Tandem Meetings 2023 | Preliminary results from Phase I study of CD123 CAR-T therapy in pediatric R/R AML

So we just presented data from our Phase I study looking at safety and feasibility of targeting CD123 with autologous CAR T cells. And we are we’ve had, you know, AML by itself is quite challenging. And unlike other malignancies which have been targeted with CAR-T cells, the success rates haven’t been as great. So for instance, the patients ALL, or myeloma or lymphoma, there’s been excellent responses and leading to FDA approval of these products. But with AML, on the other hand, it has been challenging and there are several reasons.

And one, of course has been identifying a good target which is expressed on blast, but not on normal tissues. The other has been the complexity of the patients themselves who are heavily pretreated and still have poor outcomes and therefore have infectious complications and comorbidities. And lastly, the nature of the disease itself, which is very aggressive and rapidly progressive in the relapsed/refractory setting, but also is immune suppressive by itself. Therefore, the cells that we infused tend to have limited persistence and thereby overall poor response.

So our approach has been to target CD123, which is highly expressed on AML blasts, but also on leukemic stem cells. And we developed a lentiviral construct that was actually generated in the lab of Dr Paulina Velasquez. It creates cells which are a second generation CAR that have a CD28 costim domain and also have a CD20 safety switch to ensure safety in case of toxicities. And our study is designed as a bridge to transplant approach, which therefore means that at the time of enrollment, patients must have an identified transplant donor.

We’ve had thus far about 70 referrals to the study, which is, you know, quite a significant number, but of which we’ve only able to we’ve been able to enroll about 20 patients and infuse nine on study and one on a single patient protocol. Again, I think this highlights the challenge that we see with patients with AML, where their disease itself is very aggressive and rapidly progressing, which means the window is very small in which to treat these patients, but also their accounts and infectious complications and comorbidities makes them very challenging to get onto these studies. And and again, this is very different than our experience in ALL, which highlights really why AML has been difficult.

We have four dose levels on the study so far and we’ve treated on dose levels one, two and three. And so we’re excited because we’re seeing some evidence of expansion and also antileukemic activity, starting with dose level two. And indeed we’ve seen two complete CRs, one with the patient with extramedullary disease and one patient who had a morphological CR, although with low levels of persistent. And this is especially exciting for us because these patients are very heavily pretreated and have had really refractory disease. And except for one patient who had primary refractory disease, all the other nine patients on our study have failed or relapsed following a bone marrow transplant and either 2 or 3 and even four transplants, which has been really showing the high risk nature of these patients that we enrolled. And also, encouragingly, we have not seen any dose limiting toxicities. And overall, the cells have been well tolerated. And we were really concerned with potential toxicities from CD123 targeting, including the risk of myelodysplasia, because this is also expressed in normal hematopoietic cells and also risk of endothelial toxicity. But we’ve really not seen any evidence of that so far.

And I think going forward, we plan to keep enrolling on our higher dose levels and also perhaps look at a donor derived arm where we would manufacture T cells from the transplant donor, the previous transplant donor, to sort of overcome the issue of fitness or the starting t cell product for these patients.