Investigating CAR T-Cell Signals May Lead to New Approaches

New investigations into T-cell signaling may significantly advance the immunotherapy field by leading to the development of more effective chimeric antigen receptor (CAR) T-cell therapies for patients. That’s the finding of several recent clinical studies on CAR T-cell immunotherapy, and the recent approval of a promising new agent targeting T cells in both the United States and the European Union adds to the growing body of evidence supporting their efficacy and the promise these agents hold.

Recent CAR T-Cell Therapy Approvals in the United States and Europe

The European Commission (EC) approved tisagenlecleucel (Kymriah) in late August for the treatment of relapsed or refractory B-cell acute lymphoblastic leukemia (ALL) in pediatric and young adult patients up to age 25, as well as for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) in patients over 18. The decision follows the US Food and Drug Administration’s (FDA’s) approval of tisagenlecleucel in May to treat both B-cell ALL and DLBCL.

According to oncologists from the Children’s Hospital of Philadelphia (CHOP), the latest EU approval marks a milestone in CAR T-cell therapy. The CHOP researchers helped pioneer this immunotherapy (via the ELIANA and JULIET trials), and they have now treated more than 250 patients at their institution. Additional clinical trials are underway at CHOP to further improve CAR T-cell therapy and to study their use in more pediatric cancers. The researchers are encouraged by how quickly CAR therapies are making their way into clinical practice.

Additional trials are underway outside of CHOP, too. Peter C. Adamson, MD, chair of the children’s oncology group at CHOP, said ClinicalTrials.gov lists 236 studies on CAR therapies as planned or underway. “This is a good estimate for the United States but does not necessarily include all studies,” Adamson told Cancer Network, meaning that more may be in progress internationally.

Emerging Research on CAR T-Cell Therapies

Increasing attention to CAR T-cell therapies also prompted researchers at Fred Hutchinson Cancer Research Center in Seattle, to examine the differences between CARs built with the two most commonly used costimulatory domains, CD28 and 4-1BB. Their findings were published August 21 in Science Signaling.

During the study, researchers examined how CD28 and 4-1BB affected T-cell behavior, as well as their effectiveness against human cancer cells in lab dishes and in mice. Study investigator Alex Salter, of Fred Hutchinson Cancer Research Center and the University of Washington, said there has been plenty of interest in targeting the T cells to cancer, but little has been known about the instructions CARs give the T cells­­ until now.

“Scientists who create engineered CAR T-cell therapies often incorporate one of two costimulatory domains, known as CD28 and 4-1BB, into CARs. CD28, for example, is used in the FDA-approved CAR T-cell product axicabtagene ciloleucel (Yescarta), and 4-1BB is used in the other currently approved CAR T-cell product, tisagenlecleucel (Kymriah). Prior work has shown that CD28 CAR T cells and 4-1BB CAR T cells behave differently in the lab and in the clinic,” Salter told Cancer Network.

However, researchers have not known how costimulatory domains impact the identity or quality of the T-cell activating messages delivered by CARs, according to Salter. Using mass spectrometry, the researchers found that both CD28 CARs and 4-1BB CARs delivered highly similar signaling messages. “This was quite surprising because many researchers had assumed that CD28 and 4-1BB CARs used different signaling pathways. Instead, we found differences in the patterns of the signals: CD28 CARs delivered really fast and strong messages, while 4-1BB CARs delivered identical messages, but in a slower and less intense fashion. The faster and stronger CD28 CAR messages led to T cells that were less functional in a mouse model of lymphoma,” explained Salter.

Overall, Salter concluded that these findings challenge an assumption in the field and suggest that the strength of CAR signaling influences how T cells respond. New approaches to fine-tune CAR signaling strength may allow researchers to design new types of safer and more effective CARs.