iwCAR-T 2024 | An update on CAR-T in CLL

Tanya Siddiqi:

I’m Tanya Siddiqi from City of Hope. 

Saar Gill:

I’m Saar Gill from the University of Pennsylvania. 

Tanya Siddiqi:

So I presented the updates on liso-cel in CLL today. This is a product that has just received FDA approval in the setting of relapsed/refractory CLL after BTK inhibitor and BCL2 inhibitor therapy. And the data was based on the TRANSCEND CLL study, which, basically, is a Phase I/II trial, open-label, multicenter study, that is for relapsed/refractory CLL patients who have failed at least 2 or 3 different lines of therapy and have actually all had prior BTK inhibitor therapy as well. We enrolled about 137 or so patients who were l​​eukapheresed, but 118 received the liso-cel CAR-T product. And the final sort of primary analysis subgroup/ subset that was predefined was 50 patients at dose level two who had failed both BTKi therapy as well as venetoclax therapy. Previously, we showed that the complete remission rate in this subgroup was about 20%, which is fairly good, we think, in patients who have failed pretty much everything else that was available at the time and have a very poor prognosis. These were patients with a median prior lines of five. You know, majority of patients had high-risk features, so a complete remission rate of 20% with an overall response rate of about 44% and undetectable minimal residual disease on top of it, of about 60 to 65%, were pretty deep remissions that also, at the median two-year follow-up, seem to be fairly durable. The median progression-free survival and median duration of response has not been reached yet for the complete remission patients, and is a very respectable 1 or 2 years out for the partial remission patients as well, where they don’t have to be on any continuous treatments, they’re just on observation and enjoying sort of a good quality of life for some amount of time before they need treatment again, if at all. So this product was just FDA-approved for this patient population. It’s a promising product, and of course, we still need to build further on it, still need to improve on it, but it’s a great first step. 

Saar Gill:

And so, I think, what I was impressed about with your data, Tanya, was that the patients who achieved a complete response had really fantastic durable remissions, which, of course, is what you want, and this is after a single infusion. So that’s the starting point for the abstract that I presented, which was to do with a laboratory investigation of how we can further improve the response rates of CLL patients to CAR T-cells. And it arose from two studies that we did as investigator-initiated single center studies at the University of Pennsylvania, and that you’ve participated in as well in a different setting with the multi-center studies, that relate to a combination of CAR T-cells with ibrutinib. 

And the question really, initially and subsequently, was does one plus one equal two or does it equal three. And you know, I think, with the provisos of the fact that our observations do not stem from a randomized clinical trial, I was quite impressed that maybe one plus one equals three in this instance. And so, that led to our interest in investigating the sort of laboratory correlates of this. And what we found and what I presented today was related to an immunosuppressive cell population that exists in the blood of CLL patients, as it does in the blood of a lot of other cancer patients. These are called myeloid-derived suppressor cells. They’ve actually been really difficult to characterize and define. They’ve also been very difficult to drug for various reasons. But we stumbled upon this observation that BTK, which is a target of ibrutinib, is expressed in myeloid-derived suppressor cells. And actually, ibrutinib, in our hands, seems to be really, really good at preventing the formation of myeloid-derived suppressor cells. 

And the important implication of MDSCs for immunotherapy, such as CAR T-cell therapy, is that these cells are very potent at preventing CAR T-cell functions. I think people know a lot about regulatory T-cells in cancer. Well, you might think of MDSCs as performing a very similar role in cancer. They’re really very potent at preventing T-cell function, and of course, that’s why people have been trying to drug them for a long time without success. So, at any rate, what we found was that you can make MDSCs in the lab, or indeed you can take them from the blood of CLL patients and show that they function as MDSCs. If you add ibrutinib or acalabrutinib, which is another BTK inhibitor, or even if you genetically knock out the BTK protein itself, you actually abrogate the formation of MDSCs. And so to pull it all together, we hypothesize that one reason that ibrutinib or BTK inhibition and CAR T-cells might work really well together is that you sort of prevent this counterregulatory expansion of an immunosuppressive cell population. I would finish off by saying that, of course, the way to prove this would be in a randomized clinical trial where you have CAR T-cells alone or CAR T-cells with ibrutinib to really be sure of that observation. But that’s where we have got up to so far. 

Tanya Siddiqi:

Clinically, how do you see this playing out? If you are able to show that it is synergistic and it is better in real life to combine ibrutinib or acalabrutinib with, let’s say liso-cel CAR T-cells, then how do you see patients do? Will they have lesser side effects and better efficacy or one or the other? 

Saar Gill:

Yeah, I think the issue, as you know very well, the issue with CAR T-cells is, at least in heme malignancies, is usually if they don’t work, there is no CRS. It’s not entirely true, but… So what we observed in our serial trials is actually a higher rate, not severity necessarily, but a higher incidence of CRS in the ibrutinib combination trial, and I think that’s because there’s less immunosuppression in that trial. So I don’t necessarily expect there to be less toxicity, at least not the frequency of cytokine release syndrome, I actually expect that there might be more, but considerably greater efficacy, at least I think.