Thanks to our show sponsor, Takeda Oncology
In our first MCRI episode featuring the top 10 proposals for high-risk multiple myeloma, Dr. Craig Hofmeister shares his work to use the hot-topic CAR T cell approach to target a common myeloma protein, CS1. He describes that the discovery of elotuzumab helped determine that CS1 was an effective target. For this approach, CAR T cells are withdrawn from the patient, re-engineered to target the CS1 protein and then are placed back into the patient’s system. Once inside, the CAR T cells replicate, target the cells that express that CS1 protein and essentially blow themselves up. He notes that CS1 was a target that was found on myeloma cells but not on many other cells in the body, making it an attractive target. It is a one-time therapy that is appropriate not only for patients with high-risk myeloma but all types of myeloma regardless of genetic features. In time, it could also be used as a preventative approach for smoldering patients. He addresses the promise of this up and coming approach and also addresses the potential safety issues of this type of therapy. This approach is not far from in-human clinical trials.
The Myeloma Crowd Radio Show with Dr. Craig Hofmeister, MD
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers.
I’m your host, Jenny Ahlstrom. I’m joined today by other patients including Gary Peterson, Cynthia Chmielewski, and Pat Killingsworth as co-hosts. We would like to thank our sponsor for this episode, Takeda Oncology. They have been extremely supportive in the work we’ve been doing and we’re very grateful for their efforts and their support. Now, this show is a very first in a very important series for our new research initiative called the Myeloma Crowd Research Initiative. So because this is so new, I would like to give you a little history before we get started.
The New Myeloma Crowd Research Initiative
We feel that progress in myeloma is clearly being made, but that new and additional approaches are needed because we don’t have a cure yet. We decided to jump in to fill in the gaps to find and fund excellent discoveries to ultimately find a cure for myeloma. We believe very strongly that patients need to have a seat at the table to help support new discoveries. So for the very first time, patients are joined together with myeloma specialists to help find new ideas through crowdsourcing that could have the greatest impact for patients.
What does this mean and how does it work? First, we created a patient advisory board that includes Pat, Gary, Cynthia, Liz, and myself. We also then invited an impressive group to participate as our scientific research advisory board. That includes Dr. Rafael Fonseca of the Mayo Clinic in Scottsdale, Dr. Irene Ghobrial of Dana Farber, Dr. Noopur Raje at Mass General, Dr. Guido Tricot at the University of Iowa, Dr. Robert Orlowski at MD Anderson and Dr. Ola Landgren from Memorial Sloan Kettering Cancer Center. Joining with us also are another patient, Lizzy Smith and Dr. Mike Thompson from the Medical College of Wisconsin.
Stage I: Call for Letters of Intent
As a group, we determined that the biggest need in myeloma today is high-risk because current therapies don’t help these patients for very long, and this patient group is truly desperate for new treatments. We also chose high-risk because at the end stages when you’re relapsed and refractory to things, we are all high-risk at that time because today, there’s no cure. So in February, we opened it up to receive letters of intent or summaries of investigators’ proposals and we received an amazing 36 proposals that were specific for high-risk patients, which is completely remarkable.
Stage II: Initial Scoring, Top 10 Selection
Now, in March, this last month, the Scientific Advisory Board scored the proposals and based on the scoring, they determined a top ten out of that group of 36.
Stage III: Myeloma Crowd Radio Shows and Full Proposals
In this upcoming Myeloma Crowd Research Initiative or MCRI series, we will be interviewing the top ten to learn more about their research and we would very much like you to be involved and aware of the projects so you can help select the research that would lead to a cure. Once we have the full transcripts back from the show, which is about four days from now, we encourage you to educate yourselves about it, like it on Facebook, and share it with your myeloma friends.
Stage IV: Selection of Limited Number of Proposals for Patient-Driven Funding Initiative
After we hear from the ten investigators, both the scientific and patient force will come together to select a limited number of proposals that we will then create campaigns for, and we’ve had many comments about how excellent the research was even with all 36 proposals, so this is not an easy task to narrow the field because all the research is just excellent, but again, we need your help.
We would like to kick off this series by welcoming Dr. Craig Hofmeister of Ohio State University. We are just very privileged to have you with us today, so welcome, Dr. Hofmeister.
Dr. Hofmeister: Thank you so much, Jenny.
Jenny: Sorry I had to give the intro, but I think patients need to know where we’re headed, so let me give a little introduction for you.
Dr. Craig Hofmeister is Associate Professor of Medicine at Ohio State University and is Lead of the Section of Plasma Cell Dyscrasias? In addition to his research interests, he is an attending physician in the Lymphoma, Myeloma and Bone Marrow Transplant Service. He is an ad-hoc reviewer of publications including Blood, Journal of Clinical Oncology, Clinical Cancer Research, and the British Journal of Haematology, in addition to others. He is the recipient of the Imagine MMORE Award, the Business First’s Forty Under 40 Award in Ohio, and The Ohio State University College of Medicine.
We would like to open it up — let me add a few more people here. Welcome, Gary and welcome, Cynthia!
Gary: Well, thank you, Jenny.
Cynthia: Hi, everyone! I’m here.
Jenny: Okay. Great. Dr. Hofmeister, maybe you’d like to start. We did a show, but it was quite a while ago, on CAR T cells and how they work. Maybe you want to give us an introduction of your research first and just describe what it is and how it works and why you began researching this in the first place.
Dr. Hofmeister: Well, CAR T cells are a little bit complicated when you think about it. It’s really fantastic work from the NIH with Steven Rosenberg and University of Pennsylvania with Carl June; just fantastic minds that have been working on chimeric antigen receptor T cells, so-called CAR Ts. They’ve been doing this for years, literally, essentially decades.
