Full Show: New Bi-Specific Antibody Hitting Two Targets in Myeloma, Dirk Hose, MD and Anja Seckinger, MD, University of Heidelberg

1
multiple myeloma

Thanks to our episode sponsor

Dirk Hose, MD
Anja Seckinger, MD
Interview Date: May 24, 2017

Summary
Many myeloma patients are familiar with monoclonal antibodies, or antibodies that target a specific protein on the surface of myeloma cells. Researchers Dr. Dirk Hose and Dr. Anja Seckinger of the University of Heidelberg in Germany are working on a new bi-specific antibody that joins a powerful myeloma-killing T cell with the target BCMA to selectively target myeloma cells. BCMA is found on many myeloma cells and has become a popular target for a variety of immunotherapies. On a single myeloma cell, over 2,000 BCMA molecules can be present. This is an off-the-shelf approach and impacts myeloma regardless of specific myeloma genetic features.  Watch for clinical trials using this new tool in early 2018. 

Dr. Dirk Hose and Dr. Anja Seckinger on Myeloma Crowd Radio

Full Transcript

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host Jenny Ahlstrom. We’d like to thank our episode sponsor, Takeda Oncology, for their support of Myeloma Crowd Radio. We’d like to celebrate today because today is our 100th show. Over the last three years, I’ve been privileged to interview myeloma experts on such a wide variety of topics and from investigators all around the world. I’m thrilled to help share their truly amazing work and we’re very pleased today to have some researches from Germany join us.

Our show today, we know that you’ve heard about monoclonal antibodies which target specific protein on the surface of myeloma cells. This is a very unique approach targeting both approaching on the surface of myeloma cells and at the same time an activation of T cells. We have with us today Dr. Hose and Dr. Seckinger from the University of Heidelberg in Germany so welcome, doctors.

Dr. Hose: Good morning to America from Germany. Of course it’s a very big honor for us that we are with you at your 100th birthday, so I would like also to welcome you on behalf of my second in command, Anja Seckinger.

Dr. Seckinger: Hello, also from my side.

Dr. Hose: And myself, and we are very honored to give this talk and this discussion today because I think it’s a very important point to discuss and interact, also share findings in research and to work together. We as the clinicians and researchers with our patients to finally get a hold on a cure of myeloma so Jenny, thank you for the nice introduction.

Jenny: Oh, well, thank you. Let me introduce you actually both before we get started because we have a lot to talk about. Dr. Dirk Hose is head of Multiple Myeloma Research Laboratory at the University of Heidelberg. He’s a practicing physician at the University of Heidelberg in the Department of Hematology, Oncology, and Rheumatology. He was awarded the Young Investigator Award at the International Myeloma Workshop in Paris and was granted the Ludwig Strauss Habilitation Award for Excellence in Research. I found it most interesting that your doctoral thesis was on the topic of Asymptomatic Multiple Myeloma, Molecular Background of Progression Evolution and Prognosis.

Now, Dr. Anja Seckinger is Deputy Head of the Multiple Myeloma Research Laboratory at the University of Heidelberg in Germany and practices in the Multiple Myeloma section and Department of Internal Medicine of Hematology, Oncology, and Rheumatology. She’s been significantly involved with myeloma research in Germany as well as overseas and has received awards including the Young Investigator Grant at the International Myeloma Workshop in Paris, Abstract Achievement Award at the 2015 ASH Conference and the Best Abstract Award in 2016 at the Annual Meeting of the German, Austrian, and Swiss Association of Hematology and Medical Oncology in Leipzig, Germany.

So doctors, welcome to you both. We’ll probably just start with just a broad overview so I don’t know if you can compare and contrast this with the monoclonal antibodies that patients may already be aware of, but what are these T cell bispecific antibodies and in general, how do they work?

Dr. Hose: Well, Jenny, thank you again, so this is a very interesting question. You have to think of these antibodies as something with two arms which basically couples T cells by binding on a structure which is at the surface of the T cell which is called CD3 and with another arm on another structure which is on the myeloma cell which is called, in this example, BCMA, B-Cell Maturation Antigen.

