iwAL 2019 | Immunotherapy for AML & ALL

Dr. Richard :                     Hi. I am Richard Stone from Dana-Farber in Boston. And I’m fortunate to be joined by Doctor Ivana Gojo from John Hopkins in Baltimore and by Marion Subklewe from LMU in Munich and we heard today at the [IwAL 00:00:19] session, some very interesting data about the using immunotherapy in both acute myeloid leukemia and acute lymphoid leukemia. So I’d like to start with Dr. Doyle. Tell me what … Where you think the field is right now in immunotherapy for AML checkpoint inhibitors to like …?

Dr. Ivana Gojo:                So I think that the field is moving forward. I think the problem is with many novel therapies that have been developed, you know that might slow down little bit development of checkpoint inhibitors because many studies that are currently underway will probably require its own repeating combination in some novel drugs.

Dr. Ivana Gojo:                Again, I think that there is a role for checkpoint inhibition in acute myeloid and lymphoid leukemia and I think as more real and in preclinical data that we will be able hopefully to more successfully incorporate it with transplant, with bite antibodies and everything else.

Dr. Richard :                     But right now, would you say that off … Outside the research setting, should checkpoint inhibitors be used in AML or ALL at this point in time?

Dr. Ivana Gojo:                I don’t think that outside of the research setting we have sufficient data. Although I’m at … I would challenge myself let’s say in patients who have extra measure or the relapses, would you potentially consider using [ipiliumumab 00:01:42] or similar. I think we need more data and so …

Dr. Richard :                     Now, you’ve done some very interesting work with checkpoint inhibition in ALL. Could you go over the preclinical rationale and what you’re doing now in that field?

Dr. Ivana Gojo:                So I think that we’d use bite antibodies in ALL, we have more experience. We have less in acute myeloid leukemia but it just, part of activation of T-cell is associated with [inaudible 00:02:05] regulation or multiple co-inhibitory receptors including [PD1 00:02:08].

Dr. Ivana Gojo:                And the reason why we went in that direction was because responses to [blinatumomab 00:02:14] are great. But the issue is that they are not that durable. I mean there’s … Let’s separate from minimal residual disease and also what is striking for me, from initial studies. So blinatumomab, you couldn’t really detect even difference with the transplant.

Dr. Ivana Gojo:                And so you know, how we can improve this outcome, how we can get deeper responses and whether this activation of adaptive resistance, can it be overcoming combination with checkpoint inhibitors?

Dr. Richard :                     You’re doing an interesting study now with Blinatumomab and trying to magnify the ability to activate the T-cells by using blinatumomab but then you’ll add a ipilimumab to that. So that’s a very interesting study.

Dr. Richard :                     Now Doctor Subklewe, you’ve done a lot of work in immunotherapy as well, in particularly in AML. And we talked about using checkpoint inhibitors to enhance the T-cell ability of T-cells to kill.

Dr. Richard :                     What about being able to present antigens to the immune system in a novel way? You’ve done some very interesting work using did dendritic cells, could you explain that to us briefly?

Dr. Marion:                      Yeah, so I think the challenge in AML is the target antigen that applies to the car and bytes as well as to intercellular presented target antigens. And I think if we look at the bone marrow, and there’s very interesting data on the T-cell compartment, we see we don’t have a very strong T-cell response.

Dr. Marion:                      So I think vaccine strategies and that was what I presented today, are a platform to induce T-cell responses then that might be then augmented by other strategies like checkpoint inhibitors or hypomethylating agents.

Dr. Marion:                      So what we’ve done at our center, we’ve done a dendritic cell trial. So we’ve done a lot of work in optimizing a protocol to generate dendritic cells from mono sites from AML patients, and then upload these with several Leukemia-associated antigens and then do a vaccination strategy in the post-remission setting where we were able to endure strong immune responses.

Dr. Richard :                     How do you decide what antigens to present? I mean, one approach that’s been taken, as you know, is to just take the tumor cell and fuse it with a dendritic cell, which then obviates the need to know anything about the antigens.

Dr. Marion:                      Right. So I think that’s a very difficult question to answer. Nobody has the perfect answer. So we decided to go for defined antigen, WT-1 and [Prame 00:04:37] for two reasons. First of all, they are overexpressed in the majority of AML patients and we also thought if we identify and use defined antigens, it’s a better tool also for immune monitoring so that we actually can detect what we are doing.

Dr. Marion:                      So the challenge is if you use AML [Lised 00:04:55], which is attractive, we are just using antigens. You don’t have to define the detection. And learning from the vaccine strategy is more difficult as you don’t know what you’re actually inducing.

Dr. Richard :                     Well you had a very nice summary using the algorithm, NICE. Could you explain what that meant in terms of augmenting the vaccine strategy?

Dr. Marion:                      Right. So I like to make a case that also in immunotherapy, you are not going with one strategy. Like in conventional chemotherapy and even seven plus three [inaudible 00:05:26] or something. You’re using combinations. So I think also in the immunotherapy field we need to go for immunotherapy combinations.

