MCRI Full Show: Overcoming Deletion 17p Using a Specifically Targeted Therapy with Dr. Robert Orlowski, MD, PhD, MD Anderson

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Dr. Robert Orlowski, MD, PhDTakeda-5x3-towel-logo
MD Anderson Cancer Center
Interview Date: April 16, 2015

 

Thanks to our episode sponsor, Takeda Oncology

Summary
In our fourth MCRI episode featuring the top 10 proposals for high-risk multiple myeloma, Dr. Robert Orlowski of the MD Anderson Cancer Center teaches us about the aggressive nature of del17p. He explains that when patients have del17p, they lose an important gene (p53) that typically is the “defender of the genome” that keeps genetic mutations in check. P53 is THE most commonly mutated gene across all cancers. When that gene is lost or mutated, cancer cells can grow exponentially because they are no longer properly regulated by this master regulator gene. They have found that when this p53 gene is mutated, a protein called survivin is found in higher quantities. Survivin helps keep myeloma cells alive, which is why traditional chemotherapies don’t work exceptionally well for those with del 17p. By targeting this survivin protein with an inhibitor, or “designer drug” just for this problem, then the traditional drugs like bortezomib and pomalidomide can be used to kill the myeloma cells without resistance issues.  The survivin inhibitor has already been tested in Phase I clinical trials but this is the first time that it is being used with combination therapies in multiple myeloma for a one-two punch at myeloma cells. 

The Myeloma Crowd Radio Show with Dr. Robert Orlowski, MD, PhD

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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, and I’m joined today by some myeloma friends who will help guest co-host asking questions.

We’d like to thank our sponsor for this episode, Takeda Oncology. We are very grateful for their support and helping us with this show. This is the third and a very important series featuring the new Myeloma Crowd Research Initiative. For the first time, patients (including you) are teaming up with myeloma researchers to find and fund the ideas in myeloma that could have the greatest impact for the next generation of myeloma therapies. As a group, we decided to go after high-risk myeloma for patients that have no viable options today either because they have high-risk features or are relapsing or refractory to existing drugs, we need new options. And if we can find solutions for high-risk patients, it’s highly likely that many of the ideas will work in medium or low-risk patients.

Now as it’s pretty common to pick up more aggressive genetic features as myeloma progresses, there are many of us who have become high-risk just with duration and some current medications are ineffective. For this process we ask researchers around the world to submit proposals — we received back 36 high quality letters of intent. That list was then scored by our Scientific Advisory Board. Ten proposals out of those 36 were selected and we are now holding the Myeloma Crowd Radio shows so you can be involved. We want you to understand these proposals so please listen in and ask questions, read the transcript after the show is posted, share it with your friends and your family members so you can help understand how you can receive better care through these new therapies. This is really critical work being done in myeloma.

Now after the full proposals are submitted, the Scientific Advisory Board and the Myeloma Patient Advisory Board will together decide on the limited number to fund through our patient-driven campaigns. And we have started that process; we now have a Donate button on the Myeloma Crowd site where you can donate for the project. Generally the idea of the Myeloma Crowd Research Initiative, when we choose specific proposals, we will of course let you know what those are and we are allowing time for the full proposals on all the shows to be completed before we do that.

Now we are very privileged today to have with us Dr. Robert Orlowski of MD Anderson Cancer Center. Welcome, Dr. Orlowski.

Dr. Orlowski: Thanks very much for having me, Jenny.

Jenny: Okay. We also have Cynthia on the line and Gary, as well as Liz so we will bring you all online. If you can just put your phones on mute unless you have a question, that would be great.

Dr. Orlowski, let me introduce you for a minute. Dr. Orlowski is Professor of Medicine in the Department of Lymphoma and Myeloma with a Florence Maude Thomas Cancer Research Professorship in the same division. He has a dual appointment and is professor in the Department of Experimental Therapeutics.

Dr. Orlowski is the director of the myeloma section in the Department of Lymphoma and Myeloma. He’s a member of the NCI Steering Committee, the Myeloma Tissue Bank Steering Committee, the Computerized Provider Order Entry Steering Committee, the BMT CTN SOSS Myeloma Committee, and American Society for Biochemistry and Molecular Biology. He’s the Chair of SWOG, which is the Southwest Oncology Group, and is on the Editorial Board of Hematology and the Journal of Clinical Oncology.

He has received numerous awards over a number of years including the LLS Scholar in Clinical Research, LLS Man of the Year Award, Emil Frei III Award for Excellence in Translational Research from MD Anderson. He has completed many, many studies and is the recipient of a very attractive SPORE grant from the NIH.

Dr. Orlowski, this topic that you have is quite complicated and it’s specifically for patients with deletion 17. So can you first give us an overview of the biology of what happens when a patient has deletion 17 and they end with myeloma?