Basically, the idea is pretty simple. These antibodies have two arms and bring together myeloma cells and T cells and now, T cells are the most active, let’s say, killers in the immune system. They are very active in destroying tumor cells and immune cells but usually, in myeloma patients, they do not fulfill the work because they are hindered. You can somehow compare this to T cells being kind of savage dogs but they have a muzzle and now the T cells brings the myeloma cells and this dog together and then it bites, let’s say the burglar in our example, the myeloma cell. It activates it and then the myeloma cells are killed and so you utilize the most active cell being able to attack myeloma cells which is actually the T cell to attack the myeloma cells and destroy them.

Jenny: I know patients are familiar with daratumumab and elotuzumab which are monoclonal antibodies and they activate the immune system in a certain way but differently than T cells. Can you explain the difference?

Dr. Hose: Yes. With the monoclonal antibody like daratumumab, this antibody only binds to myeloma cells and then in this example are activated and produce a hole in the myeloma cell which have been subsequently killed or other cells which are less specific from the immune system bind to the cell and attack it. T cells are the much more potent variant of this and the difference is that this T cell bispecific antibody has two binding sites so the possibility to simultaneously bind the myeloma cell and the T cells and just bring them together which is the difference in the mechanism of action.

In principle, the molecule itself is quite similar. There are some interesting differences we will talk later on but in principle, the idea behind it is very simple of just grabbing with one hand myeloma cells, and with the other, T cell, then this activates the T cells for killing myeloma cells.

Jenny: That’s a very visual description. We like to picture that in our mind of having T cells go after the myeloma cells and be joined. When you say they’re binding, you’re binding the myeloma cell to the T cell and then how strong is that binding or how does that work?

Dr. Hose: I thought this would be an interesting question because this is something for Anja and I would just pass over.

Dr. Seckinger: This is indeed an interesting question which was actually raised by Dirk because as you might now, he’s not only a physician but also a physicist and well. At one point, he asked, what is the binding strength between a myeloma cell and a T cell? Finally, we applied an interesting method called atomic-force microscopy which is able to measure the binding strength between in this case, myeloma cells and the T cell at a very sensitive level. We did so in the presence of the antibody and without, and what came out is that in case the antibody is present, the binding between a myeloma cell and the T cell is increased by a factor of about 3 to 4.

The interesting thing is that when you look at the data, the units are in picomolar or piconewton and well, at least for us, this was not really quite familiar because it sounds like not that much. We calculated what this means if you have a myeloma cells and interestingly, it’s 200 times the weight of myeloma cell that is necessary to break the binding between the myeloma cells and the T cell. Well, when you think of yourself and somebody is tearing at your arm with 200 times your own body weight, this is then quite strong binding that we see between the myeloma cell and the T cell that is caused by the drug.

Jenny: Yes, very strong binding. Well, let’s start talking about these two different arms because you explained very well how it goes after two different targets at the same time to do the binding process. So first question is, I know some of these other monoclonal antibodies are going after different targets like CD38 or CS1 and this one is going after BCMA. First, why BCMA as a target and then we’ll talk about the T cell arm a little bit.

Dr. Hose: Okay, so BCMA is called B-Cell Maturation Antigen and this basically describes at what time during the development of plasma cells from their early precursors is expressed. It’s expressed very late on plasma cells and it’s expressed on normal plasma cells and also on malignant plasma cells, so myeloma cells. The very important point is that it’s almost exclusively expressed on normal and malignant plasma cells. This is the reason why we choose it. Now, why is this important?

This is important because I gave you the example with this savage dog before and the problem is to control this dog. You do not want in our example this to attack bystanders or in our patients that T cells are forcibly activated and then cause side effects because other cell types might also be bound by these antibodies. So this is the important point, how to control the T cells only to attack the myeloma cells? This is done because BCMA is very specifically expressed on myeloma cells and on normal plasma cells so these are the only cells which are attacked. This is quite a unique pattern because for other antigens like you mentioned the CS1 or CD38, the spectrum of cells expressing it is much more broad and therefore, not only the myeloma cells as target cells are killed but it also causes some of the side effects.

This pattern of expression limited to myeloma cells and normal plasma cells but also, it’s reasonably strongly expressed on the myeloma cells. You can easily think that this is important because when you think of this grabbing actually the myeloma cells with the antibody when there are too few handles on the cell, you might go astray by trying to grab it which is something which is in place for some of the antibodies or mechanism of resistance we might talk about later on. This is the basic choice and we screened a high number of potential targets and this was actually from this expression the best target we have seen or identified. This is the specific arm binding to myeloma cells.