What got us involved, like many people, is that this area of research essentially got hot when their iterative improvements in the chimeric antigen receptor or CAR technology improved to a point that they published, (and it was all over the New York Times and a lot of lay literature about some of their great success in blood cancers).
The idea behind CARs — and that’s chimeric antigen receptors — is relatively simple. The goal is to take a white cell out of the patient’s body and this really forms the primary component of the patient’s immune system that floats in their blood and their bone marrow. These cells really go between both, but these cells are essentially taken out of the patient’s blood and put into a bag and preserved, and then they’re forced to express a protein or a receptor on their cell surface.
What that means is you’re taking a bunch of normal white cells from a patient that are preserved in a bag, you grow them up in culture, and then you force them to put something on their outer surface of the cell. Now, you can do that by any number of ways. What you’re trying to do is change the genetic instructions, changing the DNA of these white cells so that their normal machinery makes a protein which floats up to the cell surface, and this protein really is a targeting mechanism.
You can make it target whatever you want, but you need to have a specific target to make these cells, these T cells, attack any cell that has this target on its surface. Essentially, you’re taking the patient’s white cells or any white cells and targeting a protein on the cell surface for a cancer cell.
Now, there are lots of targets in my disease, which is multiple myeloma that I focus on, but this technology is being used in a variety of blood cancers and solid tumors. Glioblastoma and sarcoma were the two things that I saw in the last week come across my Twitter account, so this is really a hot area of research for most human cancers. Our interest is trying to find specific antigens, specific proteins on the cell surface of myeloma cells that we can use to target — genetically modify essentially — a patient’s white cells to go after these targets. Now, the one we have farthest along in development is called CS1.
CS1 is a target that’s been around for quite a bit in myeloma. It’s expressed on most plasma cells and it’s actually the target for a monoclonal antibody called elotuzumab, which is in Phase III testing right now. Now, I don’t know the results for those Phase III tests, but they might lead to approval of elotuzumab, which is a monoclonal antibody targeting CS1.
Well, our area of research is to make a CS1 CAR T cell, so take a T cell and target it towards any cell that expresses CS1, which are primarily plasma cells. The overall goal is to take these white cells from a patient, make them target CS1 through genetic modification, and then infuse those CS1 CAR T cells back into the patient.
Now, what’s really cool about this is that you’re infusing a tiny number of cells, literally a tiny number of cells, but every time these T cells encounter a myeloma cell that expresses CS1, it divides. And so, these CAR T cells essentially grow in concentration in the patient’s body.
In essence, they start out as a minimally effective therapy that would only work on a tiny number of myeloma cells, but within the patient, they expand, and they expand hundreds and thousands and millionfolds. So a small number of genetically modified cells that are infused into a patient expand dramatically to essentially meet the demand of all the myeloma cells in the patient, and every time they see a myeloma cell that expresses the target protein, it kills that myeloma cell. That’s the essence of the CAR T cell therapy.
Jenny: Okay. Let me ask this question. You’re basically taking the white cells out, you’re marking them with a CS1 protein, and then you’re using elotuzumab to attack that protein because it’s now marked or it’s its own therapy? Does that make sense?
Dr. Hofmeister: Elotuzumab is its own therapy. It’s separate from this, but elotuzumab essentially provided a roadmap because elotuzumab targets CS1 on myeloma cells, so what we did is we created essentially the front end. The targeting mechanism for elotuzumab is what we force a patient’s white cells to put on their cell surface and target myeloma cells, so it’s no longer a monoclonal antibody.
All it is, is the targeting mechanism from elotuzumab that we put on to a T cell, and the T cell actually has a lot more killing effectiveness than a standard antibody because the antibody basically just whops on to the surface of a myeloma cell and sits there and hopes that the patient’s immune system will attack and engulf the antibody plus the myeloma cell, but with CAR T cells, you don’t have to worry about that. They have the targeting system on their cell surface. Once they hit their target, they’re going to both expand and kill the target, so elotuzumab and the CAR T cells are separate.
Cynthia: Hi, doc! This is Cindy. Can you hear me?
Dr. Hofmeister: Yes.
Cynthia: I have a question. Is this CAR T cell therapy done alone or in combination with some other type of treatment?
Dr. Hofmeister: That’s a great question. To my knowledge, there are at least two CAR T trials that are accruing patients right now, one is at University of Pennsylvania and this is using their standard CD19 target, and they’ve used that with much success in CLL and ALL, and its use in myeloma is being evaluated there. There is another CAR T trial that is ongoing at the NCI, National Cancer Institute, and that’s targeting myeloma cells that have a protein called BCMA on their cell surface, so a different target and it’s a different trial.
Both of those trials just use the patient’s own cells; genetically modified and then infused back into the patient. There’s no immune stimulator. There is no other treatment. It’s just a cellular therapy, which makes sense because really the field is just beginning to get started in the CAR T cells especially when you’re looking at a new target and a new clinical trial. It’s appropriate to start out for safety concerns with just the genetically modified cells, but clearly a lot of the work in the background and in the forefront in the laboratory is trying to combine these CAR T cells with other therapies that might improve either the expansion of these T cells in the patient or their killing activity against the cancer cells.
Cynthia: Okay. I thought the one at UPenn was done in conjunction with the autotransplant. I’m not quite sure though.
Dr. Hofmeister: You’re absolutely right. It is an autologous transplant that’s done first, so they get high dose IV melphalan and then they move on to get the CAR T infusion. The melphalan in essence for the UPenn trial is just trying to make sure that the CAR T cells get in the patient and expand and aren’t essentially killed off by the patient’s immune system.