Dr. Orlowski: Well, thanks again for having me and I should apologize. My voice will be a little bit off as I’m battling a cold.

But as you pointed out, the initiative that your consortium is now attacking is high-risk myeloma. There are a few different patient subgroups that go into the high-risk area, not every high-risk patient is the same. And what we’ve chosen to do is look at the subgroup that has this abnormality called deletion 17p.

In newly-diagnosed patients, somewhere between 10% and 15% have this deletion of 17p but then as the disease progresses and you get first to the relapsed and then to the refractory setting, the proportion of patients that have this abnormality goes up. Some studies suggest that it can be as high as 30% and a few even suggest that it may be as high as 50% for people in the refractory area. So this really could be a major population of patients with myeloma.

What the deletion of 17p means is that a portion of chromosome 17 on the short arm, which is what the p stands for, is actually deleted. When mapping has been done to try to identify what genes are mutated as a result, the gene that is most commonly found to be lost is the gene called p53. And many of you who are cancer scholars may have heard about p53 before. It’s a very important gene. Some scientists have called it the defender of the genome, if you will.

What it does is when the p53 gene and protein are present and normal, it acts as a proofreader, if you will, so that when your cells divide, they have to make a copy of all the chromosomes which are the instruction manual for the cell about how to do its function.

As you can imagine, occasionally some mistakes are made and if those mistakes were not caught, then the genes in which that mistake is made may not function normally. What p53 does is it helps to scan the genome looking for mistakes. If a mistake is found, what p53 does is, in combination with other proteins, it stops the duplication of the chromosomes, it helps to make a correction in the mistake and then it lets the cell resume going ahead with division.

So again, it’s kind of like a proofreader. If, for some reason, the mistake cannot be corrected, the next thing that p53 does is it causes the cell to die. And that is helpful because you don’t want cells growing in your body that have mistakes or mutations in the instructions about how they’re supposed to work.

P53 turns out to be very commonly mutated in many different cancers and the reason for this is that if you think about what the cancer cell wants to do, it wants to grow very quickly. And therefore any gene or protein which slows that down and that’s part of what p53 does, the cancer cell will grow more quickly if p53 is mutated or deleted. Also, cancer cells have what’s called genomic instability which means that they make more mistakes when they copy the chromosomes and some of those mistakes may actually harm the cancer cell causing it to die but other mistakes may give the cancer cell an advantage and allow it to grow more quickly and more aggressively.

And if p53 which is the proofreader is mutated or deleted, then there is a greater chance that these mutations will occur. So by mutating or deleting p53, the cancer cell has an advantage in survival as well as in growth and we know that patients with this abnormality in their myeloma cells have a worse outcome than people who have a normal p53.

Jenny: So just a question. Is the p53 in deletion 17 patients mutated or deleted completely?

Dr. Orlowski: Well, we all have two copies of each gene because we have two of each chromosome. Usually what happens is that the deletion 17p is on one of the chromosome 17 copies and that’s a deletion. But very often, the other copy of p53 on the other chromosome 17, while it may not be deleted, it’s actually mutated so that both copies are abnormal.

What we know about chemotherapy also, by the way, is that many of the chemotherapy drugs work in part with the help of p53. So if p53 is mutated then many of the chemotherapy drugs that we use don’t work as well against the deletion 17p as they do against normal cells or against cancer cells that have a normal p53.

And that’s kind of the crux of the problem. All of the drugs that we currently use — whether we’re talking about bortezomib or carfilzomib or thalidomide, lenalidomide, pomalidomide, cyclophosphamide, doxorubicin — all of these drugs were developed without an understanding of the effect that deletion 17p and the p53 gene have. And so that’s the core, the real focus of our program.

Cynthia: I have a question too. The 17p you said people have two of those chromosomes because chromosomes come in pairs. Do some high-risk patients have deletion on both chromosomes or is that very unlikely? Is it usually a deletion on one and then mutation on the other?

Dr. Orlowski: That’s a good question. There are a few people that have deletions on both but usually what happens is that one is deleted and either the other copy can be normal or the other copy has a very small mutation which can’t be detected by the routine studies that we do now; it could only be detected by sequencing. That’s the most common way that these two things can occur.

Cynthia: So that’s why some of these patients have initial response to some of these therapies because there’s a little piece of that p53 still left?

Dr. Orlowski: That could be very much the case, yes.

Cynthia: Okay, thanks.

Jenny: So before you continue, I read a Wall Street Journal article that came out just a few days ago, and it was a book review of this woman who wrote a book about p53. The article was basically saying how amazing it was that a genomic book could be like a national bestseller type of book.