Now for the T cell arm, this binds CD3 and this is an antigen which is expressed on almost all T cells and these T cells are bound, just selected, as binding as described before and brought together to the myeloma cells. By this process of bringing the myeloma cell and the T cell together, the T cell is activated. This activation is also being done during a normal immune reaction. The CD3 is one of the main T cell receptors or structure which helps the cell to communicate from the outside to the inside and to mediate this process of the activation.

Jenny: There are lots of different targets, protein targets on the surface of cells and you hear a lot of different targets in myeloma but it sounds like that CD3 is the primary target for T cells. Is that an accurate way of saying it?

Dr. Hose: Yes. You can just imagine why I chose CD3 because it’s expressed on almost all T cells and so it’s a very good target just to select almost all of the T cells. There are other antigens of T cells like CD4 or CD8 but they are always only expressed through a sub-fraction. If you want to get more or less all the T cells activated, then you have to choose something which is almost on all T cells and it’s as easy as that, that this is the case for CD3.

Jenny: You’re enlisting more T cell help basically by going after CD3. How long does it take for a T cell to kill a myeloma cell?

Dr. Hose: Well, the killing of a myeloma cell takes about six to eight hours. You can calculate this when you just watch in live microscopy. You can just see myeloma cells being killed by T cells and you can then just calculate the time of how long this takes and this is about six to eight hours. Then T cells which are activated like this are kind of serial killers, so they cannot only kill one myeloma cell but they are able to kill one myeloma cell after another and they even proliferate so they even multiply themselves when they are exposed with this antibody so you amplify the reaction against the myeloma cells.

Jenny: Oh, that’s great that it’s not a one to one. It’s just continually expanded. So more questions about the BCMA target. I know there are a lot of myeloma cells. I had a researcher talk about how BCMA levels would go up and down and it would almost correlate with the M spike. I don’t know if that’s accurate or not but he was working on a test to look at that. If there is some BCMA but not a lot on normal cells, how do you avoid binding to normal cells of BCMA versus just myeloma cells of BCMA?

Dr. Hose: The only normal cell which actually expresses BCMA is a normal plasma cell and B cells are likewise targeted by the antibodies so they are also removed. But this can be quite easily coped because what is not removed is the cell type which evolves to this normal plasma cells, so it si the early stages of the plasma cell differentiation. Basically B cells are also involved when you are vaccinated and generate a new immune response and also when you encounter an antigen. For example, like a measles virus and B cells are then able to be differentiated into plasma cells and to again produce the antibodies. You cannot avoid the normal plasma cells being targeted but again, this is not critical because they are reproduced again in the circulation.

This effect of removing normal plasma cells is also something one sees very regularly in myeloma patients because as you know, there is also immune suppression in the myeloma patient. When myeloma cells produce monoclonal antigen, then the normal protective immunoglobulin level also drops and once myeloma is successfully treated, they also come back to normal levels. It’s exactly the same what we think will happen once the myeloma is treated with hopefully the TCB in this case.

Jenny: So your body will regulate that essentially. Now, I know that in patients, there can be different levels of BCMA expression so does this present a challenge for this type of treatment and why do some patients have more BCMA than others?

Dr. Hose: This is just a biological variable like men and women who are taller or less tall, that’s just a physiological difference which appears from individual to individual. What you can say is that the level of BCMA expression in the myeloma cells is almost as high as in the normal plasma cells so there is not huge amount of variation in between. This is just a biological thing, you know. The point is rather, whether this is a problem for treatment because let’s say, those patients who have less high expression on their myeloma cell surface would eventually react less well, but this is not the case. We found that even with very low numbers of BCMA molecules on a myeloma cell, you still have a very good activity of the compound. Just to give you an idea usually on one myeloma cell, there are several thousands of BCMA molecules, about 2,000 in the median and we even saw a killing of myeloma cells when they were only 42 in contrast to several thousand molecules on the surface. It does not pose a clinical problem and the reason for this is that the binding of this BCMA grabbing arm is really strong and is therefore able to grab the myeloma cells also when there’s not so many of these BCMA antigens on the surface of the cell.