That’s actually common for most CAR T trials. They call it lymphodepleting chemotherapy or depleting or decreasing the number of lymphocytes that are in the patient to decrease the chance that these cells would just get killed off by the patient’s immune system. Yes, that is a component of many CAR T trials up to this point and usually it’s not a heck of a lot of chemotherapy that they give. Most of these patients, especially relapsed and refractory myeloma patients, they essentially yawn at high dose IV melphalan. It’s not going to be a very effective therapy.
Now, in those patients at the University of Pennsylvania, I think it is still a pretty effective therapy, but the chemotherapy —
Cynthia: So your proposal would be in conjunction with a transplant or would it be in isolation?
Dr. Hofmeister: Our proposal is, as it currently stands, the CAR T cells are preceded by a relatively small dose of cyclophosphamide. I think that the UPenn group is targeting patients who are earlier on in their disease course and that in many ways make sense because the target that they chose, CD19, is not expressed at a high density on most myeloma cells. So at the beginning, they weren’t sure how well this would work. I think there are still a lot of questions about it because only a relatively small number of patients have received it so far.
Cynthia: Correct. Okay. Thanks so much.
Jenny: Let me just make sure I understand it. You chose CS1 because it’s a very common protein that’s found on myeloma cells and that we have an existing therapy that targets that certain protein, which is elotuzumab, right?
Dr. Hofmeister: Yes.
Jenny: And what you’re saying is you’re doing the targeting and then you’re letting elotuzumab take over, but it’s actually being boosted. For example, elotuzumab they say doesn’t show single agent activities, so they’re combining it with other things and it’s showing to be really responsive, but what you’re saying is that you can boost the power of elotuzumab because you have the cells specifically targeted and then it replicates and takes over. Is that accurate or am I not understanding it right?
Dr. Hofmeister: The key thing to know is elotuzumab simply provided us the roadmap to make the targeting system. Elotuzumab has nothing to do with our proposed clinical trial except for the fact that we used it to make the CAR T cells because elotuzumab already targets CS1.
Elotuzumab is a separate therapy and not associated with our CAR T cells. Our CAR T cells are a cellular therapy alone. And so, all we’ve done is copy how elotuzumab targets CS1 and we genetically modify T cells so that they are able to target exactly the same CS1 that elotuzumab targets.
Jenny: Well I see. It’s the same target, but two different therapies.
Dr. Hofmeister: Yes, the same target as elotuzumab, but a different therapy, and it works. We believe it will work better because elotuzumab is just an antibody, an extra protein that gloms on to a myeloma cell, but it requires that in that microenvironment of the cancer cell, the patient’s own immune system is able to clear out both the myeloma cell, as well as that antibody, but in most cases, that microenvironment is not very active against the myeloma cell.
The myeloma cells essentially create an environment around themselves that support their survival, so a simple monoclonal antibody against it oftentimes has a steep road up to be effective. And for elotuzumab, it doesn’t seem to show a lot of single agent activity, but every time T cells, CAR T cells have been used and have expanded in patients, we’ve seen some dramatic responses in other cancers. There’s still some data for a few myeloma patients at the University of Pennsylvania and to my knowledge, I haven’t seen any data about the CAR T trial at the NCI yet.
Jenny: The other groups are going after CD19 and BCMA, like you mentioned, but you are going after CS1. You chose that because…?
Dr. Hofmeister: We chose CS1 in essence because we thought one, it was going to be expressed on a large number of myeloma cells and we felt that CS1 was expressed essentially in a plasma cell’s teenage years and again kind of in the older adulthood of a plasma cell, so we’re hoping that it will be effective for both. If you believe in a myeloma stem cell, we hope that it’ll be effective in both the worker bees and the stem cell — in the myeloma stem cells, as well for myeloma worker bees.
We had a lot of safety data with the elotuzumab already there, so we’re hoping that being able to essentially target plasma cells early on in their life as well as having that safety data together made it an excellent target for us.
Jenny: Well, it’s a great approach to piggyback on a research that’s already been done and just hit the gas.
Dr. Hofmeister: That’s certainly what we’re hoping for. In essence, what we dream of essentially is combining the approaches. We would love to have a bag of BCMA CAR T cells along with CD19 CAR T cells along with CS1 CAR T cells and infuse them all at the same time.
Now, from a regulatory standpoint and from an intellectual property standpoint, that’s tremendously complicated, but just from a science and a patient standpoint, essentially you’re tripling down on what could be very effective therapy. Yes, it could be very risky, but if you could target three different things, you might be able to mop up every last myeloma cell, and that’s awful appealing.
Cynthia: That’s excellent.
Gary: Doctor, I have a question. I was wondering — first of all, I want to congratulate you on an exceptionally well-written proposal. My head is still sore from going through it. It is very, very excellent and very complex.
Dr. Hofmeister: Well, thank you so much.
Gary: One question was, do all myeloma cells express the CS1 target? If they don’t, the ones that escape, are they going to raise their ugly heads?
Dr. Hofmeister: That is the big concern for every CAR T cell trial, is number one, will your CAR T cells, when they get into the patient, will they expand? Because the expansion is increasing essentially the number of live CAR T cells in the patient. If they don’t expand, they’re not going to be able to kill all the patient’s myeloma cells, so will they expand? And then will there be a target negative cancer cell that will lead to relapse? These are the big questions in myeloma.