So when you say it’s pervasive in other cancers, how pervasive is it and is it a common target that other researchers are also looking at in other cancers?

Dr. Orlowski: Yes, that’s a great question. It turns out that p53 is probably one of the most, if not THE most, mutated gene in cancer. The 10% to 15% that I mentioned in newly-diagnosed myeloma is actually one of the low levels. If you look at solid tumors at diagnosis, sometimes 50% or more of patients have a mutation of the p53 gene. It’s actually a gene that we’ve known about for many decades and there have been wonderful scientists in the field that have studied its function. So that’s one reason why you can actually write a whole book just on the p53 gene itself.

It also is involved in some viral infections. Probably the best example is when women develop cervical cancer which often is because of infection with a high-risk Papilloma Virus, what the virus does is it doesn’t mutate p53, it actually has a gene that comes along with the virus that digests p53 inside the cell. And because the levels of the p53 protein are then very low, it’s the same as if a mutation had occurred. And this gives you an example of how important the gene is because even a virus has figured out a way how to get rid of it and that helps the cells to divide more quickly which gives the virus a survival advantage.

Jenny: Okay, wow. Please continue, we don’t mean to interrupt what you were saying.

Dr. Orlowski: No, my pleasure. It was a great question.

What we’ve done, the way we’ve attacked this problem is there are various myeloma cell lines which ultimately have been derived from patients with myeloma but they’re all different. Some of them have a mutation in p53 and some do not. But if you compare different cell lines from different patients, they have many, many differences. And so focusing just on the p53 as an abnormality isn’t enough to tell you how different they are.

So what we did is we took cells from patients that had a normal p53 and then we did something called genome editing. This is a fancy technique which allows us to put a mutation in any gene in the cell that we would like. And in this case we picked p53. So now what we have are cell lines that are identical except one has a normal p53 and one has a mutant p53. Because they’re identical otherwise, we can study them and see which drugs preferentially kill only the ones with the mutant p53 or the deleted p53 but relatively spare the normal p53.

So I like to call this concept a designer drug because what you’re looking for is a drug that doesn’t work against every myeloma; it would only work against myeloma that has a mutation in p53. And the good part about that is because every other cell in the body of the patient will have a normal p53, you should have what’s called a good therapeutic index. That means high efficacy with very good safety because the target for the drug will only be in the deletion 17p myeloma cells but not in the patient’s normal cells. And that would be I think the best case scenario and we have a number of ways that we’re approaching this in the proposal that we’ve submitted.

Jenny: Okay. Maybe you want to go ahead and explain that proposal and that process.

Dr. Orlowski: Sure. What we’re doing is something called RNA interference. And what this technique uses are so-called shRNAs or short hairpin RNAs. What these molecules do is they can shut down expression of one gene in particular in the 40,000 or so genes that each of our myeloma cells has and each RNA molecule can shut down only one gene. When you put them all together you have a mixture that can shut down in different cells all of the genes that are in the myeloma cell. And then what we then look at is when we compare the cells to the normal p53 and the cells with the mutated p53, which of these RNA molecules are involved in causing death only in the mutated p53 but not in the normal p53.

We actually have already started on this work and we have a list of actually 17 genes. So out of the 40,000 genes in the cell, we’ve narrowed the list down right now to 17 which look most attractive as targets because when you knock them down or inhibit them in the wild type or normal p53, the myeloma cell does not die. But when you inhibit them in the mutant p53, the myeloma cells do die. So that’s sort of our top priority are those 17 genes and what we’re going to do next is study how these genes are involved in causing high-risk and of course hopefully showing that when we do this for example in a mouse model of myeloma that those genes when we inhibit them also cause myeloma cell death in the mouse model.

And so what this will help us with is first of all these shRNAs, or short hairpin RNAs, there are already drug companies that are looking at whether these molecules can by themselves be used as drugs in patients. So if we validate one or more of the 17 genes in our initial list as being good targets, we could theoretically go into the clinic with one of these RNA molecules right away. What we’re also hoping to do is identify either immune approaches meaning things like antibodies or there’s a lot of excitement about these CAR T cells which are cells that you can train to attack only a certain target. These immune therapy approaches may be applicable because these same genes could be targeted with immune treatments and we’re also going to look at whether there are drugs or small molecules that may be able to target these same genes.

So really, as I mentioned earlier, this is a way to try to develop a designer drug which would be active specifically against deletion 17p myeloma and that could be used either by itself or maybe in combination. For example, one of the targets that we’re interested in, there’s already a drug available for it and we’ve done some initial studies in combination with both bortezomib as well as in combination with pomalidomide. And what we’ve shown is that when you combine either bortezomib or pomalidomide with a drug that targets one of these 17 genes of interest, we’re able to kill myeloma cells with the deletion of 17p more than the wild type or normal p53. Whereas the pomalidomide or bortezomib alone have roughly equal effect or in some cases actually have less of an effect on the mutant p53.