Jenny: Well, that’s fantastic that is not an issue, so that’s great. I have a question. Is BCMA expressed in MGUS and smoldering myeloma patients – at earlier stages of myeloma development or at earlier stages of plasma cell or B cell development?

Dr. Hose: Okay, I think Anja will take this question.

Dr. Seckinger: This is again an interesting question also for patients. If you think of maybe treating also patients at earlier stages and in fact, we analyzed about 1,000 CD138 purified plasma cell samples including patients with MGUS but also smoldering myeloma, symptomatic myeloma, and relapsed myeloma and we found BCMA to be expressed in all these stages so there’s no difference in the BCMA expression between the early stages and the late stages.

Jenny: So it potentially could be used earlier, right? If approved?

Dr. Seckinger: Yes, of course.

Jenny: Yes, that would be great.

Dr. Seckinger: This would be an option also for let’s say high risk smoldering myeloma patients. Yes, absolutely.

Jenny: Oh, that’s great. Well, that kind of brings me into another question about different genetics. As a lot of patients know, not all myeloma is the same and every patient will have different genetic features on their myeloma and some will have higher risk features and some will have standard risk features. Does this discriminate between myeloma genetics? Probably not because it’s just going after the BCMA, right? It doesn’t care if you have a deletion 13 or 17 or 11;14 translocation or anything like that?

Dr. Seckinger: Yes. This is indeed the case. So we looked again also for this and looked for different risk stratifications so not only cytogenetics but also gene expression-based risk or proliferation and also tumor mass, for example, in the ISS stage or also the revised ISS. There was again no difference in the BCMA expression between, let’s say, low or standard-risk patients and high-risk patients. It’s again applicable in principle to all patients irrespective of the risk of the myeloma.

Jenny: That’s fantastic. That’s great because then you don’t need a specific or a personalized version, I guess. Tell us a little about what you studied so far. In your study, how did it work for newly diagnosed or relapsed or even heavily pretreated patients? Because it seems like reading your paper that it worked for everybody.

Dr. Hose: Yes. Actually, it’s one of the few examples where myeloma is really easy. This is one of those examples. Indeed, the compound acts in newly diagnosed patients but also in relapsed patients. In the manuscript actually, we have also had one patient who had several rounds of pretreatment who was heavily pretreated and we would not have suspected that the patient’s myeloma cells would also respond, but this was actually the case. They were almost cleared from the sample. This is a specific surprise because usually, we think that there’s an immune defect or suppression of immunity in our myeloma patients because they are prone to infections and so on.

So you would rather think that also the T cells having seen all these pretreatment and the exposure to anti-myeloma drugs and so on are not more that active but it’s not the case. This was very important because as in all clinical trials, the first patient to be treated with the compound will be a relapsed patient. Indeed, that was very good news. We looked in a total of 48 patients and it basically showed activity after 48 hours in over 80% of these patients where you find very significant reduction in some of the samples on myeloma cells were cured in this for myeloma in a relatively short amount of time. We are thinking that indeed, it will work throughout the stages as Anja had put for the genetics also within the patients who are relapsing and also patients at a situation where the treatment options might be very limited.

Jenny: Well, that brings up a couple of questions. I know I’ve heard other doctors talk about T cell exhaustion and where the T cells just get overworked and then they get tired and maybe that’s why the myeloma cells grow out of control in the first place. Does this ever happen with the CD3 T cell or have you seen any of that, or is that totally irrelevant? Is this kind of a dumb question?

Dr. Hose: No. I would not say, because this was what we were also confronted with when we presented the data at the ASH meeting for the example. This T cell exhaustion is of course one of the things you are more or less afraid of when you give T cell bispecific antibodies. There was no indication that the cells could not be killed. Our explanation for this is, if you can think of this dog example, that these anergic or less active T cells are a little bit like dogs who are prevented from biting by having this muzzle on their nose. It really seems that this antibody, by bringing the cells together, allows this to be removed and T cells become again active. The evidence for this is given that many of the patients were heavily pretreated, so it’s not at all a dumb question but it seems that the antibody is clever enough to move away the muzzle from our T cells and they are again, able to attack the myeloma cells.

Jenny: Okay, that’s good news. Now, in your paper, you mentioned that a particular number of myeloma cells can be killed at one time by the CD3 T cells. If there’s a high tumor burden or very fast-growing cells, what does this mean for patients who have a really heavy load of myeloma? Does it have any variety of impact?

