The first FDA-approved gene therapies are living drugs: immune cells taken from cancer patients engineered to target tumor cells. However, for many patients, these advanced therapies do not result in a long-lasting remission. Now, scientists at the New York Genome Center and New York University have developed a genetic screening platform to identify genes that can enhance immune cells to make them more persistent and increase their ability to eradicate tumor cells.
In the journal Nature, the researchers describe 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—led by Neville Sanjana, assistant professor of biology at NYU, assistant professor of neuroscience and physiology at NYU Grossman School of Medicine, and core faculty member at New York Genome Center—profiled the impact of nearly 12,000 different genes in multiple T cell subsets from human donors. The goal of this large-scale genetic screen was to identify precisely those genes that enable T cells to proliferate and to understand how those genes impact other aspects of immune cell function relevant to fighting cancer.
Previous efforts to engineer T cells have focused on the targeting of specific tumor types by careful selection of cancer or tissue-specific proteins (antigens). Since first developed more than 30 years ago, chimeric antigen receptor (CAR)-T cell therapy has proven highly effective in targeting blood cancer cells, resulting in multiple FDA-approved CAR-T therapies. CAR-T cells have antigen receptors on their surface that recognize specific proteins present on cancer cells to target and destroy them. Some patients are cancer free even a decade after their CAR-T cell therapy, as the T cells introduced years earlier are still doing their job. But one of the major challenges facing biomedical science is to understand why a large majority of cancer patients who receive CAR-T cells fail to achieve lasting remission.
Sanjana, senior author of the study, explained, “To date, genetic engineering of T cells has been focused on finding new antigens or new CARs. We took a radically different approach: Instead of changing the antibody, we thought why not try adding genes that transform T cells into more aggressive cancer fighters? These modifier genes worked very well in blood cancers, and we believe they will likely work for multiple antigens and in solid tumors.”
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 like a molecular fountain of youth: with LTBR, T cells multiply, have a greater proportion of younger, more stem cell-like cells and resist becoming exhausted over time. Adding LTBR also caused T cells to secrete more cytokines, which are vital for the anti-tumor activity of T cells. Cytokines play an essential role in enabling T cells to better communicate with other immune cells in the body and launch coordinated attacks on the cancer. Interestingly, LTBR is not normally expressed in T cells, which highlights the power of the genome-scale screen to find genes that activate completely new cellular programs.
