John Gribben:

Hello, I’m John Gribben. We’re at the iwCAR-T meeting in Tampa, Florida, and we’ve just come out of this CLL session, although we’re going to cover some stuff that isn’t CLL related. We had a usual combination of live speakers and virtual speakers, but I’m joined today by my two colleagues who were talking to us live: that’s Saar Gill from University of Pennsylvania, and Mazyar Shadman from Fred Hutch, in Seattle. So great session guys, let’s talk about it. So Saar, let’s start with you. CLL, we were just discussing almost the very first patients that we saw the promise of CAR-T and here we are long time later with still no approved product. So what’s the biggest challenge that we face in seeing an approved product where we can see such tantalizing [inaudible] but always just not quite there.

Saar Gill:

Thanks John. Well, I think there are two major challenges. The first one has been on the clinical response front, and I think that while the first few cases were very exciting, had high response rates in a small number of patients, and then most importantly, extremely durable with some recent reports of patients now, 10 years out, we’re still we’re recirculating still active CAR-Ts, still with B-cell aplasia telling you that those T-cells are functional and likely protecting the patients from relapse. Those were minority of patients. And then there was actually somewhat, I think a disappointing lull in clinical activity in really from several different centers, several different products. And while that was happening, there was a surge of activity in ALL and lymphoma. And that’s how we got to this situation where we are now. But I think addressing that clinical challenge is perhaps now we are seeing better responses, perhaps quite good response rates with liso-cel for example as monotherapy. But as I showed in my presentation and has been presented and published by a couple of other groups as well, rational combinations with CAR-Ts in CLL and by rational, an agent that does not disrupt the activity of the T-cells and indeed may even immunomodulate are now leading to very high response rates, and those response rates are very durable and are associated with extremely deep responses in the order of less than one in a million cells, so that’s the first challenge. The second one is what is on the other side of the equation? What is the competition if you like, what are the alternatives? And I think that talking to other hematologists, oncologists, talking to patients, talking to companies, there is always the retort, well, these results might be really good, but we have many effective agents for CLL. And so I think that’s the other challenge is what is the alternative? Is there an unmet medical need or not? I would say yes, but some would say no.

John Gribben:

In CLL, the data has clearly shown that since ibrutinib and venetoclax came along, the number of allotransplants has really fallen off. But of course, the problem with allotransplant in CLL has always been that the vast majority of the patients are really just not terribly fit for it. But is it just a time before, patients eventually become resistant even to these new therapies that we have and when is the ideal window to be offering these types of therapies? Is it always going to fail if we waited until the patients have failed everything and they’ve got really bulky disease, or do we need to think about an optimal time that an immunotherapy, like a CAR-T approach can work in these groups of patients, now maybe come back to both of you on this one. So let’s start with you.

Mazyar Shadman:

Sure. I think in clinical immunotherapy, one of the challenges is to take care of patients specifically with CLL diagnosis and mantle cell lymphoma. And as you mentioned, one of the most common problems is that these patients are mainly referred to us when they have active disease or progressive disease. So to get to your question of what is the right time for considering CAR-T, I think when disease is responsive, but either because of disease parameters or because of the prior treatments you consider the patient high risk. So we always encourage patients having a consultation, at least talking about CAR-T therapy and cellular therapy approaches. When we know that one of the novel agents is no longer an option for them, BTK inhibitors or venetoclax, in real world, though, that doesn’t happen. So we usually get patients after the two major classes of drugs have failed them. And that’s a situation that you have a lot of work to do to get them even ready for the CAR-T therapy.

John Gribben:

Now, I always tell my patients that you really don’t know when the ideal window of therapy was until it’s just a little too late and you’ve missed it. So that’s remains a challenge, but Saar, you’ve taken the opposite approach in the study. You’ve just published, which is, you’ve got a cohort of patients that you’ve taken to CAR-T and first remission on ibrutinib who’ve got really spectacular results after CAR. I know the number’s are quite small and I’m sure even you want to see longer follow-up, but those results look really spectacular.