Dr. Hose: That is a very interesting question also. I mean you have to take into count what fast growing means and you have to answer this question to set it into perspective. The doubling time of a myeloma cell which is usually not below several weeks and the time for killing of one myeloma cell which is around six to eight hours, so even if myeloma grows fast then still, the killing of the myeloma cells is pretty much faster by a high amount, let’s say ten or 100 times faster compared to how long myeloma cells take to multiply, to divide and proliferate. This means that it should also work in patients who have quite a high tumor load and aggressive myeloma because even then, the doubling time or the time in which the myeloma proliferates is quite lower.

We had seen, however, in our paper in an animal model, (in a mouse carrying a myeloma) that in three of six animals, there was no activity. In three of nine animals, there was no activity or only minor activity but in this experiment, there was used a myeloma cell line which had very much higher proliferation or accumulation rate so only in this setting of a mouse, we were not able to see some of the myelomas being removed and this again, the rate of how these cell lines proliferate is much higher. We don’t see that this might be a problem in the myeloma patients because we also saw, when you look at the number of T cells which are in our specific sample, that this can be quite low compared to the number of myeloma cells. So to summarize this from what we know yet, this should not be a problem.

Jenny: That’s great news. I know that there have been some articles come out recently about daratumumab that sometimes, when patients start getting treated by daratumumab, their cells will start losing their CD38 signature on the surface and so then daratumumab has nothing to go after. Can patients lose the BCMA signature also or is that kind of escape unlikely?

Dr. Hose: Well, that’s a very good question. Basically, there have been publications several years ago showing that there are no viable plasma cells without BCMA so if you remove it in an experiment then also, the plasma cells die. This prompts us to think that it is a very good target because one should think that the myeloma cells cannot down regulate it or completely cut it off so that the grabbing of the TCB goes into void.

But of course, this is something which in the end has to be tested within the clinical trials. Myeloma cells are of course quite clever when it comes to avoiding strategies and this might eventually later on prompt us not to use the compound as a single compound but also in combination with other compounds where we might discuss later on. If the evidence that myeloma cells could lose BCMA in our experiments of what is known little to none but you can of course not exclude it until you have really tested the compound within a clinical trial.

Jenny: Yes, that makes a lot of sense. Let’s talk about how you use it in the clinic or you’ve used it in the clinical trials or how is it administered? It’s an infusion? And then how often and what kind of schedule would you be using? Those types of things.

Dr. Hose: Yes, so we have tested it in the animals giving it IV or subcutaneously. Basically, it has quite a long half-lifetime in the animals of about four days and presumably longer in humans because in animals, it’s always shorter than in humans for these kind of antibodies or TCBs. The idea would be to give it once or twice a week either IV or in the vein or subcutaneously. It would be more or less comparable from the schedule to antibodies like daratumumab are given but the exact way of how it is dosed and how often that it’s given to you to lead to the maximum effect and treatment would of course have to be determined within the clinical trials and the phase one clinical trial. The idea at least is the treatment schedule we used in the animal experiments to that end.

Jenny: I guess you’d have to test that in the clinical trial too, but what would your initial guess be if you had to say how often is it administered? Is it something like daratumumab where you get the first infusion kind of longer and then you get it repeatedly but it kind of spaces out over time or I guess you would just have to see, right?

Dr. Hose: You cannot really answer this because you have of course to balance the convenience to the patient. This is the main reason why you decrease the daratumumab over time and because you think that you come into a situation so you cannot get too much higher when you add another around every week or every two weeks and then it’s also convenience for the patient and for this, it’s really too early to answer. The initial schedule would most likely be twice a week but then everything has to come from how it really works out and also from how the pharmacokinetics are in the patient, meaning how long the compound is stable in the patient, how fast it’s excreted and so on. Most likely, we will start with twice weekly administration.

Jenny: Okay. Let’s talk a little bit about side effects or toxicity, infusion reactions, that kind of thing. I know the CAR T cell work on BCMA and it’s probably the most well-known BCMA type of target in myeloma is that it has a cytokine release. In reading your paper, it sounded like this approach had a really low toxicity profile.

