CAR-T Meeting 2024 | CAR-T therapy in ALL: exploring dual-targeting of CD19 & CD22 to overcome resistance

So CAR T-cells have been a great revolution in the field of acute lymphoblastic leukemia.

Unfortunately, now that we are 12 years after the first pediatric patient infusion, what the real-world data have shown us, including the long-term [data] of the previous clinical trial, is that the overall outcome is approximately 50% event-free survival, which means that unfortunately, in advanced relapsed refractory B-ALL, approximately half of the patients will relapse. So we definitely need to improve the field.

So one of the problems of the CAR T-cell experience is that the target we look at is at some point a moving target. Why? Because the malignant cells are very smart and they can escape by masking or not editing at the surface the CD19 target. Because of that, trials to target two targets instead of one have been done and there are many ways to do it, and the three main ones are the following:

The first idea is to say, okay, I will use two different CARs, one against CD19, one against CD22, and there are two ways to infuse them -both at the same time, which is called co-administration, or one and then the other one, each after lymphodepletion, which is called sequential administration. Two trials have been recently published with those two antigens and are extremely interesting. The first Chinese one, led by Ching-Hon Pui from Memphis, has included nearly 200 patients with an event-free survival of 85%, 70% for patients not transplanted after the CAR. But unfortunately, in this trial, CD19-negative relapse has been observed, and also still CD19-positive CD22-positive relapse, which means non-persistence of the CAR. But very promising results. 

The sequential administration also shows promising results. Less patients, approximately 70 if I’m right, but again CD19-negative relapse is happening. Which means that the double administration whether co or sequential does not prevent completely the problem.

The only paper that has shown some prevention unfortunately with a very low number of patients, 12 patients, was done in the Great Ormond Street Hospital. They have tried a different system, which is to say I will cotransduce the two CARs at the same time, in the soup if you want, so you will have cells expressing a CD19 CAR, cells expressing a CD22 CAR, and cells expressing both -so it’s a mixture of different types of cells. Interestingly enough, in this trial, no CD19-negative or CD22-negative relapses have been observed, but it’s only 12 patients and they have a problem, they say in the paper, of persistence.

So they are trying to come back to the manufacturing issues to have more immature cells, more stem cell memory cells, etc., in order to have more persistent cells. And then with higher numbers and more persistence, we will see if this very successful outcome is to be reproduced.