Now, we do know that there are — for the BCMA CAR T trial — we do know that there are myeloma patients where their predominant clone, which means the majority of the myeloma cells that you see in a patient’s bone marrow biopsy, didn’t express the BCMA target, so we knew that referring them to that NIH trial was not going to be effective. So we know that BCMA is not going to be the end all and be all, and we would expect that there would be a group of patients where CS1 won’t be expressed, but have we found a cluster of our patients that are CS1 negative? No. We’re in the midst of looking just for those very things.
In fact, we’re interested in looking at the people who are BCMA negative to see if they’re also CS1 negative. We’re hopeful that because CS1 seems to be an important part of the plasma cell’s makeup from essentially even their teenage years all the way through adulthood that we’re hoping that a CS1 negative plasma cell is not going to be common, but really with the improbable abnormalities coming up here, it’s certainly leaning on the experience of cancer in the past.
It’s certainly concerning to me that there’s going to be myeloma cells that are going to be CS1 negative and either they already exist in the small proportion of patients or we select them out through the CAR T therapy, so we’re very concerned about that. We have a number of initiatives in the laboratory to try to get around that problem.
Gary: I was wondering. Does that mouse model that you did — I assume what you did is you infected a bunch of mice and then you had three different things, one of which included the CAR T. The CAR T one looked like the mice were cancer-free. Is that what I saw? If so, does that mean that for whatever the reason, there doesn’t seem to be a lot that are escaping, at least in mice?
Dr. Hofmeister: Exactly. Literally, we’ve cured legions of mice of cancer, but —
Gary: Yay! You’re remarkable, cancer-free mice.
Dr. Hofmeister: Really inbred immunodeficient mice are not where we want to head, and even the immunocompetent mice that we test in the laboratory with a variant of myeloma is not fully reflective of the complexity of human myeloma.
Now, there are other animal models that are currently percolating for which we’re not clear how well that they reflect. Cats and dogs both have some myeloma analogs apparently that are currently being worked up. There are newer mouse models that are always creeping up and being tested here and there, but it requires a tremendous amount of effort to find a reflective species of animal that has myeloma that’s reflective of the human experience. Thus far, we’re still not all that close.
Gary: But it does show that none of those mice had anything after you were done. You don’t usually find that, do you?
Dr. Hofmeister: That’s true.
Gary: In the mouse model?
Dr. Hofmeister: You’re absolutely right. That’s true and that’s exactly what we found.
Jenny: And that’s why you’re excited, right?
Dr. Hofmeister: Yes, and that’s one of the reasons we’re very excited.
Cynthia: This is exciting research.
Gary: Yes. What you have in there — and this is my last question and I’ll let everybody else time in for a while. I’ve got a few more after that — is that this CAR T cell that you have also has a little bomb in it, doesn’t it, the lentivirus? Can you explain that?
Dr. Hofmeister: Sure. I glossed over this at the beginning and essentially, the idea is that when you take T cells from a patient, you need to force the T cells to put that CS1 targeting mechanism on their cell surface. Now, you can force it any number of ways. There are retroviruses. There are lentiviruses. There is essentially something called electroporation, which in many ways just shakes the cell, but there’s a lot of ways to get the genetic code into the cell.
And so, the lentivirus for us we believe has the right mix of efficiency and safety to get the genetic program into the patient’s T cells so that those T cells are forced to express the CS1 targeting system. That isn’t really a bomb. All that is, is a mechanism to put the targeting on the cell surface.
The bomb is essentially the fact that you put that targeting system on the cell surface and most T cells probably, when they are right next to and bound to their target, they become agitated and they are their own bomb. When they’re that close to and bound to another cell, it’s very hard for them not to blow up. It’s just the nature of T cells. Clearly, myeloma cells have worked out ways to diffuse that bomb normally in patient’s T cells. What we don’t know is will they be successful at diffusing CAR T cells.
Gary: Thank you, doctor.
Jenny: Well, I’d like to ask a couple of questions about safety because when we interviewed Dr. Rapoport, he said these are extremely potent, very powerful, and then you have to be very careful with them. Can you explain any safety issues that you foresee about using CAR T cells?
Dr. Hofmeister: There are lots of safety issues and they’re incredibly complicated. The first thing that you think about is, well, if I’m genetically modifying a T cell and they attack anything with CS1 or whatever target on its cell surface, there probably are going to be more cells other than myeloma cells that have that protein on their cell surface.
And so, we call them “on-target, off-tumor” effects, and that has been a big trouble with CAR T therapy in the past in that minor expression of some targets on cells that you didn’t expect them like in the heart or the lungs. That could be a big problem if your CAR T cells not only are targeting your cancer, but oh my gosh, they’re leading to a horrible inflammation in your heart causing it not to beat appropriately. That’s terrifying.
There’s lots of work that we’re doing now and others have done to try to verify that the expression of CS1 and other CAR T targets are limited to cancer cells or other normal plasma cells that if the patient didn’t have any plasma cells, they could still get along.
The other big problem that has occurred in patients, or at least one of the other big problems, is that when the CAR T cells are infused into the patient and then they expand every time they see a myeloma cell with a target, one CAR T cell becomes two, and those two, they become four. Well, that expansion can happen all at once. When you have that many T cells expanding so quickly, that can be very unpleasant for the patient.
It has a lot of complicated names, but one of them is cytokine release syndrome. Basically, when all those T cells become agitated, they ooze out these inflammatory cytokines, these inflammatory chemicals in the patient’s bloodstream, which can cause a patient to look for all the world like they’re becoming septic.