Dr. Hose: Yes, that’s absolutely true. I mean also from the additional data we have obtained up to now, you see no toxicity in terms of organ toxicity or anything like this and the only thing you actually see is some mild cytokine release in the monkeys which is not surprising. You more or less cannot activate T cells without some cytokine release, but in the animals it doesn’t hinder them in any way. Of course, this is something you have to look at in the clinical trials but we of course know how to administer antibodies because they are used for quite some time. I would say that this is not really a problem and definitely not something which would be more of a problem compared to other antibodies like daratumumab.

The really good thing as we see it now is there is a very favorable toxicity profile for the drug which also connects to a question you had early on whether this might — and Anja actually answered that, whether to treat patients also with let’s say asymptomatic myeloma. That of course, if it really will have this toxicity profile, this would be another argument to rather treat the patients early but again, in the end, you only know when you conduct the clinical trial. We have high hopes that it’s not toxic but we have to see in the patient. From the preclinical data in the animals, there’s nothing which prompts us to assume that there’s some toxicity or strong toxicity.

Jenny: That makes sense. When do you see this coming to a phase one clinical trial? How does that work in your regulatory process and when do you estimate that that might happen?

Dr. Hose: Well, actually, that’s quite a set schedule to bring the TCB compound, anti-BCMA into the clinic and this is scheduled for the first quarter of 2018, so this is really quite fast. It always takes some time to develop a compound and then to do all the regulatory things so this is presumably done — it will be done actually I know because I’m a part of this of course within the year and so that we will be able to start hopefully in the first quarter of 2018 with the enrollment of the first test.

Jenny: How many patients will you have in that first trial? This will be obviously a phase 1 trial, right?

Dr. Hose: This still is in the process of being determined with the authorities which are involved quite early because it’s also a novel type of treatment and we would like to go for innovative strategy in performing this trial. Usually the number of patients is anything between 20 and 80 and this has to be determined in detail. We do not yet know because this is still something in the process of discussing because it’s clearly not in a larger trial including several hundreds of patients, but rather to this number.

Jenny: I know in early phase 1 clinical trials, you’re trying to assess dose and safety and things like that and then a phase 2 trial, you’ll look at how effective it is and once you get to phase 3 trials and beyond, then you start thinking about combining it with other therapies. In general, as a myeloma expert and team of experts, you’ve been working on myeloma for a long time, and typically, myeloma therapies are combined. So could you see this being combine with other myeloma therapies? Which ones and how would you see that happening?

Dr. Hose: I think this is the several million dollar question to answer also because all the compounds are quite costly. Besides that, I think we will have to determine what the efficacy of the compound really is. After the phase 2 trial which would be a combined phase 1 and 2 trial, you would think of combining it with compounds which stimulate the immune system like lenalidomide would be an obvious choice. Also, it would be an obvious choice to use daratumumab.

– system glitch –

Dr. Hose: So obviously, I shouldn’t have made the joke about this myeloma treatment cost. I don’t know whether there are some connection, presumably of course not (you know there are all kinds of conspiracies but I think that we can exclude this here. )

No, so coming back to the topic, I think there are some natural combinations and one would be lenalidomide. Something stimulating the immune system would of course make sense. Also, it would be an idea to test the compound together with daratumumab for example because the two compounds have both quite good toxicity profiles and they attack the myeloma cells from different directions. Basically, you would think also of combining it with something like dexamethasone and this again, has to be determined but in the end, we would also think that most likely, it will be part of a combination therapy. If the hope holds true that it’s really having a good efficacy but a low toxicity, then it would be a very good combination partner. But again, you never know until you have tried.

Jenny: Right, and maybe the system just knew how much patients hate dexamethasone and dropped the line when you said it, I don’t know J. I think the idea of daratumumab other immunotherapies would be so exciting and I know that dexamethasone impacts the immune system, kind of suppresses it, so that would be interesting to see a drug like lenalidomide or daratumumab or combine this as a triplet or something, that would be really fascinating to see how that affects the immune system.

Dr. Hose: This is indeed a very interesting question and there’s also the discussion within panels of myeloma experts whether it might be a good idea to add dexamethasone or antibody treatment and also of course specifically to things like T cell bispecific antibodies and there are two effects which go in different directions. One is that dexamethasone is one of the most active agents in killing myeloma cells and the other is that you are always of course afraid that you hinder especially T cell function and which of the two would be more important again would have to be determined in a clinical trial. I would rather put my money on the dexamethasone but as I do not have to take it, I can easily say this.  Again, you would just have to determine it because there’s no way to do this up front without really seeing how it works out in the patients.