Saar Gill:

So six of the patients actually were on first line ibrutinib had been diagnosed largely they had poor risk features. They had been diagnosed with CLL. They were being controlled on ibrutinib. They were not in a CR, but they were in a PR or stable disease on ibrutinib. And that gave us plenty of time to manufacture them. This, I often say, John, this is one of the easiest clinical trials I’ve ever done. They were so stable and there was time to manufacture the cells and so I think that’s a real plus actually, which often isn’t really captured on essentially intend to treat analysis or per protocol analysis. So that’s a big plus, and I know that conservatively, the right answer is that you wait for the right window, but I’ve been very encouraged. Yes, small number of patients. My own personal opinion, I would love to see newly diagnosed patients with high risk features, getting ibrutinib, getting manufactured and getting what has in some patients been a one and done treatment.

John Gribben:

We were asked questions about the economics of this whole thing. And for people who are going to be on frontline ibrutinib patients can be on the drug for many years, actually a CAR-T approach potentially curative in that setting actually could work out to be financially advantageous. I know we’re moving more and more towards fixed duration rather than continuous therapy, but on a patient who is going to be on continuous therapy or even on a patient who’s going to be on intermittent combinations of ibrutinib and Venetoclax, you could quite easily make the financial case that the CAR-T becomes a reasonable approach here.

Mazyar Shadman:

There’s nothing more than more fixed duration than CAR-T as long as you have the right safety profile and of course you need the efficacy. So that’s why bringing CAR-T to early lines of therapy is really important either in combination with other novel agents or thinking about sequencing novel agents and CAR-T in a fixed duration of time early on. And, but again, we need to get much better in terms of both efficacy and safety profile for a disease like CLL.

John Gribben:

Now what a lot of my patients talk to me about is, oh, could we not just freeze my cells? There are issues I know in terms of using a previously cryopreserved product to then manufacture, but you guys have done this many times before.

Saar Gill:

It’s very doable. So what we’re talking about, I guess, is that you identify a patient or a patient self identifies as someone who’s willing and interested to do that. And there’s some background for doing that both in the CAR-T world, as well as in people who want to freeze their blood cells right? I mean that does happen. And that is a choice that we give them in some situations. So I think it is doable as to whether that is going to be acceptable and translatable to a product that a drug company will sign off and say, yes, this is the same as what has been done in our studies. That’s a different story, but we have done that particularly across children’s hospitals that’s being done quite often.

John Gribben:

Yeah, of course, you’re absolutely right, you’re then freezing the sales and you’ve got your chain of command, because you’re doing it in the center that manufacturing’s then happening. It’s a different issue when you’re having the sales cryopreserved in one place and then given to a company someplace else, the whole regulatory issues raise their heads then, but I do want to come back and talk of course about what you talked about today. A little bit of a standout of the whole session, but very interesting talk, nonetheless, using the CD20 rather than the CD19 CAR. And the other interesting thing you’re doing there is a third generation CAR that is with both CD28 and 4-1BB co-stimulation. So if you want to just tell us, why it is you’re interested in this approach and why you’re excited about the studies you’ve got so far.

Mazyar Shadman:

So CD20 is a proven target in CLL. So in US at least all three monoclonal antibodies targeting CD20 are approved by FDA for treatment of CLL, we use it concurrently with venetoclax and with chemotherapy, it gave us the overall survival advantage. So the idea of using a CD20-directed CAR in CLL makes a lot of sense. Now it’s a third generation CAR, so the hope was at the time of the design to get the benefit of the both co-stimulatory molecules of CD28 and 4-1BB in clinic, though, we are seeing that this CAR is behaving very similar to 4-1BB CARs. But yeah, so the study is ongoing and this is a study that started at Fred Hutch and we are including patients with CD20-positive B-cell lymphomas, including CLL. Most of our experience so far is a non-CLL B NHLs and…

John Gribben:

Other way, hold on to that a 100% response rate you’ve got in your one CLL patient.

Mazyar Shadman:

You know, a lot of it is for what’s going on in the field, as it was mentioned in cell therapy and non-cell therapy for CLL, there has been competition even for other CARs. Now we have a number of patients on this study and hopefully in future meetings, we’ll present more data on CLL patients. But in general, what we showed is that it’s an outpatient CAR. And so far small number of patients, we have seen promising safety profile. We have not seen grade 3 or 4 cytokine release syndrome or ICANS. Again, we need to treat more patients and get more experience. And so far effective in indolent lymphomas like follicular lymphoma and again, limited experience in other histologies. So the study is now moving to the next level of having a multicenter study and we have some other academic sites involved with a dedicated cohort for CLL. So we are really looking forward to treating more patients. And as you mentioned, the one patient we treated has had a great response with deep undetectable, measurable residual disease and in almost a year in remission. So we have shown that no one works, but of course there’s a long way to go, but we’re just looking forward to having the next study.

