Tracing the Path of CAR T Cells

By adding a radioactive tag to CAR T cells, researchers at Stanford University in Palo Alto, CA, have been able to monitor these engineered cells as they home in on brain tumors in patients. The technique could also help scientists figure out why CAR T cells sometimes go astray, says Sanjiv Gambhir, MD, PhD, a professor of radiology and the study's senior author.

Gambhir and his colleagues tested their strategy in a CAR T-cell therapy trial for patients with glioma at City of Hope Comprehensive Cancer Center in Duarte, CA, and at the University of California, Los Angeles. They transfected IL13-targeting CAR T cells with the HSV1-tk reporter gene, then infused the therapeutic cells into 7 patients. By administering [¹⁸F]FHBG—a radioactive tracer that accumulates only in cells expressing HSV1-tk—to the patients, they were able to use PET imaging to monitor CAR T-cell trafficking. They observed that the cells readily homed in on primary tumor sites and, in 1 patient, even found additional small tumors that had hitherto gone undetected.

Gambhir's hope is that this approach will enable oncologists “to see what's really happening in a given patient instead of shooting blindly,” thereby promoting a deeper understanding of why CAR T-cell therapy isn't more broadly effective, and why resistance sometimes develops.

Martin Pomper, MD, PhD, director of the Johns Hopkins nuclear medicine and molecular imaging division in Baltimore, MD, considers this study “a tour de force, and an important step forward in being able to look at the disposition of transplanted and other cells within the body.” It's particularly impressive, Pomper adds, because of the many hurdles the Stanford team needed to overcome, from optimization of the reporter gene constructs through being able to conduct the study in a way that was compatible with patient safety and clinical workflow.

Gambhir also notes that how CAR T cells are delivered may be more crucial than previously appreciated. Convection-enhanced delivery—inserting a catheter device directly into the brain—likely improved cell trafficking and survival, he says.

“We're learning that each patient is highly variable with respect to the number of CAR T cells that seem to survive,” he adds. “Why that occurs is not well understood, but studies like ours should provide more insight and help improve this form of immunotherapy.”

Steven Larson, MD, head of the molecular pharmacology program at Memorial Sloan Kettering Cancer Center in New York, NY, also praised the research, adding that next he would like Gambhir's team to try quantifying the CAR T cells that successfully reach tumor sites and start proliferating.

“This is just the start,” Larson says of the study findings. Now, “we want to know far more about the fate of the cells, their longevity, and those kinds of features.” –Karen Weintraub