Gene Editing of Healthy Cells Improves CAR T-cell Therapy for AML, Preclinical Study Shows

Gene Editing of Healthy Cells Improves CAR T-cell Therapy for AML, Preclinical Study Shows

Genetic modification of healthy blood stem cells prevents off-target effects of chimeric antigen receptor (CAR) T-cell therapy for treating acute myeloid leukemia (AML), a recent preclinical study shows.

The study, “Genetic Inactivation of CD33 in Hematopoietic Stem Cells to Enable CAR T Cell Immunotherapy for Acute Myeloid Leukemia,” was published in the journal Cell.

Nowadays, CAR T-cell therapy is one of the most promising strategies to fight cancer. It genetically alters T-cells — a type of white blood cell that recognizes foreign molecules through specific membrane receptors — so that their receptors specifically recognize and kill tumor cells.

CAR T-cell therapy requires taking blood from the patient, isolating T-cells, changing the cells genetically to attack proteins associated with cancer, and then infusing them back into the patient. The most suitable target protein is the one that’s highly expressed by tumor cells and absent in healthy cells.

However, this is very difficult to achieve, and so far, CAR T-cell therapy not only targets tumor cells, but also healthy ones, called “off-target effects.”

One of those examples is AML, a type of blood cancer that causes the overproduction of immature myeloid cells, which are blood cells that give rise to red blood cells, platelets, and special types of white blood cells.

The use of CD33 — a cell surface molecule highly expressed in AML cancer cells — as a target of CAR T-cell therapy for AML results in the destruction not only of cancer cells, but also healthy myeloid cells.

To develop a specific CAR T-cell therapy against CD33, researchers at the University of Pennsylvania’s Abramson Cancer Center designed and evaluated the effectiveness of a new approach that combines CAR T-cell therapy with transplantation of modified healthy stem cells that no longer have CD33.

The removal of CD33 from healthy stem cells was achieved with the CRISPR/Cas9 gene editing system, which allows researchers to edit parts of the genome by adding, removing, or changing specific sections of the DNA.

Human stem cells lacking CD33 were found to be functional not only when grown in the lab, but also when injected into mouse and primate models.

The injection of these modified stem cells, along with CAR T-cells against CD33, in a mouse model showed that CAR T-cells selectively attacked CD33-positive cancer cells, without affecting healthy cells.

“This study represents a significant advance toward effective and safe targeting of leukemia cells using CAR T cells,” Cynthia E. Dunbar, the study’s co-senior author, said in a press release.

“Think of this as bone marrow transplant 2.0; the next generation of transplants,” said Saar I. Gill, the study’s co-senior author. “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,” he said.

The researchers believe this approach will lead to higher response rates in AML patients, and they now hope to move to human trials. In AML patients in remission, instead of modifying the patient’s cells — which can still have undetectable cancer cells — this approach could be performed using cells from a healthy donor.

The researchers noted this strategy might be used for other cell-surface molecules, or to other forms of targeted immunotherapy, opening the door to new and improved treatments in AML.