‘Gated’ CAR T-Cells Are Effective Against AML—With Less Toxicity

Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for children with B-cell acute lymphoblastic leukemia (ALL). But unfortunately, CAR T-cells have been far less effective for another blood cancer: acute myeloid leukemia (AML).

Now, a new study led by Babak Moghimi, MD, at Children’s Hospital Los Angeles has shown that a special “gated” approach to CAR T-cells is effective against AML in preclinical models—while minimizing toxic effects on healthy cells.

The findings, which were published Dec. 3 in Blood Cancer Discovery, mark a significant step forward in advancing the development of CAR T-cell therapy for AML.

“Current versions of CAR T-cells often cause unintended toxicities in AML,” says Dr. Moghimi, Head of Transplantation and Cellular Therapy at Children’s Hospital Los Angeles. “By targeting two antigens in this gated approach, we found that the T-cells maintained their effectiveness against the cancer, while sparing healthy cells.”

How it works

One of the key challenges with developing CAR T-cell therapy for AML has been finding the right antigens for T-cells to target. The problem: Antigens on AML cells are also expressed on many healthy cells, including bone marrow cells.

To get around this issue, Dr. Moghimi and his team developed SynNotch gated T-cells that target two antigens—CD33 and CD123—that are expressed by virtually all AML cells.

Importantly, the cells are organized in an “if-then” logical circuit—similar to logic gates used in computer programming. The circuit requires both antigens to be present before the T-cell attacks a particular cell.

“If both antigens are present, then the gates open, and the CAR is instructed to kill,” he explains. “But if only one antigen is there—which is the case for normal cells—the gates remain closed, and the T-cells do not attack. It’s highly specific and precise.”

The study tested this approach in two types of mouse models—those with AML from cell lines, and those with AML from patient-derived tumor samples. In both, the gated CAR T-cells completely cleared the cancer, while preserving normal hematopoietic stem and progenitor cells.

The team also found that the gated CAR T-cells had lower levels of “exhaustion markers”—indicating that they could fight the cancer for longer before tiring out.

Our hope is that this gated approach can eventually be a new and less-toxic option that can improve the long-term outcomes for these patients.

Babak Moghimi, MD

No inflammatory ‘storm’

One particularly exciting finding was that the gated cells did not cause cytokine release syndrome—an intense storm of inflammation that occurs with currently available CAR T-cell therapy.

That’s important because recent studies have shown that this inflammatory storm can specifically feed AML cells and allow them to escape CAR T-cell therapy.

The fact that this did not occur with the gated approach is promising.

“With our logical circuit, the signaling is not as intense, which may be why it did not trigger cytokine release syndrome,” Dr. Moghimi says. “This could be a very important aspect to successfully using CAR T-cell therapy in AML.”

Planning for a clinical trial

The team is now applying for grant funding to potentially test this approach in a clinical trial for patients. “Our goal is to launch a clinical trial in the next three to five years,” he says. “Meanwhile, we are working on improving gated T-cell circuits even further for AML.”

For Dr. Moghimi, a clinical trial cannot come soon enough. For patients with AML under age 20, five-year survival is between 60% and 70%—far below the 90% cure rate for ALL. And once disease has relapsed, survival rates plunge.

“There is a tremendous need for new treatments in AML,” Dr. Moghimi says. “Our hope is that this gated approach can eventually be a new and less-toxic option that can improve the long-term outcomes for these patients.”