So it’s a way to focus in on the bad actors, if you will, and kill off these aggressive versions of myeloma.

Jenny: Well, let me ask you a clarifying question. So you have taken these 40,000 genes and lowered it down to 17 as potential targets. When you say potential targets, are these like partner genes or companion genes or something that affect the p53 gene? And then you’re finding molecules that will manipulate those 17 genes potentially? Is that how you would describe it or is there another way describing that?

Dr. Orlowski: That’s actually a very good description. What we are using as our hypothesis is that when you mutate p53, the myeloma cells become dependent for survival on one or more genes that are not important when p53 is wild type (normal). One of the genes that we’ve identified is a cell survival gene which is increased in expression when p53 is mutated. And therefore the myeloma cells with the mutant p53 depend for their survival more on this gene than if p53 is normal. And when you block the gene with this drug, they die more rapidly than do the normal p53 cells.

And so those are one of the ways that we’re looking at and I think your description is spot on.

Jenny: So is this the Survivin that we read about in the proposal?

Dr. Orlowski: Correct.

Jenny: Okay. Can you explain exactly what that does? I guess you just did but if you have any more things to elaborate on that gene.

Dr. Orlowski: Sure. Well, Survivin as it sounds like is a gene which is involved in survival of cancer cells in general but when there is a normal p53 present, Survivin levels are very low. What we found is that when you mutate or delete p53, Survivin levels go up. One of the effects of Survivin is that it reduces the amount of cell death that is caused when these myeloma cells are treated with chemotherapy.

So if we inhibit Survivin, chemotherapy drugs work better and this is especially true in the mutant or deleted p53. And there’s actually already a drug that inhibits Survivin which has been in clinical trials but it hasn’t been looked at specifically in combination with Bortezomib or with pomalidomide in mutated p53 myeloma. So if these studies continue to be positive, our proposal would be to do a trial in myeloma patients with deletion of 17p where we would combine this survivin inhibitor with Bortezomib or pomalidomide or maybe put all three together and really do a number on these deletion 17p myeloma cells.

Jenny: Well, it sounds like the drugs, because of how you described it, they just don’t work alone for that deletion and you described in a very clear way why. I’ve never understood that before; I don’t think many of us have. I think it’s fabulous especially since a lot of work has been done already on p53 to take advantage of that work, especially with an existing drug. That’s remarkable to already have something you can test.

Dr. Orlowski: Exactly. And what we’re hoping with the funding that we would get is to both prove it further in the laboratory and also to be able to convince the pharma companies that are involved that this is a good way to go forward.

Another option would be of course to try to do this through a cooperative group setting, for example through SWOG as you mentioned and also it may be interesting to try to do this through the Multiple Myeloma Research Consortium.

Jenny: Is the Survivin gene something that can be targeted through these CAR T cells like you mentioned or is that completely separate? This drug target that they’ve created is just something completely different?

Dr. Orlowski: Actually what we’re doing is we’re working with Laurence Cooper here at MD Anderson. He is one of the world experts on CAR T cells and he has developed CAR T cells that recognize Survivin. So we would be able to theoretically target this both with a drug and possibly also with an immune therapy.

So we’re looking at both because we don’t want to leave any stone unturned.

Jenny: Well, that’s a great way to do it. Okay, that was one of Jack’s questions. Cynthia and Gary and Liz, do you have other questions? I know you gave me a whole list of questions.

Cynthia: Well, I have some questions. Some were answered in my list and I have a couple of others that as he was talking changed my mind.

Jenny: Go ahead, Cynthia.

Cynthia: Well, my first question was that Survivin gene. Is that only expressed on the myeloma cells of deletion of p17 or is it expressed on other myeloma types of cells?

Dr. Orlowski: There are some levels of Survivin in other myeloma cells and there is some expression of Survivin in normal cells as well. But the level in these deletion 17p cells is much higher and as a result, they are much more susceptible to drugs that would target it. Plus if the expression of the gene is much higher and the protein is present at a higher level, then we can attack it with immune therapies better because the immune therapies are going to work best against cells that have high levels of the target.

Cynthia: Okay, that sounds great. The other question I think you answered back when you were talking about moving on in combination therapy with just the Survivin target would stop is that most people that has deletion of 17p chromosomes also have different other mutation. So just to give a drug that goes against the Survivin might not be enough, you must need to use it in combination with Bortezomib or pomalidomide or some other drug. Is that correct?