Jenny: Well, completely. One thing that I think is really interesting about this is that in a lot of the other immunotherapy approaches that are coming out right now, they are more personalized so let’s say the CAR T cell, you’re modifying a particular patient’s T cells. Is this more of an off the shelf approach that patients could get similar to an off the shelf drug that we have right now in myeloma?

Dr. Hose: Yes, exactly. I mean it’s just like from the way you give it, let’s say like daratumumab or things like lenalidomide. It’s not in any way, patient-specific which is the good point and this is also why we put so much work in checking that it’s really expressed on all the different types — we had the genetics of myeloma and all the different stages and so on so this we’ve shown and so it’s really or is foreseen really to be an off the shelf medication.

Jenny: Right. Can you compare and contrast I guess with other immunology or immunological type of approaches? Like I’ve heard a little bit about the BiTE technology and then we’re actually funding a CAR T cell technology project so I’m quite familiar with that and I know a lot of people are more familiar with that. I know the BiTE is newer but maybe you could kind of put these things in perspective for us.

Dr. Seckinger: I think the main advantage over the BiTE technology is that with our antibody, we have an extended elimination half-life so allowing, as Dirk has pointed out already, a convenient dosing schedule for the BiTE, in contrast, it usually requires a continuous infusion via a pump that is carried by the patients for weeks and which at least to me, is maybe not that convenient so this is I would say the main advantage over the BiTE technology.

I think well, as you have already mentioned for CAR T cells, you need a patient specific generation which is costly and EM801 is as we have already heard about in principle, applicable to all patients and furthermore, the TCB antibody is of course eliminated from circulation within maybe around one to two months compared to described long term persistence of engineer T cells in a case of CAR T cell approaches.

Jenny: Well, it’s so fascinating. I’m really thrilled that you are working on this. It’s such an exciting opportunity I think and I think it’s really genius that you have come up with those and are working on it. I want to open it up just for caller questions. If anyone has a question, they can dial 347-637-2631 and then press 1 on your keypad and we’ll have a caller question. Go ahead with you question.

Caller: Hello, doctors. Thank you for joining the show. I have a quick question. Could US patients join a phase 1 clinical trial if they wanted to?

Dr. Hose: Sorry, I think I didn’t hear it correctly.

Jenny: The question is if you are running a clinical trial in Germany and a US patient wants to join, is that possible?

Dr. Hose: Well, this is in principle possible but we will not only run the trial in Germany but they will also be likely one side in the US being opened. In principle that would be possible but of course it would have to be negotiated with the respective insurance from the American side. From our side, it would not be a problem. We also should mention this that this initiative which is run not only by us but also initially from the colleagues from the EngMab, so the initial company producing it, and it will be also be opened in one side in Spain together with the Bruno Paiva and Jesús San Miguel who is the head of the group there. It will be planned to be at three sites. We also had this in mind when choosing the sites so they will be very likely also open in the US. You don’t have to come to Germany for being recruited for the trial.

Caller: Thank you so much.

Jenny: Okay. Thanks for your question. Let me ask you some more questions about EngMab. Would the clinical trial be a pharma-sponsored clinical trial which would be open in multiple sites like you’re saying in Germany and Spain and then sites in the United States or how does that work and maybe you want to share a little more about that company as well?

Dr. Hose: Okay. This is also an interesting question. This company has started as a three-people company by Professor Klaus Strein and Dr. Minh Diem Vu and just one investor from Switzerland and then they developed their antibody together with us – if I mentioned also with the clinic from professor Jesús San Miguel from Pamplona, Spain and Bruno Paiva and then we presented the data — actually, Anja presented the data at the ASH meeting in 2015.

And then later on, something really strange and funny happened because then, the company was bought by Celgene for actually a huge amount of money so for €600 million which is more or less the same than US dollars. Before you ask me, we did not get anything for this so we still have to continue working which you would anyway do. The trial will be sponsored and run by Celgene but of course, me and also the EngMab team and also the group of Pamplona will be involved on this and for the phase 1-2 trial. The plan at the moment is to have one or two sides at the respective countries but also to start the trial obviously in the United States.

