CAR T cells expressing natural RNA can activate the body’s own T cells against solid tumors

Chimeric antigen receptor (CAR) T cell therapy, which uses modified T cells to treat certain types of cancers, has often been a difficult approach for the treatment of solid tumors. CAR T cells must recognize a specific target on cancer cells in order to kill them. However, cancer cells don’t always have the target, or they find ways to hide the target and remain invisible to attacks from CAR T cells. A new study from Penn Medicine, published online in Cell, demonstrates that RN7SL1, a naturally occurring RNA, can activate the body’s own natural T cells to search for cancer cells that have escaped recognition by CAR T cells. This may help improve efforts to treat solid tumors, which account for the most human cancers.

CAR T cells are generally like lone soldiers without backup. However, if given the right tools, they can jump-start the body’s own immune system and help them against missed cancer cells with CAR T cells alone. “

Andy J. Minn, MD, PhD, co-lead author, professor of radiation oncology at the Perelman School of Medicine at the University of Pennsylvania and director of the Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation at Penn

The first tool is an endogenous RNA, or RNA from the body’s own cells, called RN7SL1. However, when delivered to a tumor by CAR T cells, RN7SL1 mimics viral RNA. Just like after a viral infection, an arm of the body’s immune system called innate immune cells wakes up after seeing RN7SL1 delivered by CAR T cells. These innate immune cells can now function to stimulate the body’s T cells, mobilizing them to join the attack on cancer. However, like CAR T cells, the body’s natural T cells also need a target on cancer cells to recognize and attack. Therefore, the second tool that CAR T cells provide are foreign antigens, which are “painted” on the surface of cancer cells, essentially marking them for death by natural T cells.

Using mouse models, the researchers showed that arming CAR T cells with this punch to recruit the body’s own immune system prevents tumor relapse even when many cancer cells cannot be recognized and killed by CAR T cells alone. Therefore, engineering CAR T cells to provide RN7SL1 and foreign antigens can help fight the common ways in which solid tumors escape from CAR T cells, thereby improving efficiency.

In addition to helping recruit the body’s natural immune system, the study shows that RN7SL1 may improve the function of CAR T cells themselves. CAR T cells that express RN7SL1 have the added benefit of persisting longer, better infiltrating tumors, and retaining greater function against tumors.

“Strategies that simultaneously utilize CAR T cells, enhance endogenous T cell function, and neutralize common suppressive mechanisms may offer effective combinatorial approaches to enhance solid tumor responses,” said lead co-author Carl H. June , MD, Richard W. Wave Professor of Immunotherapy in the Department of Pathology and Laboratory Medicine and Director of the Center for Cellular Immunotherapies and the Parker Institute for Cancer Immunotherapy at the University of Pennsylvania.