Dr. Orlowski: Well, what we’ve shown is that the Survivin inhibitor drug by itself works against myeloma cells with deletion 17p; it also works to some extent against the normal p53 myeloma cells, just not as well. So we would predict that if you take let’s say bortezomib and treat a patient that has a mixture where some of the myeloma cells have normal p53 and some have mutated p53, bortezomib would work well against both but would tend to work better against the wild type cells (normal cells) and therefore the mutant cells might have a better chance of surviving.

Whereas if we go in with a combination, the combination would still work against both but if anything, it would do a better job against the deletion 17p cells. And because those are the ones that are more aggressive, those are the ones that you would prefer to get rid of. But it could work against both.

Cynthia: Okay, great. Just another question is, I don’t think it’s part of your proposal but just in the back of my mind. Does anyone know why p53 gets deleted and is there a way to insert an artificial p53 into your body? Is there a mechanism that happens or you don’t know that yet?

Dr. Orlowski: Well, that’s a great question; you’re talking about gene therapy almost. There are people that are studying that. And you’re right, that if we had a way that we could put back a normal p53 into the myeloma cells that have a mutation, then they would behave better if you will and they would be more likely to die.

The problem is of course finding some way to do that only to the myeloma cells but not have the p53 get into normal cells. The reason for that is if you express very high levels of p53 even in a normal cell, you will cause that cell to die. And right now, we don’t have a good way of delivering a gene just to myeloma cells without having any effect on the normal cells.

Cynthia: Thank you. Thank you very much.

Dr. Orlowski: That’s a great question.

Jenny: Thank you so much. Gary, I know you have some questions. Would you like to ask them now?

Gary: Yeah, certainly. Dr. Orlowski, thank you again for all you do for the myeloma patient community. Your work is outstanding and this is just an example of it.

You say that 10% to 15% of patients have this 17p deletion?

Dr. Orlowski: At the time of diagnosis, correct.

Gary: At the time of diagnosis, okay. It was my understanding that 85% of people were low-risk so that would mean 15% of people are high-risk. I guess I’m a little confused. Not all people who are high-risk has 17p deletion or do they in combination with other high-risk features? So I’m a little confused with that unless there’s more high-risk disease.

Dr. Orlowski: Thank you for your very kind words. That is something I should’ve said. There are different definitions of high-risks but in general, the feeling is that somewhere between 15% and 20% of myeloma patients fall into this high-risk category. And deletion of 17p is one of the most common types and that’s one of the reasons that we are going after it because there are others.

For example, there are translocations where there is exchange between two different chromosomes that lead to high-risk. One is a translocation between chromosomes 14 and 16, another one is between chromosomes 14 and 20 and those abnormalities are present in about 1% or 2% of patients. So those are interesting as well and similar studies to what were; doing could be looked at in that kind of a background. But what we wanted to do is go after one of the most frequent abnormalities and if this approach works there, then we could probably take it in the other less common abnormalities as well. We just don’t have enough people in the laboratory to be able to do all of these at once. I would love to do that.

Gary: If it’s 15% and 2% are other things, that means 13% or so or probably 85% of the high-risk patients would be affected by your work. Now that’s surprising to me but that’s new information for me so thank you very much for helping with my education.

And I guess my other point would be and you say that I guess you say there’s other work to be done. But if this works on 17p, might it not work on the other high-risk features — the 1% or the other 2% of the total patients?

Dr. Orlowski: It might work and we would certainly be happy to test it. But our thought would be that if you have a different mutation, then those cells depend for their growth and survival on a different set of genes and therefore it might take a different drug combination to rationally kill those cells.

Gary: So now they’re not Survivin…? You don’t know if they also depend on Survivin or survival?

Dr. Orlowski: They probably do express Survivin but the attractive part about the deletion 17p is that the Survivin is at a higher level and therefore the cells are more dependent on it for their survival. Whereas in these other abnormalities our prediction would be that the Survivin levels would be no different than any other plasma cells and therefore there may be no benefit to adding an inhibitor of the Survivin protein.

Gary: Okay, although there might be the same benefit meaning —

Dr. Orlowski: Oh, sure!

Gary: — but you don’t know, I guess.

Dr. Orlowski: That’s right, we don’t know and in science we always like to be a little bit cautious.

Gary: Another thing I don’t know, the use of YM155 is the Survivin inhibitor, correct?

Dr. Orlowski: Yes.

Gary: Has that been used in other cancers with the Survivin target? And if so, what were the results?

Dr. Orlowski: There have been clinical trials with this drug and fortunately what they found is that the drug was well-tolerated but the efficacy against other cancers has not been as well determined. And one of the reasons we think that that may be the case is that you need these other combination drugs. As you know, most chemotherapy drugs, including in myeloma have a modest or very low level of activity by themselves and you have to come in with a combination.

