CAR T cell therapy may eliminate tumor cells missed by surgery

In the study, published today in Science Advances, the researchers applied a special gel containing human CAR T cells to surgical wounds in mice following partial tumor removal. They found that in almost all cases, the CAR T cells apparently eliminated the residual tumor cells -- allowing the mice to survive when they otherwise would have succumbed to tumor recurrence.

Surgery can be curative when a solid tumor cancer has not spread. However, where a tumor ends and healthy tissue begins is often very difficult for surgeons to discern. Thus, for many cancer types, post-surgical recurrence due to remaining microscopic tumor cells is common. One possible approach to this problem is to apply an anti-tumor treatment to the remaining tissue margins immediately after tumor removal, to kill any residual tumor cells. In the study, Penn researchers tested that approach using CAR T cells.

"As we continue to advance CAR T cell therapy forward, finding applications for use in solid tumors is a major goal," said study senior author Carl June, MD, the Richard W. Vague Professor in Immunotherapy and director of the Center for Cellular Immunotherapies at Penn Medicine's Abramson Cancer Center. "Based on the promising results in this study, our colleagues have planned a clinical trial in patients with locally advanced breast cancer."

CAR T cells are T cells -- a powerful type of immune cell -- that are engineered to target specific proteins. All the CAR T treatments that have been approved for clinical use target proteins found on cancer cells. Typically, the T cells are harvested from the patient's blood, engineered in the lab, and then put back into the patient to work as a "living drug." June and colleagues at Penn helped develop and test what became, in 2017, the first U.S. Food and Drug Administration-approved CAR T treatment. There are now six approved CAR T cell therapies targeting a variety of blood cancers, which have provided fresh hope for patients who have run out of conventional options.

Solid tumors, so far, have been a harder target for CAR T treatments, due in part to tumor bulk and tumor anti-immune defenses. However, another group of researchers showed in a study last year, in a mouse model of brain cancer, that CAR T cells might be useful for the more limited task of clearing up residual cancer cells after surgery. In the new study, June and colleagues tried this same approach against two other cancer types: triple-negative breast cancer, which lacks all of the three major breast cancer markers, and human pancreatic ductal carcinoma, the most common type of pancreatic cancer. Both of these solid tumor types are notoriously hard to cure.

The CAR T cells were engineered to home in on the protein mesothelin, a surface marker on both types of tumor cell in the experiments. Without the CAR T cell and fibrin gel, the remaining tumor tissue grew and the mice succumbed within about seven weeks. With the gel, however, residual tumor tissue swiftly disappeared in 19 of 20 mice, and these animals survived without wound-healing complications or other apparent side effects for the remainder of the observation period.

Further experiments showed that CAR T cells targeting mesothelin have the potential to attack healthy cells bearing that protein marker after intravenous injection, and the toxicity was decreased by local injection of the CAR T cells compared to direct injection of the cells into the blood.

"This study demonstrates the promise of CAR T as an add-on to surgery for solid tumors," June said. "We also think that this approach could be broadened to deliver other cellular therapies and anticancer agents in addition to CAR T cells, potentially boosting the antitumor effectiveness even further."

Additional authors include Ugur Uslu, Tong Da, Charles-Antoine Assenmacher, John Scholler, Regina Young, and Julia Tchou.

Funding for the study was provided by the Mildred-Scheel-Postdoctoral Fellowship of the German Cancer Aid, the Abramson Cancer Center, and the National Institutes of Health (P01CA214278).