Not many patients, but some patients have had that and it’s been life-threatening. Some patients passed away because of cytokine release syndrome. So with appropriate follow-up, with close monitoring of patients, ideally — and the knowledge now as we get on to the second and third wave of CAR T trials, there’s acknowledgement of this clinical syndrome and medication is given early on to decrease the cytokines and their inflammation into patients, which we hope will decrease the risk of this.
I was thinking the last big thing that’s come up in some CAR T trials is encephalopathy or essentially mental status changes. I don’t exactly understand why this occurs, but it seems to occur in patients where they become confused. It’s almost like they have a stroke and it’s related to some aspect of these CAR T trials, but really the whole pathophysiology of how you get expansion of CAR T trials and how this leads to confusion in patients is not clear to me.
It doesn’t seem to be relevant for the brand of CAR T trials that we are interested in studying, but it still is a concern that we’re going to have as we’re trying out a new CAR T target. And so, in many ways, you’re starting as a first in human trial where all sorts of things could occur and the first in human trial certainly has safety concerns as some of the top priorities.
Jenny: Right. Now, in monoclonal antibodies anyway, two targets have really been a standout. The CS1 that elotuzumab is targeting now, you’re targeting with these CAR T cells, and also CD38, so can you talk to — I guess it would be a totally separate target and a whole separate area of research, right?
Dr. Hofmeister: It absolutely is. There are CAR T cells that have been in essence created and tested and perfected in the laboratory against CD38. That work has been done primarily in Europe. And although other groups may have done it and haven’t published it yet, that looks very interesting, but there’s a significant mountain to climb there because CD38 is expressed on the cell surface of many cells, not just many white cells, red cells, platelets, but other organs express CD38. And so, the on-target, but off-tumor effects of the CD38 CAR T strategy could be a big hurdle to overcome.
One of the ways that researchers have postulated to get around this is to create what they call biodegradable CAR T cells, which I think is a great way to think about it, but essentially a way to create a group of CAR T cells that don’t last that long. They essentially infuse, expand a little bit, but essentially are wiped out and do not persist. That allows them to do potentially some killing, but maybe without killing important CD38 expressing off-tumor cells that a patient may have.
This strategy is being considered in leukemia, myeloma, and a number of cancers, and also different targets other than CD38. The CD38 target is an excellent one, but there’s going to be some significant hurdles to get around its expression on off-tumor cells in myeloma.
Jenny: How long do the cell’s expansion process typically last? Does it just keep going until it finds them all and it shuts down? What’s the process there?
Dr. Hofmeister: In many ways, we would think the kinetics of how these cells expand, it seems that once they infuse somewhere in the first two weeks, they can have a huge expansion. And then as the number of targets ideally decreases in the patient, their density in the patient’s bloodstream slowly decreases.
In essence, what everyone is hoping for in many ways is to build an immunity towards these cancer cells so that should a patient relapse or these myeloma cells begin to proliferate, so too do the CAR T cells begin to expand and kill off the returning cancer cells. I’m not sure if that’s actually what happens. We do know that from the University of Pennsylvania experience that most of these CAR T cells expand within the first two weeks and that their persistence can last months and years.
Jenny: Okay. That makes sense.
Cynthia: I have a question.
Jenny: Go ahead, Cynthia.
Cynthia: I was just thinking back to the target of CS1 and that may be being on all the myeloma cells, relating that to the current trials that are going on with the CD19 cells and leukemia, do most leukemia patients have CD19 cells? And is leukemia — like with myeloma, many people, there are so many different types of mutations that we’re always afraid that we will target something, but there will be one very aggressive mutation that will continue to go proliferate itself. Is that the same for leukemia or is myeloma a different monster?
Dr. Hofmeister: No. CD19 really is on the cell surface of many B cells, so it includes some leukemias and some lymphomas. I think that’s a concern as well for essentially CD19 negative cancer cells to come up despite having CAR T cells targeting CD19 floating around in the body because they’re floating around in the body looking for their target on a cancer cell, but the cancer cell has hidden that target. Clearly, we’re concerned about that. I think that that’s a concern for any cancer.
Cynthia: Okay. Thanks.
Jenny: I have a follow-up question. How is this appropriate for high-risk patients? And then, does it work just as well for low-risk patients?
Dr. Hofmeister: Great question. Just the basics, so low-risk and high-risk, really low-risk is described in essence as patients who become resistant to their current treatment slowly and high-risk patients become resistant to whatever treatment they’re on quickly. That is how in essence we’ve described low-risk and high-risk patients. Low-risk patients, no surprise, live longer and they require less chemotherapy to keep their myeloma in control. High-risk patients generally require more drugs at any given time and they become resistant to cocktails of drugs more quickly than low-risk patients.
Now, all of that happens in many respects because of the cellular machinery inside the cell. What makes this strategy of CAR T cells appealing for high-risk myeloma is that it is very effective in other diseases and we haven’t yet tested a lot in myeloma, but it’s very effective over a very short period of time. It doesn’t matter what treatment the patient has had in the past because all of that complicated, disrupted, mutated cellular machinery that has become stronger and more resistant over the patient’s prior line of therapy, none of that matters if the target is expressed on the myeloma cell surface.
And so, in many respects, I think some investigators described it as an agnostic treatment. I’m not exactly sure why that phrase has stuck, but in essence, it doesn’t matter what the patient has gone through before, what they’re resistant to, what’s going on inside the cell. As long as they have that protein on the cell surface, the T cells should be able to kill it. And so, I think that’s why in many respects it’s appealing to think of it for high-risk patients and we hope that it will work just as well in low-risk patients.
Jenny: And then you don’t have to worry about any genetics, specific genetic features like a deletion 17p or a t(14;16). You’re saying it would just work for everyone in the same way.
