Yvonne Chen, an associate professor at the University of California, Los Angeles and a member of the Johnson Comprehensive Cancer Center, genetically modified immune cells such as T cells to attack the most evasive enemy: cancer. New cancer immunotherapies produce immune cells that can effectively kill blood cancers, but it is difficult to kill solid tumors. She is designing ways to allow immune cells to "beat" solid tumors. She presented her research at the 64th Annual Meeting of the Society for Biophysics, San Diego, California, USA, on February 18, 2020.
T cells are white blood cells that patrol and attack invaders in our bodies, but they also need to avoid attacking our own cells, a way in which cancer can evade immune system surveillance. Solid tumors are cancers that form tumor masses in the body, accounting for 90% of cancer cases and can even inactivate immune cells. These tumors can be surrounded by a protein called transforming growth factor beta (TGF-β). The protein TGF-β can inhibit the activity of T cells in the tumor environment. Chen discovered a way to help T cells overcome TGF-β inhibition to resist tumor cells.
T cells are genetically engineered to express a receptor called the chimeric antigen receptor (CAR), which is designed to recognize tumor-associated proteins, the tumor antigens. Once a cell presenting a target antigen is encountered, CAR-T cells can bind the target cell and kill it. Given that CD19 is an antigen found on B cells, T cells engineered to express a CAR that targets CD19 (CD19 CAR-T) have been approved by the US Food and Drug Administration (FDA) for the treatment of B-cell leukemia and lymphoma.
Although CD19 CAR-T cell therapy has shown encouraging clinical results, sometimes a cancer cell population without CD19 appears throughout the treatment. "Clinical trials have shown that 50% of lymphoma patients treated with CD19 CAR-T cells relapse within 6 months, and many of these cases involve tumor cells that no longer express CD19," Chen said. To avoid this, Chen designed T cells targeting CD19 and CD20 to reduce the likelihood of any cancer cells escaping therapy. This bispecific CAR-T cell therapy is currently being tested in a phase I clinical trial carried out at UCLA.
Besides hematological cancers, solid tumors have been the focus of many ongoing research efforts in Chen's laboratory. "Immunotherapy works well for hematological tumors, but not for solid tumors, in part because of TGF-β-induced immunosuppression," Chen said. Her new approach to using CAR that has been genetically engineered to target TGF-β is a good start for solid tumors. "TGF-β CAR has shown the potential to safely and effectively enhance the antitumor efficacy of T cell therapy."
Chen and colleagues constructed CARs that could respond to TGF-β by enhancing defense. "T cells expressing TGF-β responsive CAR are not inhibited in response to TGF-β, but are ready to meet and attack tumor cells when exposed to high concentrations of TGF-β," Chen said. Chen and colleagues are developing TGF-β CAR-T cells that also target another tumor-specific marker in order to develop next generation T cell therapies that can be effective against immunosuppressive solid tumors.