David Maloney:

I’m Dr David Maloney from the Fred Hutch Cancer Center in Seattle Washington. I’m joined by my colleagues here from the first day of the lymphoma session, leukemia session at iwCAR-T, Dr Noelle Frey from UPenn and Dr John Gribben from Barts in London. I think we had another really exciting day one. We started it off with, I guess, where CAR-Ts really kind of started off with ALL. What do you think the highlights of the day were?

Noelle Frey:

Well, I think the ALL session was really inspiring because just as you said, is kind of where it all started. And all of our discussions today acknowledge these initial successes that we’ve seen with CART-19 and ALL and it was really about the next steps, how we can make things better. And so we talked about using humanized CARs, dual-targeted approaches, off-the-shelf CARs and had a lot of discussions about different approaches to optimize all those potential ways of improving relapse-free survival. So it was an inspiring session.

David Maloney:

Yeah. I was struck by what we’ve learned in the relapses. This whole concept of being able to tease out the patients who have sustained CAR-T activity with consistent B-cell depletion, and then they’re the ones that are relapsing with loss of antigen whereas the other group that’s relapsing antigen positive, the problem is that probably the T-cells are… And so those strategies really detail different ways we could approach it. I thought that was fascinating.

John Gribben:

I completely agree and I think what was clear is that we’re not going to have one solution because the problem is very different. So there’s not going to be one solution fits all of those. But then what we really need, isn’t it? Is a way of identifying quite early on, exactly what the mechanism of failure is to be able to come up with a strategy that addresses why that particular patient failed. I completely agree with you. I thought coming into this session, gosh, what are we going to learn new about ALL when we’ve had one of these every year? Now, this is their fourth year and we’ve had one every year. But every year, even in the disease where we think we know the most about it there’s more stuff that comes out.

Noelle Frey:

Yeah. And I think it just highlights how for our patients, we’re never satisfied with things are so much better now than they were five years ago. We’re four years into it and we’re making all these advances, and it’s exciting to think about where we will be in a few more years with ALL.

David Maloney:

Yeah. That actually led to a lot of interesting discussions at the end of the day, where we were trying to figure out where will we be in 2027, for example. And I think there’s a lot of speculation of how to move CAR-Ts earlier, especially as you were trying to do in ALL. I think the other approach is, how are we going to get combinations approved or the multi-targeting CARs or the human CAR? These approval strategies are challenging. Now to turn to something that was actually a little more challenging, AML. We’re still waiting. What did you think about progress in AML?

John Gribben:

Yeah. I mean, it’s really difficult. Thinking both about the CAR-Ts and the bispecifics. What we’re hearing is of course, we don’t have a CD19 equivalent in AML or anything near it. And if there’s heterogeneity in terms of complexity of what should be the target in AML, we have not even established what the target should even be in AML yet to know what we are doing. Also, the whole approach of what it is that we are trying to achieve with immunotherapy, are we talking about it exclusively as a bridge to transplant, or are we potentially looking to develop this as a curative strategy? I was hearing most of the studies today about how do we get a refractory patient as a bridge to a transplant. So I think we’ve got a long way to go. And of course, almost all of that relates to how similar the AML blast cell is to the normal hematopoietic cell. So where’s the therapeutic window for immunotherapy to be able to come in and target those cells.

David Maloney:

Yeah. We just don’t have good antigens that can distinguish between the two. So that led to, again, interesting discussions about whether we should just ablate hematopoiesis and then send people for transplant, but there seems like there’s some progress being made, but I don’t know. We’ve been waiting quite a while for AML. We’re actually starting some trials now. So I think it’ll be interesting.

John Gribben:

Well, I mean, it’s a really neat approach is that what Saar is doing at your place, knocking out the CD33 to bringing back hematopoiesis that doesn’t express the target. But even Saar said openly that maybe CD33 is not the answer, but there’s at least a creative step towards getting to what we want to do, which is at least to replace the hematopoiesis, which enables you to at least go in and continually target this without the toxicity that we see associated with targeting something that is expressed on normal hematopoietic progenitors.

