Researchers from the Keck School of Medicine of USC have developed a new type of chimeric antigen receptor (CAR) T cell that elicits a more controlled immune response to cancer in mice—effectively killing cancer cells, including those that typically escape detection, with fewer toxic side effects. The engineered CAR T cells may someday offer a way to more safely treat blood cancers and reduce the chance of relapse. The results were just published in the journal Science Translational Medicine .
CAR T cell therapy is a form of cancer treatment that modifies a patient's own immune cells to fight cancer. It has shown great promise for treating blood cancers such as leukemia and lymphoma, but still faces some significant challenges. Approximately 30-50% of patients who received CAR T cell therapy relapse within one year of treatment; others have dangerous immune reactions, known as cytokine storms, which can be fatal. These problems often stem from issues such as CAR T cells not surviving long enough in the body, cancer cells becoming harder to recognize, and treatment-related toxicity.
CAR T cells express a receptor on the cell surface that recognizes cancer cells and signaling molecules inside the cell that activate the immune response. To address the safety and efficacy issues with existing CAR T therapies, researchers from the Keck School of Medicine focused on redesigning the second component—the cell's internal signaling machinery. The new technology, developed with support from the Houston Methodist Fund and the National Institutes of Health, is known as Synthetic TCR signaling for Enhancing Memory T cells (STEM).
In mouse models, STEM-engineered CAR T cells outperformed conventional CAR T cells in several ways. They survived longer, remained in a healthier memory-like state that helps them survive and respond to returning cancer, and even eliminated cancer cells that typically evade detection by existing CAR T therapies.
"We found that our CAR T cells can destroy cancer cells at least as well as FDA-approved CAR T therapies, but with fewer toxic side effects," said Xin Liu, PhD, a postdoctoral research associate in medicine at the Keck School of Medicine and the study's lead author.
Reducing relapse and toxicity
All CAR T cell products currently approved by the U.S. Food and Drug Administration use the same signaling protein—CD3 zeta chain, or CD3ζ—to activate T cells for cancer destruction. While they often work well, these cells can lose strength too quickly and may not survive long in the body, which means some patients will see their cancer return. To look for a safer and more effective alternative, the researchers screened molecules involved early in the T-cell signaling process—proteins that help guide how strongly and how long T cells stay activated.
One molecule, ZAP70, stood out for its ability to strongly activate CAR T cells without overstimulating them. The researchers tested several forms of the molecule and found that one piece, known as ZAP327, provided the best balance of safety and potency. The team then replaced CD3ζ with ZAP327 to create the next-generation CAR T cells.
Next, the researchers tested the new CAR T cells in mouse models, comparing them with conventional, FDA-approved CAR T cells and other recently engineered CAR T cells. Compared to FDA-approved CAR T cells and other new varieties, the STEM-engineered CAR T cells performed as well as or better against cancer cells and kept their cancer-fighting abilities for longer. This suggests they may be more effective at recognizing and preventing disease relapse after remission.
Importantly, STEM-engineered CAR T cells also performed better against "low-antigen" cancer cells. These cancer cells escape the body's immune response, learning to display fewer signs that they are unwelcome invaders, which makes them harder for T cells to detect and kill.
Finally, the new CAR T cells produced fewer cytokines (molecules that trigger immune responses) in mouse models. This indicates they could be safer than existing therapies, with a lower risk of dangerous immune reactions.
"Toxicity has been a major issue in CAR T immunotherapy, and these substantial reductions in cytokine release could make the therapy safer and more tolerable for patients," said Rongfu Wang, PhD , professor of medicine and pediatrics at the Keck School of Medicine and senior author of the study.
Next steps for STEM
Following these encouraging early results, the research team will pursue a clinical trial that tests STEM-engineered CAR T cells in patients. They are also working to develop CAR T cells that can recognize and target more than one protein on cancer cells, making it easier to detect and distinguish them from healthy cells.
The researchers are also testing the STEM approach with T-cell receptor T cell (TCR-T) therapy, a different type of immunotherapy that is more effective with solid cancers.
About this study
In addition to Liu and Wang, the study's other authors are Jiayi Zhang and Yi-Jou Chen from the Department of Medicine, Keck School of Medicine of USC, University of Southern California; and Junjun Chun, Chen Qian and Helen Y. Wang from the Department of Medicine, Keck School of Medicine of USC, University of Southern California and the Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
This work was supported by Houston Methodist Fund; the startup fund of University of Southern California; the National Institutes of Health [R01CA101795, R01CA246547 and U54CA210181]; and the U.S. Department of Defense [BCRP BC151081, LCRP LC200368].
Rongfu Wang, Helen Y. Wang, Chen Qian and Xin Liu are inventors on a patent application for the ZAP27 CARs described in this manuscript. Rongfu Wang is a scientific founder of Immunova Therapeutics. Helen Y. Wang and Xin Liu are employees of Immunova Therapeutics and the Department of Medicine, Keck School of Medicine, University of Southern California.
