CAR-T cells with a navigation system

Chimeric Antigen Receptor T-cell therapy (CAR-T) has transformed treatment for blood cancers. The immunotherapy involves reprogramming a patient’s own immune cells to recognize and attack tumor cells; it offers many patients long-lasting remission and even a cure. Yet the approach still fails in many lymphomas – cancers that affect the lymphatic system – especially when cancer cells are located in lymph nodes.

Researchers at the Max Delbrück Center led by Dr. Uta Höpken, Group Leader of the Microenvironmental Regulation in Autoimmunity and Cancer lab at the Max Delbrück Center, and Dr. Maria Zschummel, a former doctoral student in her lab, have found a way to help CAR-T cells reach their targets. By engineering the cells to express the receptor CCR7, the team improved both their ability to migrate into lymph nodes and to kill lymphoma cells. The research was published in “Cancer Immunology Research.”

“Many lymphomas grow primarily in lymph nodes,” explains Zschummel, who is now a postdoctoral researcher at Massachusetts General Hospital in Boston. “If therapeutic immune cells cannot reach these sites efficiently, even powerful therapies may fail. By restoring the receptor CCR7, we essentially gave the cells a better navigation system to find the tumor.”

Better homing and a quick death

“Under normal conditions, immune cells use CCR7 to guide them into lymph nodes,” explains Höpken, whose lab has been studying the receptor for many years. However, the manufacturing process used to produce CAR-T cells reduces expression of this receptor, which limits the cells’ ability to migrate into lymph node tissue. 

To overcome this problem, the researchers tweaked the genetic engineering of CAR-T cells so that they permanently express CCR7. They then tested the modified cells in a series of experiments using human immune cells, lymphoma cell lines, and mouse models of lymphoma.

They found that their CAR-T-CCR7 cells regained the ability to migrate into lymph nodes and accumulated more efficiently. In mouse models, these cells also eliminated lymphoma cells more effectively than conventional CAR-T cells.

“This was a surprise,” says Zschummel. “We expected improved migration, but CCR7 also boosted the cells’ killing efficiency.”

More effective immunotherapy 

The work has important implications for cancer therapy. Boosting the ability of CAR-T cells to zero in on lymphoma cancer cells has the potential to make the therapy more effective; it may also reduce the incidence of cancer relapse.

The strategy could also be applied to other cancers that spread to lymph nodes, adds Höpken, senior author of the paper. “We show that improving the ‘navigation system’ of immune cells can make them generally more effective fighters against cancer.” 

Before the approach can reach patients, further studies will need to evaluate safety and long-term effects, she adds. “Nevertheless, the work highlights how insights from basic immunology can help refine next-generation cell therapies.”

Max Delbrück Center

The Max Delbrück Center for Molecular Medicine in the Helmholtz Association aims to transform tomorrow’s medicine through our discoveries of today. At locations in Berlin-Buch, Berlin-Mitte, Heidelberg and Mannheim, our researchers harness interdisciplinary collaboration to decipher the complexities of disease at the systems level – from molecules and cells to organs and the entire organism. Through academic, clinical, and industry partnerships, as well as global networks, we strive to translate biological discoveries into applications that enable the early detection of deviations from health, personalize treatment, and ultimately prevent disease. First founded in 1992, the Max Delbrück Center today inspires and nurtures a diverse talent pool of 1,800 people from over 70 countries. We are 90 percent funded by the German federal government and 10 percent by the state of Berlin.