It’s really a quite interesting story almost of course of those who initially started it like a fairy tale but it explains also why we are really proud to be part of this and we’re looking forward to see first patient treated. Y   ou know, this is our ultimate motivation treating patients and seeing that at some time, you might end in a situation which is very difficult for the patient because you do not have any more treatment options and then on the other hand, of course always this kind of research can be really frustrating when you try to develop compounds or work in this and then at one we’ll have a stage that does not work out. In this case, we are really pleased and happy that we will indeed bring it together with the colleagues to the clinical trial.

Jenny: Well, to me, this is a great success story. I interviewed Dr. Craig Crews the inventor of carfilzomib and he talked about this valley of death period that happens between that initial development that you talked about with three-people person company. It’s a challenge because you need the funding in order to get the research resolved in order to look exciting enough to be pursued. This sounds like a terrific opportunity and one that was picked up quite successfully, so that is terrific that you will have the resources that you need to continue to run these clinical trials and take it all the way through the process. This is very exciting.

One thing I want to mention is that this show was founded on the importance of joining clinical trials. Products like this, or research like this, that’s happening is really moving the bar in myeloma therapy and helping you as researchers come to better conclusions more quickly so I would just encourage patients to be aware of trials like these. We will continue to follow your progress and post on this topic when the clinical trial opens so that patients are aware of it and can join it but it’s really critical for patients to think about joining a clinical trial whether they need treatment right now or not.

In my opinion, you really need to plan ahead and be aware of things like this that are happening in the world of myeloma so that if you need to make a decision on your treatment, you can put yourself in a position to join a clinical trial like this.

Dr. Hose: Oh, I think I could not agree more to this. You have to be aware that everything we know now about myeloma and also which drugs work and which actually don’t is based on former patients being included in clinical trial and being willing to help in this, even if several of these patients did not actually by themselves profit eventually from the treatment there. Only by this joined effort mostly between physicians and also patients makes it very important for patients to consider being part of a clinical trial.

So only with this, we will eventually be able to cure myeloma at one time. You might also want to stress that there are very different types of clinical trials, so some trials where the medication is almost approved or which I have at a very late stage, several hundreds or even thousands of patients have already been treated. Then in contrast, it’s really as we have talked today, something which is the first use of a drug in men and of course one has to stress to discuss with your treating physician as a patient what might be the options and then to think about it.

And then this again, we could not agree more. It’s important to think about whether to participate in a clinical trial and to this end, we of course also thank all our patients who are willing to undergo the extra effort. You have to come some extra times to the center where the trial is performed. We really appreciate the effort of all our patients to be willing to undergo this eventually for a scientific question, then another bone marrow aspiration which of course we also know as volunteers for this to be quite a painful procedure. We really appreciate it and I think if we will be able to cure myeloma, we will only be this as a joint team between physicians, researchers, and patients.

Jenny: Well, I believe it is mutually beneficial. I think it’s wonderful when patients decide to do that. I think they should always do that with their own care in mind but I’ve seen research that shows that patients who join clinical trials actually do better do with their overall survival and maybe that’s because they’re followed so carefully. It is extra work and extra effort but you really do benefit from it.

Well, Dr. Hose and Dr. Seckinger, I am so appreciative that you joined us today. What an amazing topic and what exciting research. I’m just thrilled that you’re working on it and I can’t wait to see what happens in early 2018 with this study. Thank you so much for joining us today.

Dr. Hose: Thank you also for this opportunity to discuss about it and also for your effort to really bring this to the patient. I think shows like this bring together patients and US organizations and also us as clinicians and researchers. It’s a wonderful thing to indeed have a discussion in spread. So we thank you and we’ll begin our evening while you are only in the middle of your morning. Perhaps, with a post-show coffee eventually at least this would be what we would do and so we wish you a very good day and all the best from Germany.

Jenny: Well, thank you so much for joining us and to our listeners, thank you for listening to Myeloma Crowd Radio. Tune in next time to learn more about the latest in myeloma research and what it means for you.

Share.

About Author

Jenny A

Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio and the CrowdCare Foundation.

1 Comment

  1. Marge Hallyburton on

    Thank you for focusing on this important breakthrough. We’ll be watching the clinical trials carefully.

Leave A Reply

Please enter the correct captcha code to verify that you are human.