Gene Editing Could Reduce Toxicity of CAR T Treatment in AML


A new approach using gene editing technology could allow chimeric antigen receptor (CAR) T cells to target CD33 in patients with acute myeloid leukemia (AML) but prevent the cells from attacking healthy stem cells, too.

Using gene editing to remove CD33, a protein targeted to treat acute myeloid leukemia with chimeric antigen receptor (CAR) T cells, from healthy stem cells could reduce toxicity experienced by CAR T-cell therapy, according to a study published in Cell.

A group of researchers at the University of Pennsylvania (Penn) and collaborators at the National Institutes of Health hypothesized that deleting CD33 from healthy cells could create an antigen that only targets the cancerous cells.

Previous attempts to target CD33 with CAR T therapies have damaged healthy cells. When CAR T cells are used short term, the damage is prevented, but that goes against the purpose of the treatment, which is to ensure CAR T cells remain in circulation within the body for years, thereby preventing relapse.

The new approach would genetically engineer normal stem cells, so they are different enough from the leukemia that the hunter cells don’t attack them.

“This study represents a significant advance toward effective and safe targeting of leukemia cells using CAR T cells,” Cynthia E. Dunbar, MD, a senior investigator at the National Heart, Lung, and Blood Institute and a co-senior author, said in a statement. “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.”

The approach has already worked in mouse and monkey models and in human cells in a laboratory setting. The work will no need to move into human trials at Penn.

“Think of this as bone marrow transplant 2.0; the next generation of transplants,” said the study’s co-senior author Saar I. Gill, MD, PhD, an assistant professor of Hematology-Oncology at Penn. “It gives you a super powerful anti-leukemia effect thanks to the CAR T cells, but at the same time it has the potential to get rid of the main toxicity.”


Kim MY, Yu K-R, Kenderian SS, et al. Genetic inactivation of CD33 in hematopoietic stem cells to enable CAR T cell immunotherapy for acute myeloid leukemia. Cell. 2018;173(6):1439-1453.

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