Noelle Frey:

And there’s just such an unmet need in our AML patients. And I think we saw a lot of redefining the goals, like you said, to get patients to a better place. And I thought it was interesting. And part of the discussions people mentioned that it might be, if our goal is to myeloablate and get someone to that transplant, it might be an interesting role for an off-the-shelf CAR.

John Gribben:

Sure.

Noelle Frey:

Because you don’t have that goal of long-term persistence getting you to your end point of remission just because it might not be feasible.

David Maloney:

So the other major disease we talked about, well, your favorite disease I guess is CLL and it sounds like there’s some hope on the horizon potentially with [inaudible].

John Gribben:

Yeah. Finally, there’s some hope on the horizon. And you said of course we started with a ALL, but of course we started with CLL. Carl June and David Porter’s first report out of UPenn was actually the ALL and of course such hope that those first two patients did so well. Unfortunately, we’ve had some major setbacks along the way. I think all of us believe a lot of that has been to do with the T-cell dysfunction that’s so intrinsic in CLL. And of course, the other reasons probably getting a bit better now is that the chemotherapy that we’re using for CLL, the fludarabine-based regimen, nothing’s more immunosuppressive than that. So trying to collect fit T-cells from CLL patients has been a real challenge.

John Gribben:

And of course, what we spend a lot of time, maybe too much time talking about today, because we ended up hearing three different approaches, all talking about the same thing, which is how a BTK inhibitor, namely ibrutinib is able to very clearly improve the fitness of the T-cells that you collect. The issue, I think that we’ve got in CLL, as in pretty much every other disease is once we get the CAR-T approved to who and when in the patient’s journey is the right approach. If you wait too late, we’ve all seen when patients have failed these therapies, the disease can really accelerate very quickly when a patients develop mutations to the BTK binding site, those patients can really accelerate the risk of Richter’s transformation and how you can’t salvage those patients back, mean that you can miss the window of opportunity that a CAR-T has. But with the successes we’ve got, with the current treatments we’ve got, offering a CAR-T too early also raises its own ethical issues. But what we did hear from the companies today was a very clear timeline of when we can expect at least liso-cel to be commercially available. So at least, we’ll have a product that we can, as we’ve done in other diseases, start to explore when and in which patient population, we are able to do this outside the setting of clinical trial, where that’s defined for us. And I think as an academic center, so I think we’re very well equipped to answer those types of questions.

David Maloney:

Yeah. I was struck by the fact that most of our patients have still been treated with multiple regimens and then the UPenn experience recently with ibrutinib, in fact, some patients were frontline patients with only six months of ibrutinib and went directly into CAR-T and there, at least the survival was 100% in that population. So I think if we can get a CAR-T approved in the safe, which we desperately need, then we can start trying to see whether can we eradicate MRD? Can we do that with no toxicity or with less toxicity? And I think that’d be a great advance. I was surprised about the discussion with ibrutinib, in that, I thought maybe naively, that this was clearly a TKI effect on T cells. I’m now not so convinced because you could equally say it’s the TKI effect on the CLL cells modulating their impact on the T cells. And that’s an area I know you know a lot about, but you think it’s more just that cytoreduction of the disease or the change in that histology? Or do you actually think we’re modifying T-cells?

John Gribben:

Well, I think it’s probably almost certainly both, but there’s a huge amount of data out there now. So ibrutinib and all the BTK inhibitors down modulate expression of PD-1 on the PD-L1 pathway. So there’s very indirects that can have BTK is highly expressed on myeloid cells and particularly on myeloid-derived suppressor cells. So there’s a whole complex way in which these agents can modulate the whole microenvironment, which of course is where if you get those CAR-Ts in there, so I think it’s much more complicated than just the fitness of the T-cell alone. I think it does impact those T cells, but I think it impacts the whole tumor microenvironment and induces a much more better environment for those T-cells to be able to have their activity.