When the Survivin inhibitor’s been looked at before in clinical trials, it was not targeted specifically to people with deletion 17p and it was not used in combination with drugs like in this case, bortezomib or pomalidomide. And so that’s why we think that we would have a better shot if we pick the right people to be treated.

Gary: Okay. In your proposal, you said there was an encouraging data in vitro for YM155 I guess against this 17p deletion. How do you determine these encouraging results? What is the measure of success? Is it like 100% kill, 60% kill of the myeloma cells in vitro or in vivo? How do you determine success?

Dr. Orlowski: What we do is we have measures that we look at to differentiate between cells that are alive and cells that are dead. So what we found is that when we expose the wild type of the normal p53 cells versus the mutated p53 cells to the Survivin inhibitor, we got more death in the mutated p53 cells. And when we did the combination of the inhibitor with either bortezomib or with pomalidomide, first of all the combination was more active than either of the single agent drugs by themselves and this tendency for the mutant cells to die more quickly was also seen.

So that’s what we were considering to be encouraging. Of course it needs to be verified when we do this in animal models and also we need to do this in patient samples not just in cell lines that were derived from patients in some cases, 10, 15 years ago. So we do need to do additional work, these were just preliminary data but at least they were encouraging preliminary data.

Gary: When you say that, is there a measure like 100% of the cells were killed when you used the combination therapy or 60% of the myeloma cells?

Dr. Orlowski: We do measure it compared to just treatment with a blank and the blank is set at 100% survival and then we measure survival in the other conditions compared to that.

At some of the conditions that we tested, we were able to wipe out 100% of the myeloma cells in the dish. But we have to be a little bit cautious with that. Certainly it can’t get any better than 100% but myeloma cells in a dish are usually more sensitive to chemotherapy unfortunately than myeloma cells in patients. So we would still have to make sure that we could see similar levels of killing first in a usually mouse model because of course we want to make sure that the level of drug that we’re using is not just effective against the myeloma but that it relatively spares normal tissues.

Gary: Oh, I’d say 100% is pretty encouraging.

Dr. Orlowski: I would agree.

Gary: I also see that you looked at the potential of using Survivin-specific CAR T cells. And I assume that what you’re trying to do then is to have the CAR T cells focus on or go after the Survivin signature —

Dr. Orlowski: Correct.

Gary: How does this CAR T cell approach that you’re looking at, how does that compare to the work that we recently heard about from Dr. Hoffmeister in this T cell research?

Jenny: And that was targeting CS1.

Dr. Orlowski: Correct. So CAR T cells, this is an approach whereby you can take out T cells from the blood of a patient, you can train them in the laboratory to recognize any target that you’re interested in and then reinfuse them back into the same patient except now they’re much more targeted and in some cases much more aggressive in going after the cancer cells like an antibody.

For example now in myeloma, we have Elotuzumab coming hopefully soon, which is an antibody against CS1 or it’s now called SLAMF7. And we have Daratumumab which is also an antibody but it recognizes a different target called CD38. And both of the antibodies so far have looked very exciting and we’re very hopeful that both of them will be approved and that both will have a role to play in myeloma therapy.

So it’s the same thing with the CAR T cells. You can direct them against different targets and it may be that in the future, what we’ll be doing is a combination of CAR T cells against more than one target. Because just like with chemotherapy, when you combine different drugs, you get a better effect, I think the same thing will be true with these CAR T cells. Because what we know so far for example from some of the studies that Carl June has done at the University of Pennsylvania – he’s one of the leaders in the CAR T cell field. What they’ve seen is that when they’ve treated leukemia patients with a CAR T cell against CD19 which is a protein on the surface of lymphoma cells, sometimes those patients do relapse and then their cancer cells do not express CD19 anymore. So the way they become resistant to the CAR T cell is by removing the target for the T cell.

And the same may be true if we use a CAR T cell against CS1. You may relapse with myeloma that just doesn’t express that target anymore. But if you go after the myeloma cells with CAR T cells against several targets at once, it will be more difficult for the myeloma cells to get rid of several of these target proteins.

Gary: So what are the targets that your CAR T cells will be going after?

Dr. Orlowski: Well, the CAR T cells in this project would be going after Survivin which is a different protein than CS1. In the future it may be that we would combine the two. We could combine the CS1 CAR with the Survivin CAR. But for right now we’re trying them one at a time because if they don’t work by themselves, then the chances that they’ll work in combination are decreased.

Gary: Okay. I think you’ve answered my other question and that was the Survivin. I was wondering if it was perhaps the answer, THE answer. Apparently it’s the answer for 17p but it’s certainly not the Holy Grail for all myeloma, even low-risk.