Dr. Hofmeister: Right because many of those genetic features describe primarily how quickly a patient becomes resistant and certainly has downstream scientific background in terms of how it changes the microenvironment, how it responds to specific treatments, and a lot of details that go along with specific mutations, but if you think of it, many myeloma patients start out with a diagnosis with two to six different clones.
So you’re already starting out with some significant heterogeneity in a patient. What we hope is that CS1 will be expressed on all the clones and what we don’t know is how often that will be the case.
Jenny: So you’re looking at this as a very efficient way to attack myeloma.
Dr. Hofmeister: Right and a way that ideally won’t allow a real selection pressure, but instead ideally obliterate the clones that express the target and make the remaining clones unable to survive. This is what I think we all dream of, and whether that’s actually going to happen or not, we’re going to see over the next months and years.
Jenny: Great! Can you give us an idea of the process that you’ve been going through to discover this and the steps in the process, I guess? Maybe give us the highlight or overview, and then where you are in the process and how far it takes to get from where you are to the clinic.
Dr. Hofmeister: With an autologous CAR T trial, you need to have some evidence right in the laboratory that you can take some white cells, you can force them to express the targeting system, and that in your laboratory, they kill the best model cells for your cancer. And that if you choose to do it in an animal system that each proves to be effective and safe in that animal system as well.
That is the necessary research to make most academicians say, “Okay. This looks to be effective. Now, how do we go from the lab to the clinic?” Well, first you talk to the FDA and say, “Does this look okay to you?” The FDA will look at your data and then if they say, “Yeah, that looks pretty good,” and that’s usually called a pre pre-IND. It’s starting an investigational drug application before you start getting an investigational drug application. It’s kind of like pre-boarding.
When you do this step, then the next step is generally a pre-IND sometimes in between having the NIH review your clinical protocol and data as necessary by a so-called recombinant DNA advisory committee. But in between that, you’ll get to the pre-IND, which is the pre-investigational new drug application, and they think of this cell therapy as a drug. Eventually, you’ll get an investigational new drug application, an IND, which is your FDA’s approval that you’ve passed the necessary safety blocks and efficacy blocks that make everyone at the FDA think, “Hey, this could work.”
Once you do that, you take it back to your home institution or university and sell everyone there on it, so you have to sell your Scientific Review Committees, your Institutional Biosafety Committees, your IRBs, your Investigational Review Boards, to go over this application, this protocol of treating patients and everything you’ve done, and see if everyone agrees to it. If they do, you have IRB approval, you have FDA approval, then you’re able to go to a patient and say, “Okay. Here’s this idea we have. Here’s what we know. You’re one of the first in human to ever try this. What do you think?”
In general, you’re talking to patients who have been there, they’ve done that. Their myeloma is marginally controlled and they know that things are not going to go well for long. It’s important to have an appropriate process there of having patients understand the risk and benefits of trying something being a first in human to use a potentially life-threatening and potentially life-saving therapy.
The timeline for all this and the cost for all this are quite variable. It depends on the specifics for cell therapy, the target, the research involved, the requirements of the FDA, and can stretch from a couple of years to a number of years. Where we are in the process is that we ideally are going to request the FDA evaluate the pre-IND, which is the binding process towards the end of 2015, and we would really like to have a clinical trial available for patients by mid-2016. That is our hope at this point.
Jenny: Okay. In terms of funding, I know sometimes — Gary, I know you had a question about funding.
Gary: Well, actually my question wasn’t really about funding. It was really about the cost of the treatment. What that was, was that on the CD19 target, for whatever the reason, they were saying that the cost for that treatment would be someplace in the half million dollars per treatment for CD19 T cell treatment and that’s because it’s so significant. The cost to duplicate the CD19 T cells is so significant. And so, my question to you, do you see the CS1 treatment to be more economical?
Dr. Hofmeister: No, I don’t see it more economical. I think that doing something autologous using the patient’s own immune system, genetically modifying it, and then infusing it back is incredibly expensive because anytime you take — just to say it, taking somebody’s immune cells out and genetically modifying them and putting them back, you have to do that in an incredibly sterile and sophisticated environment, which your prejudices and mine are probably that, “Oh gosh, that’s going to be wicked expensive.”
I think it’s still wicked expensive. Any autologous CAR T trial is going to be wicked expensive. What you and I all hope for — I think what we all hope for is we all hope to be able to have some CAR T cells that are not from the patient, but in fact, CAR T cells that are from somebody else that are universal donors, that won’t react, that won’t cause graft versus host disease when they’re infused into a patient, but are targeted towards CS1 or BCMA or CD19 or whatever target you’re interested in.
I think an allogeneic CAR T treatment could be much more economical because if you have essentially a lot of doses of these genetically modified CAR T cells available, but they aren’t from the patient, they’ve just been sitting around from somebody else for a long time and you have tons of them, that if we’re able to do that, that could be both exceptionally effective and economical. I think that’s the world that I hope to be living in, but it’s a necessary step to start with the patient’s own cells because immune reactivity is very complex. And trying to have essentially universal donors is not an easy thing to even conceive of, but I think —
Gary: Well, that is one of the downsides, the cost implication per treatment and having it covered by your insurance company.
Dr. Hofmeister: Yeah. I don’t see that as a likely durable solution to having an autologous CAR T because of the cost, but I do think that allogeneic CAR T is where everyone I think would like to go. I do see that as economical.
