New Study Looks at Low-Dose Radiation That Could Make CAR T Cell Therapy More Effective

Background: A preclinical study published in the journal Molecular Therapy by researchers at Memorial Sloan Kettering (MSK) provides evidence that radiation therapy could improve the efficacy of CAR T cell therapy for solid tumors.

The success of chimeric antigen receptor (CAR) T cell therapy for treating certain leukemias and lymphomas owes, in part, to the presence of a clear target: a molecular flag on the surface of blood cancer cells called CD19. CAR T cells outfitted with a protein that latches onto CD19 can easily find and destroy these cancer cells.

Whereas CD19 flags nearly all tumor cells for most patients, such ubiquitous targets are hard to come about. This makes it challenging to extend the benefits of CAR therapy to many other cancer types, including solid tumors like lung, breast, and pancreatic cancer. One way to address this problem, new research suggests, is by combining CAR therapy with radiation therapy.

Findings: Pancreatic adenocarcinoma (PDAC), the type of cancer the team studied, is a deadly cancer that is currently hard to treat with anything other than surgery. The tumor cells are often heterogeneous with respect to expression of potential targets. Thus, although some cells make distinguishing surface markers that could be targets for CAR therapy, not all cells express them, making it difficult to design a CAR that would work against every cell.

One marker that is found intermittently in pancreatic cancer is called sialyl Lewis-A (sLeA). Researchers gave mice low-dose radiation before administering the sLeA-specific CARs. They found that the combination of radiation and CARs did indeed improve the amount of tumor that was destroyed, including not only those tumor cells that expressed sLeA but those that lacked it.

Researchers won’t know for sure whether the same holds true in people with cancer until they conduct a clinical trial, something that is currently being planned.

Journal: ”Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape” was published in the journal Molecular Therapy on October 25, 2018. 

Authors: Michel Sadelain, PhD, Carl DeSelm, M. Lia Palomba, Joachim Yahalom, Mohamad Hamieh, and Justin Eyquem. 

Author Commentary: “We found that radiation sensitizes tumor cells to killing by CAR T cells through a mechanism that does not depend on the target’s expression,” says Michel Sadelain, Director of Center for Cell Engineering at MSK and the corresponding author on a new paper published today in Molecular Therapy. “We made the discovery in a mouse model of CAR therapy for cancer of the pancreas, but the approach is applicable to any cancer and CAR therapy in principle.”

Funding: This study was in part funded by the MSK Core Grant (P30 CA008748 S5) and U54 OD020355-01, the Integrated Genomics Operation Core funded by the NCI Cancer Center Support Grant (CCSG, P3014CA08748), and the XRAD225Cx animal irradiator funded by a Geoffrey Beene Research Foundation Shared Resources grant. The authors declare no potential conflicts of interest. A patent application has been submitted by MSK based in part on results reported in this manuscript.