A new approach pioneered at the University of Pennsylvania’s Abramson Cancer Center may provide a new path toward treating acute myeloid leukemia (AML) with CAR T cells. To treat AML, investigators have to target a specific protein—CD33—that’s also expressed on healthy cells, meaning the therapy cannot attack the cancer without causing other serious damage to the residual normal bone marrow. The new method uses the gene-editing tool CRISPR/Cas9 to remove CD33 from healthy blood-forming stem cells, leaving the cancerous cells as the only targets left for the CD33 hunter cells to attack. Penn researchers and their collaborators at the National Institutes of Health published their proof-of-concept findings in Cell today.

AML is the second most common type of leukemia, and the American Cancer Society estimates there will be almost 20,000 new cases in the United States this year. Many of these patients will undergo a bone marrow transplant. To treat a related leukemia, called acute lymphoid leukemia (ALL), investigators at Penn previously developed CAR T-cell therapy, which involves collecting patients’ own immune T cells, reprogramming them to kill cancer, and then infusing them back into patients’ bodies. Currently, both CAR T-cell therapies approved for use by the US Food and Drug Administration target cells that express a protein called CD19, for ALL and non-Hodgkin’s lymphoma. However, this is not an effective target for AML, since AML does not express CD19. Researchers have, therefore, been looking for other potential cellular targets.

One promising example is a protein known as CD33, but previous attempts to target CD33 have proven damaging to healthy cells. While damage to healthy cells could be prevented by making the CAR T cells short-lasting, this would defeat the purpose of one of CAR T’s greatest strengths—their ability to last for years, circulate in the body, and protect the patient from relapse.

“This therapy is meant to be a true living drug, and we know that CAR T cells can live on in patients’ bodies for years after infusion, so turning them off would be self-defeating,” said the study’s co-senior author Saar I. Gill, MD, PhD, an assistant professor of hematology-oncology at Penn. Cynthia E. Dunbar, MD, a senior investigator at the National Heart, Lung, and Blood Institute, is a co-senior author. The co-first authors are Miriam Yunhee Kim, MD, then a postdoctoral researcher in Gill’s lab, and Kyung-Rok Yu, PhD, a postdoctoral fellow under Dunbar.

“This study represents a significant advance toward effective and safe targeting of leukemia cells using CAR T cells,” Dunbar said. “A key to this advance is the use of next-generation, gene-editing technology to achieve this type of antigen-specific immunotherapy, even when the target is also present on normal bone marrow cells.”