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The 2022 Tandem Meetings | Universal CAR-T therapy for T-ALL

John DiPersio, MD, PhD, Washington University, St. Louis, MO, comments on the challenges to CAR-T therapy in T-cell acute lymphoblastic leukemia (T-ALL), and explains how multiplex CRISPR-mediated gene editing can be used to engineer a universal CAR-T therapy for this devastating disease. To begin with, normal and malignant T-cells express the same antigens and are phenotypically similar, which means that is difficult to both find a suitable target antigen, and to separate malignant and healthy T-cells for genetic manipulation. To overcome that, normal T-cells can be genetically manipulated to delete one of the T-cell receptor (TCR) subunits playing a role in self/non-self recognition, as well as the antigen that will be targeted by the CAR. This allows generating universal CAR-Ts targeting an antigen that will not be recognized by healthy T-cells. This interview took place at the Transplantation & Cellular Therapy (TCT) Meetings of ASTCT™ and CIBMTR® 2022 in Salt Lake City, Utah.

Transcript (edited for clarity)

So T-cell ALL is a very rare disease, but it’s devastating, and when you relapse with T-cell ALL, the chance of you being alive in 10 years is around 3-5% and only 20% of patients are alive in one year, so it’s a devastating disease. The cure rate for patients, both adults and children, with T-cell ALL is around 50%, but when you relapse, you’re in trouble and there really are no targeted therapies...

So T-cell ALL is a very rare disease, but it’s devastating, and when you relapse with T-cell ALL, the chance of you being alive in 10 years is around 3-5% and only 20% of patients are alive in one year, so it’s a devastating disease. The cure rate for patients, both adults and children, with T-cell ALL is around 50%, but when you relapse, you’re in trouble and there really are no targeted therapies. So there are nice targeted therapies for B-cell malignancies like B-cell ALL or B-cell non-Hodgkin lymphoma or B-cell myelomas, with CAR-Ts or with bispecifics, but that’s not been possible to target a T-cell malignancy with a CAR-T because the targets you would be going after are exactly the same as targets on the T-cells themselves. So the effector cells that kill the cancer also have that target, so what they do is they just kill themselves and they never get to the malignancy. So no one’s been able to figure out how to get around that.

The second thing is that you can’t separate normal T-cells from a patient with T-cell ALL because they phenotypically look similar to the malignancy, and so you will always have contaminating malignant cells in the normal T-cells, which would be a problem because you genetically manipulate them. You’re also going to be genetically manipulating the malignant T-cells, and then you would be infusing those cells back into the patient, which would then be resistant to any treatment. So to get around this, we figured out how to do what’s called multiplex CRISPR, and that is to do multiplex gene editing to delete the target in the T-cell that you’re going after in the T-cell malignancy. And then to also delete the T-cell receptor subunit, the alpha subunit. You can delete many subunits in the T-cell receptor. If you delete any one of the five subunits, the whole thing can’t make it to the surface and that’s the complex that allows a T-cell to recognize non-self tissues as non-self. And so I can take your T-cells and in one day, I can delete that target in your T-cells, and then also at the same exact time, with gene editing, take out your T-cell receptor. So now, your T-cells can treat anybody in this conference center with impunity because they don’t recognize any of them as non-self, because there’s no T-cell receptor. And I’ve taken out the target from your T-cells so then when I put a car to that target in them the next day, that CAR will not recognize itself because that antigen is gone. So that’s called a universal CAR-T and we’re just starting that trial now, so I think that’s going to be maybe the first targeted CAR-T therapy for T-cell malignancies.

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