Gary: Well, when I talk about economical, all they’re saying is that it will be on — with the CD19 CAR T cells, they said that it would be equitable to a transplant. Well, I’ve already had a couple of those. I guess the point being is that if it’s a half a million dollars and I can have that instead of a transplant and it’s equal, so from a patient’s perspective, if I’m cured for $500,000 versus having a couple of transplants and not being cured, then obviously — hey, I’m already the three million dollar man, you know.
Dr. Hofmeister: Exactly.
Gary: The patient wants cure. Damn the cost, but insurance companies are — wow, you know? “Wouldn’t it be nice if he’d just go away?”
Dr. Hofmeister: Well, I think the insurance companies want you cured because you become a lot less expensive when you’re cured.
Gary: Exactly, or we die.
Dr. Hofmeister: We’re getting pretty morbid here.
Cynthia: I do have a follow-up question to that, too. In theory, this C1 target, and you right now do individual therapies, so for each person, you have to take out their T cells and genetically engineer them and put them back, so that’s very, very expensive, but once they’re back in your body, it’s a one-time treatment. Is that correct?
Dr. Hofmeister: Yes.
Cynthia: That immune response is going to stay in your body and anytime your myeloma cells maybe in the future might be acting up again and if they have CS1 on their surface, that treatment you got several years ago in theory should still be effective. Is that correct?
Dr. Hofmeister: That’s the goal.
Cynthia: That’s the goal, so it should be a one-time therapy if it works and anytime your myeloma flares up, the immune system will get into response and knock it back down.
Dr. Hofmeister: That’s the hope. The problem I think is that the — I guess the concern that I have is that if it flares up, that means that it’s percolating around quietly while those CAR T cells are infusing or while those CAR T cells are persisting. If that’s the case, then probably the only way it could flare up is if they are target negative, if they don’t have the CS1 target on them anymore. That’s my concern and I think that’s everyone’s concern in the CAR T trials.
Cynthia: Is there a way that through a bone marrow biopsy, you could look at someone’s myeloma cells and see if they have that target on their cells ahead of time?
Dr. Hofmeister: Yes, and that’s part of the BCMA CAR T trial. It requires that as an eligibility criteria and we’ll likely have that on our trial as well.
Cynthia: Okay. Thanks.
Dr. Hofmeister: Absolutely.
Jenny: Okay. My last question isn’t meant to be a trick question, but it’s about just funding. In this stage that you’re at right now, how would you use additional funding to get to your follow-on stages and how much would you need basically?
Dr. Hofmeister: Great question. We estimate that each patient would cost at least a hundred grand once to treat them, and that’s probably a bare minimum. The problem is getting to that point, getting to a point where you’re ready to enroll a patient because right now, we’re at a spot where we’ve chosen a lot of our final stuff. We’re verifying one or two last things and then we’re going to start doing dry runs essentially, making sure that we can force a lot of cells to express CS1 on their cell surface and try to ship some cells down and run it through.
Whenever you go in to one of those sterile facilities and do anything there, open the door, it costs a tremendous amount of money. So we’re probably anywhere between $200,000 and $400,000 away from getting to a spot where a clinical trial could begin. I think what we’d use the money for primarily is that testing. We call it a GMP facility and it’s essentially a sterile, scientifically specialized environment where you can manipulate somebody’s cells in such a way that it’s safe and then give them back to the patients. It’s got to be done in this specialized facility to be safe and effective.
Jenny: Okay. Great. Those are all the questions that I have. Cynthia or Gary, do you have more? Because I would like to also open it up to caller questions.
Gary: Okay. I’ve got another one. You had mentioned that you have the CD19 target and it also, they said, wipes out all the B cells. But in the analysis that I saw on the Penn research, they said you don’t need B cells. It seems like they’ve got to be there for some purpose in any event.
In the mouse model that you had, was there anything that took out — did it grow a third leg in the front or did it have seven ears, anything that you could see that the CS1 also wiped out? The mouse was clear of myeloma, but was walking around or wiggling and not moving much.
Dr. Hofmeister: Wiggling and not moving much, and I think that no third leg, third ear, something like that.
Gary: So it didn’t look like there was anything obvious, which is a good thing that the mouse seemed like he was doing pretty good. He wasn’t flopping around or anything.
Dr. Hofmeister: Nope.
Gary: So that’s a great sign.
Dr. Hofmeister: Yes.
Gary: What you’re telling me just sounds like some fantastic work on your part, and $100,000 is one-fifth of what they’re talking about at Penn, so I’m so excited about what you’re doing, Dr. Hofmeister.
Dr. Hofmeister: Well, we’re excited, too, and certainly very hopeful to get to work on this area.
Gary: One other thing is that because of CAR, it seems like you can go on Google and there are 45 billion entries, and as a result — and it seems like everybody is jumping on the bandwagon. Is there a ton of competition with regard to myeloma and the myeloma research that you see, or because we’re not that big of a disease that you’re kind of a lone stranger?
Dr. Hofmeister: No, certainly not a lone stranger because the UPenn group and the NCI are already there in myeloma. I think Memorial Sloan Kettering or Boston has a trial that’s going to enroll myeloma patients as well, another CAR T trial. I’m sure that more will come up quickly.
I think that from my perspective, this is a hot topic area. People are very excited about the chance of great responses as we are. There’s going to be a lot of people looking at this for many cancers.
Gary: I just saw there were like a couple of them that had just gotten $150 million, $127 million —
Dr. Hofmeister: Yes. In many cases, these companies are forming in hopes that this could be one of the next big areas of cancer treatments. We certainly are excited and believing that it is going to be one of the next big areas. That’s why we’re so interested in this research.
Gary: Well, it sounds like you’re doing some great work.