Dr. Orlowski: Well, we have to try against different types of myeloma and see if it does work against others. But frankly, if this is something that turns out to be effective for deletion 17p and nothing else, we’ll be very happy with that outcome because it will help a lot of patients.

Gar: Oh, absolutely! Well, it looks like 85% of high-risk patients in that area based on your information. So thank you so much for your work, Doctor. Again, excellent research. Thank you.

Dr. Orlowski: Thank you.

Gary: That’s it for me.

Jenny: Now we would like to open it up to caller questions. So if you have a question for Dr. Orlowski, you can call 347-637-2631.

Lizzy: Hi! This is Lizzy and I do have a question about the study. So provided this study continues to go forward, at what point will you be ready to start recruiting patients and seeing some measurable results?

Dr. Orlowski: Well, thanks for your question, Lizzy. I think that if the study continues to show encouraging data, I would say that within one year, we would have done enough in the laboratory to be able to then go into the clinic.

The advantage here is that there is already a drug that goes after this target, we just feel that it hasn’t been used in the right patient population and we could. Therefore now this may be a little optimistic. We sometimes go more slowly than we would like, but ideally we could be ready to go to the clinic in a year.

Lizzy: Wow! And how intensive would that be for patients, I mean as far as travel? Would they potentially need to travel and what kind of time commitment would be required?

Dr. Orlowski: Yes, definitely. It depends a little bit on which mechanism we use for the study. If we do it just at MD Anderson then people would need to travel here. But as I mentioned earlier, we may be able to do it through some of the networks. For example SWOG which used to be called Southwest Oncology Group, has member-institutions all over the country and if we open a trial through SWOG, every center that’s part of SWOG would have the option to open it.

And another option would be the Multiple Myeloma Research Consortium. They’re not quite as large as SWOG in terms of number of sites but they also cover many sites across the country. And so if we had that available through there, patients would not necessarily need to schlep down to Houston. We’re not yet at the point where we can define exactly what the best schedule is in terms of how often the treatment would need to occur so in terms of time commitment, that’s not something I can yet answer for you.

Lizzy: Okay, very good. Sounds exciting.

Dr. Orlowski: Thank you.

Jenny: Okay, thank you so much. Cynthia and Gary, do you have any additional questions? I have a final question.

Cynthia: I have, just as we were talking, a couple questions. This YM155 is the anti-Survivin therapy. Now what is it? Is it a pill, is it infusion, is it an injection? Do we know that yet? Has it been materialized i guess? I don’t know what the word is.

Jenny: But it’s in clinical trial, right?

Dr. Orlowski: Yes. From the studies where this drug has been used so far, it is an IV and it has been given as a continuous infusion over one week. Now we can look at other schedules but that was one of the most commonly used schedules.

As you know, the more we learn about a drug, the better we are able to use it and one option could be that if in the future we find that the drug is effective, we could try to give it for example as a subcutaneous injection which was what was done with bortezomib. At the beginning we used to give it IV. Later on, more recently, we’ve been doing it almost exclusively as an injection under the skin.

So the first step is usually to prove that there is a benefit because if there is then you have a lot of reasons to look at more convenient ways to do it.

Cynthia: Sounds good. The YM155, has that been used in humans and different cancer types?

Dr. Orlowski: Yes, it has. And it was used as I mentioned as a one week IV infusion and it’s also been looked at in combination with other drugs but it hasn’t been used in combination with drugs like bortezomib or pomalidomide against myeloma which is where I think the opportunity lies.

Cynthia: Great. So the efficacy was not there in the other cancer, so what were the side effects?

Dr. Orlowski: The side effects were felt to be relatively minor. So I’m actually right now looking at a study which was just recently published which was looking at breast cancer patients where the study was given in combination with a drug that’s called Docetaxel which is one of the taxanes. And the main side effects that were seen first of all there was neutropenia which is a decrease in the white blood cell count. There was hair loss, there was fatigue, and there was nausea. But this was actually a randomized study where patients got either Docetaxel alone of the combination and actually the combination was a little bit better tolerated. So that suggested a lot of the side effects were from the standard chemotherapy drug.

Cynthia: That sounds exciting. And this is why YM155 is an immune therapy?

Dr. Orlowski: I wouldn’t call this an immune therapy. This is a small molecule, essentially a drug which reduces the level of expression of Survivin in myeloma cells. And it does that both by reducing the gene expression as well as the protein expression.

So it’s not really an immune therapy like an antibody. The immune therapy we’re considering is that CAR T cell; that would be considered an immune therapy.

Cynthia: Okay. So if my understanding is correct, with the CAR T cells, you have an immune therapy, once it’s in your body, it will stay there hopefully forever and ever and continue to do its job. Whereas this small molecule you would have to continually use this Survivin anti-therapy and so all the myeloma’s gone. Is that correct?