John Gribben:

Now the whole [inaudible ] there’s lots of differences between CD28 and 4-1BB, but one issue seems to be this issue of persistence of the CAR-Ts. In ALL, we’ve got very clear data that persistence matters. In diffuse large B-cell lymphoma, lot more controversial as to whether it matters quite so much or not, but a lot of that might just be the methodology of picking up some residual CARs. Of course, CLL fits somewhere in between it’s classified as a lymphoma, but it’s got that leukemic component. Pretty much all the published data, I’ve seen has actually been with 4-1BB CARs. I can’t think of any studies that have got a pure CD28 CAR in which I’ve seen any data. So it’s very hard for us to know whether persistence really is an important feature or not. But I guess from the pen studies would suggest that you’re usually seeing in those long-term remitters persistence.

Saar Gill:

We do. And you’re right. I think we just can’t disentangle those particularly because the expectation is that ALL will relapse a lot faster than CLL. And so that might be why we just don’t have that signal personally. And again, it’s a feeling without a control, but I think persistence is important and well, I think biologically CLL, clinical behavior, we think of it more as a lymphoma. I wonder a little bit about whether the cell of origin is important and the cell of origin in CLL, I imagine will be closer to a differentiated B-cell than to ALL. So I can’t biologically tell you that there’s a good reason why persistence should be important in CLL, but what’s making it difficult for us to do discern a signal is just the latency to relapse if there was to be one, having said that again, they always correlate persistence of CAR-T cells with B-cell aplasia in CLL. So we can’t answer that question.

John Gribben:

Now, it was interesting, at least for me to see that when you’ve got the 4-1BB and the CD28, you did see persistence of the CAR suggesting at least to me, and see if you agree that the 4-1BB component don’t see if you like a CD28 driven exhaustion of the cells that leads to the loss of those cells, as long as the four 4-1BB domain is also there. Any thoughts? And do you think this is going to be important in terms of looking at these other B-cell malignancies having persistence?

Mazyar Shadman:

I think so, one could argue that for indolent lymphomas including CLL actually persistence does matter, having initial response is not difficult. The reason we can’t cure these conditions is that they come back. And the question is with, if you’re really looking at the competitive landscape and if you’re really trying to be in a good way, some other targeted drugs that we have, you really need to see progression-free survival of reasonable time of three, four, five years. So how much that persistent CAR-T helps you? I would say it does, but it also comes with the cost of B-cell depletion and infections. And so it’s very important to have long-term information and those toxicities as well.

John Gribben:

So I’ve got to end with just one last question that I know you cannot answer because we had the company in the room, we tried to get the answer from them and couldn’t, but it is frustrating that we still don’t have a commercial product we are able to offer our patients for these diseases, it’s like CLL, already. So any thoughts as to how realistic you think, how close are we? Are we getting close? Are we still years away? What’s more is it going to take?

Saar Gill:

I can’t answer that question, but I would like to believe that it will be soon, you need the data of safety and the data of efficacy and we’re getting there.

John Gribben:

So there you have it, we’re there with the world’s experts talking about the role of CAR-Ts in CLL. As I already mentioned, the first disease in which we actually saw the efficacy of these cells, lots of interest, lots of ways in which we were able to add other agents into modulate, lots of ways. We can think about manipulating the CAR-T product to get what we’re looking for and potentially a disease where we would be looking to give the CAR-Ts with an agent like ibrutinib. So thinking about one of the model diseases in which we’ll be thinking about a dual approach and how to treat the patients. So like all of you, I’m looking forward to the rest of the meeting, and I’m really looking forward to following up to this session next year at our next CAR-T meeting, where we’ll see where the field has taken us in CLL. So thank you very much for your attention and thank you both for joining me today.

Saar Gill:

Thank you John.