However, researchers at the New York Genome Center and New York University have managed to create a novel genetic screening platform that pinpoints specific genes that boost immune cell function, increasing their likelihood of destroying tumor cells.
In the past, scientists have relied on engineering T cells to target specific antigens that are found on the surface of cancerous tumor cells. Since its discovery over 30 years ago, this form of therapy known as CAR-T cell therapy has been highly effective at targeting blood cancer cells in the short term. While many patients have seen lasting remission for decades following the start of CAR-T cell treatment, others have failed to see the same long-lasting results.
The researchers describe their discovery of these synthetic gene programs in the journal Nature, which engineers immune cells called T cells to make them more effective at fighting cancer cells in the long run. The impact of 12,000 different genes in T cells from human donors was observed by Neville Sanjana, assistant professor of biology at NYU, to identify which specific genes caused T cells to function in ways that are related to fighting cancer.
The researchers combined their novel program with past CAR-T cell therapies to reach a truly effective method of combatting cancer. Through their new screening, the scientists found a specific modifier gene known as lymphotoxin beta receptor (LBTW), which acts similarly to a “molecular fountain of youth.” This gene allows T cells to multiply rapidly, having a greater proportion of younger and more stem-like cells which are more efficient. This gene also caused T cells to secrete more cytokines which aid in communication with other immune cells. This allows the immune system to launch better-coordinated attacks on tumor cells and fight cancer more effectively. Most important of all, however, is the fact that the LBTW gene is not normally expressed in T cells. By engineering T cells to express this critical gene, these researchers have underlined the power of genome-scale screening to find genes that create entirely new cell programs.
The researchers also discovered that activating the LTBR gene completely rewires the T cell, causing the expression of many other cancer-fighting genes. The researchers used a new method called OverCITEseq to examine the effect of different modifier genes on the expression of other genes, antigens, and their receptors. Using this method, the researchers discovered the true effects of the LTBR gene, which led them to discover NF-kB, a well-studied modulator of gene expression that was responsible for many of these changes. This gene programming was observed at a higher rate in unconventional T cells, which are less abundant than normal T cells but target a broader range of tumor cells.
Most T cells obtained from cancer patients are in poorer condition than T cells obtained from healthy donors. As a result, the researchers decided to test the LBTR gene's ability to rejuvenate cancer T cells in patients, and the results were astounding. They discovered a significant increase in T cell function by combining LBTR with CAR to T cells from patients with diffuse large B cell lymphoma, a type of blood cancer.
However, the researchers demonstrated that engineering these modifier genes helps to eradicate not only leukemia cells but also pancreatic cancer cells. These findings give scientists hope that CAR-T therapies will be able to target solid tumors, a field that has long been difficult to establish effective CAR-T immunotherapy.
Works Cited:
Communications, N. Y. U. W. (2022, March 16). Programming the immune system to supercharge cancer cell therapies. NYU. Retrieved March 17, 2023, from https://www.nyu.edu/about/news-publications/news/2022/march/programming-the-immune-system-to-supercharge-cancer-cell-therapi.html
Ledford, H. (2022, December 15). Cancer treatments boosted by immune-cell hacking. Nature News. Retrieved March 17, 2023, from https://www.nature.com/articles/d41586-022-04465-y