Dr. Orlowski: Well, if you use a drug that works well enough and kills off, let’s say we can be optimistic, if it kills 100% of the deletion 17 p cells, then you could stop using it and not have to continue it forever.

In terms of the CAR T cells, different types of these CAR T cells persist in the patient for a different period of time. Sometimes they can be present for months but other times they are present for a shorter period of time and there are cases in which they may need to be reinfused. So it’s not necessarily the case that one infusion of the cells is going to be enough to keep them around in your body for the rest of your life.

Cynthia: Okay, great! This works is so exciting, thanks so much.

Dr. Orlowski: Thank you.

Jenny: Well, in myeloma, it sounds like the wily nature of myeloma will prevent it from ever being a single bullet type therapy. And we love the approach that you have of finding existing drugs that’s already through early clinical trials and some of the safety to be able to use it and apply it to something and combine it with other therapies. It’s terrific.

My last question is can you give us an outline — you did a little bit with with Lizzy’s questions, but can you give us the milestone steps and then the budget requirements that are necessary for the proposal that you have in place?

Dr. Orlowski: Yes, definitely.

What we would look to do is that in the first year, we would continue studies with the 17 genes that I mentioned earlier because we want to try to narrow that down further. We do have Survivin as one target but it may be that one of the 17 that I mentioned is an even better target and what we would like is of course to be working with what we feel is the absolute best target.

So we’re going to look at these other 17 genes as well. During that period we’re going to continue to do the studies with the Survivin inhibitor to make sure that we can verify that this preferential killing of deletion 17p myeloma cells occurs not just in the dish with myeloma cell lines but in animal models and in samples from patients. And probably if we can show that over the first six months, in the second six months of the first year, we would work on designing the clinical trial with the combination of either bortezomib or pomalidomide or both and that way we would be in a position to be able to get into the clinic during the second year.

The funding initially would be for one full time post-doctoral fellow who would work on this project and generally when you include salary as well as fringe benefits, that comes out to somewhere in the $70,000 to $80,000 range. Some of the money would go for supplies that would include the chemicals that we use including the bortezomib, the pomalidomide, the YM155. It would include some of the assays that we’re doing looking for the cell death of myeloma cells. It would look at using at the mice as models of myeloma and also some of the flow cytometry and other imaging techniques that would be used and that’s where most of the funding that would be awarded would probably go on the first year.

And then with subsequent years, in addition to moving the clinical trial forward, possibly with the Survivin inhibitor, we would again look at some of these other 17 genes because it could be that what we would want to do is go into, as we’ve talked about earlier, with a combination because maybe two drugs targeting deletion 17p myeloma preferentially would be better than just one drug and give us a better shot of killing those particular cells.

Jenny: Okay, perfect. Well, we are so grateful that you’re working on this. I know the patient community that has deletion 17p is looking for new options because it’s a very aggressive and scary feature and we want to find solutions for these patients.

Dr. Orlowski: Oh, I can certainly understand that and I know that our lab and I know that other people are interested in this area as well. And as I mentioned, we’re collaborating with a couple of groups here at MD Anderson because a team approach is really the best way to try to push things forward.

Jenny: Oh, absolutely. Well, thank you so much for all you do and thank you for participating today.

Dr. Orlowski: My pleasure. Thanks again for having me.

Jenny: Thank you so much for listening to Myeloma Crowd Radio and the new Myeloma Crowd Research Initiative series. We know that patients can help support the discovery of a cure and we encourage you to become involved.

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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. John W Post Jr on

    Thank you so much. I was diagnosed in 2007, became active in 2008, had PBST at Dana-Farber in 2009, and was on rev. maintenance for 3 years when the myeloma showed up again. I continued maintenance for another year and then began Velcade in January2013 for several months. Due to neuropathy it was discontinued and I was off chemo for the summer of 2013. Starting in Sept. 2013 I had 16 mos. of kyprolis (dex. was always present too 🙂 20 mg. a week. When the m-spike reached 1.6 in Dec. 2014, Dr. Shain at Moffitt took me off kyprolis and in January 2015 when the m-spike was 2.3 he put me on pomalyst 3 mg. days 1-21 (weak kidneys) plus dex. 20 mg. 1 x a week plus Cytoxan 30 mg. (days 1,8,15). The m-spike has decreased to .9 in Apr. when we saw dr. Shain at Moffitt. I’d definitely be interested in your trials since the BM biopsy I had at Moffitt in Dec. showed 17p deletion and TP53. I’d be happy to talk with you or to have you see Dr. Shain’s records.
    John W. Post Jr. Bradenton, FL and Holland, MI

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