Dr. Marion:                      So I suggested NICE for using neoepitopes. So these, hopefully neo epitopes, antigens derived preferentially from Oncogenes. So we have less of a problem of antigen escape. We use checkpoint inhibition to augment these induced T-cell responses, then use a vaccine like a dendritic cell vaccine together with hypomethylating agents, which have shown to have a positive influence on the T-cell compartment but also on expression of leukemia-associated antigen and on the MHC 1-2 machinery of the cells.

Dr. Marion:                      So I think NICE, combining these strategies might be a way to go and it’s more complicated than just the vaccine, but I think that’s the way it is.

Dr. Richard :                     So going forward, how much of that those components need to be developed before you’d want to do a randomized trial against the standard of care and these things which is observation?

Dr. Marion:                      Right. So we’re going to initiate a trial together with MD Anderson where we’re going to do a double checkpoint with hypomethylating agent. Different to the trials that are currently already running. We are using a [luxry 00:06:37] antibody, which in our preclinical work has been shown to be highly relevant as a negative immune checkpoint inhibitory.

Dr. Marion:                      And we are currently developing a vaccine strategy that is targeting dendritic cells in-Vivo that are then presenting neoepitopes. So we’re going to do this combination trial and then in the next step, combine it with a vaccine that is linked to a neoepitope.

Dr. Richard :                     Absolutely, good. And, Doctor Gojo, do you want to say something about using the Blinatumomab in the post transplant setting, which is also very interesting? We know that it works as on some MRD erasers shown by Doctor [Gloco 00:07:11], quite elegantly. What about … How would we fit it into the post-transplant setting in ALL?

Dr. Ivana Gojo:                So I think the major problem in post-transplant setting is that when we react to the relapses too early. So the question is when do we, when do we intervene? And I think that worst outcome in post-transplant setting are in patients who relapse early post-transplant and generally once you’re behind one year your chance of durable remission is significantly increased.

Dr. Ivana Gojo:                So because this is leukemia meeting, I think there is a lot of concern about transplant-related mortality. Maybe, I benefited from the fact that I’m am at Hopkinson. We use post-transplant cyclophosphamide platform which is associated, even in large study, with significantly reduced transplant-related mortality. Probably at the rate 15% or less. And in our own institution, rates are probably around 5-7% or less.

Dr. Ivana Gojo:                So that allow us really that we early on can intervene. We don’t have much toxicity, we have reduced intensity conditioning and we can stop immune suppression early.

Dr. Ivana Gojo:                So that kind of shifts the attention from the toxicity of the transplant to the relapse, which actually in all the studies is showing to be the major cause of that. So by post-transplant [inaudible 00:08:25], we hope that early intervention will eventually delay relapse and potentially improve the relapse resurvival in these patients. And then you know, from the science standpoint, I think there’s some elegant data on HLA-down regulation and PD1-up regulation as alternative mechanism, of leukemia relapse.

Dr. Ivana Gojo:                And it is possible that with Blinatumomab, which we are going to examine in correlative studies, that we are actually maybe up regulating some of these HLA through interferon gamma secretion and so on. So study is exciting. We did pilot data and nobody relapsed so far. It’s a short follow up. Toxicity is pretty much none. No GVHD exacerbation.

Dr. Richard :                     That’s exciting. Now just to finish up, I’d like you each think quickly about what you’ll be talking about next year. What will be the key thing that’s going to happen in the next year that’s going to cause you to talk about it?

Dr. Marion:                      So, I think the future’s going to be combining molecular diagnostics and technology with immunotherapy. So, I clearly think teamwork in immunotherapy partners but also in diagnostics, trying to identify maybe more individualized target antigens might be a way to go.

Dr. Marion:                      And then elicit immunotherapy through maybe a more individualized approach depending, for example, on the biomarkers that have been identified for patients maybe with a higher T-cell infiltrate in the bone marrow, looking at the genetics. And then picking the suitable immunotherapy. I don’t know if it’s actually going to be next year but hopefully in two years or so.

Dr. Richard :                     We’re signing up for a busy year.

Dr. Ivana Gojo:                Yeah, I totally agree. I mean I think it would be key, but specifically talking about checkpoint inhibitors and immune intervention, I think it’s key is going to actually two things. One thing that I’m really excited about is one, to really can be the safer based on this t cell infiltrates in the bone marrow or not. Which immune intervention would be more appropriate for individual patient.

Dr. Ivana Gojo:                And then second thing, I think many studies are done, but what I’m really excited also to learn mechanism of resistance and relapses. We already mentioned we have excellent responses in combination with checkpoint inhibitor in Blinatumomab, but yet we do still see extra major relapses. So can that be overcome with dual inhibition?

Dr. Ivana Gojo:                What other intervention we need to do? So I think that’s also the way how we are going to learn more how to implement some of immune intervention upfront. So I’m really excited about that for next year actually.

Dr. Richard :                     It’s very exciting. Well we’ve heard a little about personalized therapy for the mutations that occur in these leukemias. Personalized immunotherapy offers a really special way to perhaps make a big dent in these diseases. So thank you both very much for these excellent comments, and we look forward to a great year of productivity in the lab or in the clinic.