Tandem Meetings 2023 | LBA: CD33 CRISPR/Cas9 gene-edited donor allograft in patients with AML at risk of relapse post-HSCT

So this is a trial by Vor and it’s based on work done in at Columbia and especially at Penn some time ago in which CD33 a an antigen expressed on early progenitor cells also expressed on differentiated myeloid cells such as neutrophils and monocytes, is deleted in the stem cell population. So the transplants occur from a CD34-selected allograft donor and the gene is deleted and the and the cells are then transplanted in a myeloablative conditioned recipient. The first question is would CD33 deleted hematopoietic stem cells engraft in a lethally myeloid ablated recipient? And the answer is yes.

So two patients have been treated so far. The third patients being treated now and has not quite engrafted yet, but we’re waiting for the engraftment for the third patient. So the first two patients engrafted on time for both neutrophils and platelets. So that’s encouraging. The second is that the full phenotyping was available and suggests that as predicted, the hematopoietic cells of the donor are deficient in CD33, so that’s also exciting. That means that the gene editing process that was done on the stem cells from the donor was effective and persisted after engraftment. And the third is at least the first patient has been treated with several doses of gemtuzumab, which targets CD33 and did not result in any change in the blood counts of the transplant recipient, suggesting that the target was eliminated effectively and that that target was not present on the stem cells and the maturing progenitors in the recipients so that those cells, in theory would be resistant to gemtuzumab. And obviously the residual leukemia cells would have CD33 on the surface. So in theory, the, the ADC gemtuzumab is going to be selectively effective against the residual leukemia cells. But those stem cells that have been gene edited are going to be resistant. And so there’s not going to be any decrease in the blood counts. That’s a proof of principle. It looks like it’s holding true.

Now the question is whether this will be an effective approach for patients with acute leukemia. And will will patients actually have long term remissions? So there’s two ways to do this. One is that you can treat the patients after transplant with an ADC to CD33, and fortunately there is one that’s approved, gemtuzumab. Or you can develop a CD33 CAR, in which case the donor T cells would then be genetically modified to express a CD33 CAR. And so that could also be the implement or the effector mechanism to kill residual leukemia in the host, which should be expressing the target CD33, while the normal engrafted gene edited stem cells will not express a target and so will be resistant.

So they also did pharmacokinetic studies and showed that the level of gemtuzumab was higher than expected, which makes sense because there’s no target in these recipients. So the drug doesn’t bind the target. And if the drug drug doesn’t bind the target, it doesn’t get internalized and degraded. And so the level of gemtuzumab was higher than expected based on the amount infused, which is also reassuring because that means you can potentially still kill the residual leukemia cells without exposing the host to high levels of gemtuzumab or multiple doses of gemtuzumab because, you know, the level you need to achieve is going to be higher than expected based on the dose because the engrafted stem cells and all the myeloid cells in the host don’t express CD33 and so there’s no target for the drug to bind to. And therefore the levels of the drug are going to be higher. And the only cells that express CD33 in theory should be the residual leukemia cells. So again, it’s a proof of principle only and whether this will effectively eliminate leukemia sufficiently to get people to transplant or provide patients with long term remissions remains to be seen.