CAR-T Meeting 2024 | The challenges with CAR T-cell therapy for T-ALL and the progress made to overcome these challenges

So T-cell acute lymphoblastic leukemia is a really underserved population at relapse because we know that at relapse the prognosis is really dismal. So CAR T-cells for T-ALL pose a very difficult problem. Why? Because CAR T-cells are T-cells.

So if you manufacture them and you do not have a leukemia-specific target, the CARs will kill themselves. So it’s called fratricide or as the Americans say, “friendly fire”. This is the first problem.

The second problem is, in B-ALL, when you destroy normal B-cells, you can live without B cells if you substitute them with immunoglobulin, which is the case of the first famous Emily Whitehead patient -she still receives immunoglobulin 12 years later. But you cannot live without T-cells so T-cell aplasia is to be prevented or treated.

And the third problem is because T-cell blasts look like T-cells, contamination during the manufacturing process is very difficult to prevent and if you do not, you will put CAR in a blast, which is not what you would like to do, obviously.

So these are the main problems. And also if you talk about allogeneic CARs, then the problem is you risk inducing so-called graft versus host disease with a T-cell bearing the CARs that you infuse which are not the same HLA type as the recipient’s.

So at the moment, all these problems have been tackled and very elegantly. The first one, which is, I would say, the predominating model is to say, let’s abolish the target inside the CAR T-cell, and I will look for this target on the leukemia. So the antigen, which is the most fashionable at the moment is called CD7. So there is a very elegant way, either by knockout or by retaining the information, retaining the protein inside the cell, not at the surface, so that the CAR T-cell does not express any more CD7 and there is no fratricide. So this problem has been overcome.

The elegant way also, when wanting to give allogeneic CAR T-cells, is to say I will destroy the TCR (the T-cell receptor). So this has been done by many methods, including CRISPR and, more elegantly, with base editing. So there is a beautiful English publication in the New England Journal of Medicine, with three patients being edited and receiving allogeneic CAR-T, and then being brought to transplant successfully, at least in two of the three cases. So these are, let’s say, embryonic results.

And there are also nice company-driven, biotech-driven results with 25 patients with a very promising overall response rate at the recommended Phase II dose, which is pretty high (900 million cells flat dose, which is six times what we infuse generally). But with this dose and with the adapted conditioning regiment, which was presented at ASH 2023, the overall response rate is 100%. Obviously, these are allogeneic CARs, they do not persist and you will probably need a transplant for most of the patients, but let’s say that compared to a few years ago, the field of CAR T-cells for T-cell ALL is advancing a lot.