Noelle Frey:

And I loved how one of the things that came up in the discussion was using what we’ve learned about the CART-19 for CLL with ibrutinib to potentially apply ibrutinib to other diseases where ibrutinib is not necessarily a standard of care to treat the disease. And I think just highlights how helpful this type of meeting is, because we’re-

John Gribben:

I know, yeah, totally.

Noelle Frey:

… hearing things from other subspecialists

David Maloney:

I think that [inaudible ] at Penn. Well, just through Penn, Steve Schuster did a study with ibrutinib in large cell lymphoma and I-

John Gribben:

Well, at least you can make a rationale because of course there’s been studies done of thinking that ibrutinib might have a role in certainly from the work that [inaudible] done, at least in ABC subtypes of diffuse large B-cell lymphoma, which are highly like to be the ones that land up going to CAR-T. But what we’re talking about here is diseases in which there’s no expression of BTK, there’s still the potential to be using those agents to modulate the immune environment. You could imagine doing this in myeloma and in ALL and in solid tumors. And I think there’s every rationale to believe that those would be effective.

David Maloney:

So I think we saw a great day on those three diseases, and then we kind of finished it up with some wild speculation. What were your thoughts from that effort?

John Gribben:

Well, I think both you and I were a little bit worried about this was an idea we had of just let’s throw some ideas out there about where we’re going to be in five years. And I thought you and I thought this session could be over in five minutes, but in fact, it, right from the very first question stimulated some great discussion among us and among the audience. I still wish our colleagues from the pharma companies would get up and be more involved because lots of those questions would be actually been better answered by them. And I wish they just would stop being quite so shy and really step up with one notable exception. But they-

David Maloney:

But interesting, interesting. I did get feedback about, wow, this is such an open discussion. You guys are just like… because there’s no holds barred there in terms of what people are asking, not coming from pharmacists.

John Gribben:

Well, that’s the whole point. This is why it’s a workshop. And this is why we don’t want this meeting to be 500 people. The concept of being able to talk openly, have the time to discuss it and have, as you say, what I love about it is we’re so used to going to a meeting in our own disease and just hearing how other people are thinking about the same problem from a slightly different perspective, just opens your eyes to different opportunities, doesn’t it?

Noelle Frey:

Yeah.

David Maloney:

And this was pretty informative because yesterday we had done the solid cancer day and a lot of those people stuck around and there was a lot of cross-fertilization. So I thought this was a really outstanding meeting to get back together. It was partly hybrid. We did have probably 20% of the talks virtually, but that actually worked quite-

John Gribben:

We also had a big audience who were just watching virtually that-

David Maloney:

But in terms of the speakers.

John Gribben:

Oh, in terms of the speakers. But I’m always worried about… I think personally that hybrid meetings are the way we’re going to go forward. I don’t think we’re ever going to come back to the day where everyone’s going to get on a plane and travel halfway around the world to give talks. And I think as the technology continues to improve, I think it worked pretty smoothly today, the transition between those speakers who were presenting virtually. In fact, you could argue that they’re the ones whose talks were usually the 10 minutes, but even in terms of the interactions we were able to have with the… we had a couple of issues with the [inaudible]. But once we’d overcome that, the technologies there for people to be able to have a fully interactive process, and I’m the one who stressed the importance of doing a workshop, I didn’t feel that the people who were there virtually were not contributing towards the discussion.

Noelle Frey:

Yeah. I agree. I think going forward, we’re going to be able to have these workshops with this hybrid method, just be more inclusive and more interactive because COVID has pushed us all to make-

John Gribben:

It’s the gift that keeps on giving.

Noelle Frey:

… this engagement of people who aren’t on site meaningful and productive. So I thought it worked really well too, the hybrid model.

David Maloney:

All right. Well thank you both. And we’ll look forward for day two.

Noelle Frey:

Yeah.