Dr. Hofmeister: Thank you.
Jenny: Well, before we open it up for caller questions, I would just like to mention that as a foundation ourselves, we will be reviewing these proposals and then selecting a number of proposals to fund. The research is just really exciting, but I’d also like to mention that your research right now has an open fundraising campaign through the MMORE Foundation. So if you would like to donate to this campaign immediately because we will take a few months to get to where we are creating our campaigns, take a look and join in on their site.
We, as a foundation, believe that collaboration is really key, that it helps everybody and that one organization or one individual can’t do this alone, so we support the work being done by all organizations and right now, their campaign is open and ready for donations.
Dr. Hofmeister: Thank you so much.
Jenny: If you have a question for Dr. Hofmeister, you can call 347-637-2631 and press 1 on your keypad. Go ahead with your question.
Caller: Hi, Dr. Hofmeister! Thanks so much for taking my call. Dr. Hofmeister, I have a couple of questions. What criteria other than being CS1 negative would exclude a high-risk myeloma patient from being eligible to join this research trial?
Dr. Hofmeister: Well, unfortunately, there are a lot of criteria. The reason is because it’s a first in man trial. It’s difficult for everyone to evaluate whether the treatment is safe and effective if there are a lot of organ systems already affected in the patient.
So what we’ve proposed currently is the patients have moderately good kidneys, that the patient doesn’t already have an ongoing infection, that the patient’s heart is functioning well, that their liver is functioning well. I know this may sound like, “Oh, I’m sure that’ll be fine,” but that’s not always the case especially in myeloma where patient’s kidneys are affected in a large proportion of the population of myeloma patients, so limiting them to patients who essentially have normal kidneys really aggravates me, but it’s a requirement to get your foot in the door essentially to start the process.
I think that that really takes up the majority of the exclusion criteria, is patients who are otherwise sick where you worry that if you get some of the CAR T cells in them and they start expanding drastically and the patient gets sick that they won’t be able to tolerate being sick for a little bit as we try to decrease the cytokines that are flowing around in the patient, so I think that will limit a lot of the patients. I can think of a number of my myeloma patients who are on dialysis who curse this very fact that in most clinical trials, dialysis patients are excluded. It’s certainly something we’re trying to fix.
Caller: Okay. Thank you. I’m a smoldering myeloma patient and I’d like to really understand how do we get the smoldering myeloma community interested and excited in your research proposal. I realized the Myeloma Crowd Research Initiative focus on high-risk active myeloma research, but I also understand that if you can find an effective therapy leading to a cure in this subgroup, the standard and intermediate risk groups will eventually benefit as well.
Can you see this therapy, if successful — and I know it’s probably years away — someday moving into the smoldering myeloma population
Dr. Hofmeister: Absolutely
Caller: Or do you need a greater tumor burden for this to potentially work?
Dr. Hofmeister: No
Caller: Is CS1 expressed on myeloma cells in this stage of the spectrum?
Dr. Hofmeister: Yes.
Caller: I mean, you said that so definitively. You didn’t hesitate, so that’s really neat.
Dr. Hofmeister: No. Think of it as MGUS, smoldering myeloma, myeloma are all part of a spectrum and increased number of mutations, increased aggressiveness of the mutated plasma clone, that’s what really characterizes the progression from MGUS to smoldering to active myeloma, so wouldn’t we all want to be able to treat patients before they have any of the dreaded CRAB criteria that you could eliminate and kill off the entire tumor clone. That’s exactly where I think this research is headed.
Caller: It’s wonderful. That’s exciting. That’s very exciting for smoldering patients to hear and understand because you hear high-risk myeloma and you think, “I’m not there yet. Why should I be bothered?” but this is really critical to understand that what we do today is eventually going to trickle down to the precursor states.
Dr. Hofmeister: Absolutely. I absolutely think that’s where we’re headed.
Caller: All right. Well, thank you so much. If you need a patient down the road, call me.
Dr. Hofmeister: Thanks!
Caller: Okay. Thanks so much, Dr. Hofmeister. I appreciate the call.
Dr. Hofmeister: Bye-bye.
Jenny: Thank you so much. I know we’re keeping you over, but we have two more questions, if you don’t mind.
Dr. Hofmeister: Sure.
Jenny: Okay, go ahead with your question.
Caller: Thanks for the opportunity to speak with the doctor, to the foundation and to the doctor. I came in late, so I apologize. Maybe you’ve touched on this. The focus of daratumumab, which has, as far as I understand, shown good results and it focuses on the CD38 receptor. Is this something that you’ve considered and is there any potential for this? I guess that’s it for now.
Dr. Hofmeister: Sure. Well, thank you for the question. We are very interested in all of the CD38 antibodies and we know of three. Daratumumab is one of them. Daratumumab and the Sanofi CD38 antibody each shows single agent activity and we find them very exciting. We think that they’re going to be FDA-approved much sooner than the CAR T cells will be FDA-approved in myeloma, so we’re excited for them as an option.
The problem with having CD38 CAR Ts is that CD38 is expressed on a number of non-cancerous cells, and having CD38 targeted CAR T cells could lead to a lot of problems if a lot of normal cells are attacked. So I think it could be done, but there are some significant hurdles to make it happen. I know that a number of groups both in Europe and in the US are actively working on that problem.
Caller: Okay. Thank you. Just a quick follow-up, would that be the same issue with — I believe there’s like a CD42 that Stanford has worked with a doctor out there, perhaps Weinstein, and it’s shown some efficacy. It’s early in its development, I believe, but it’s expressed likewise on a number of other cells, so I guess that’s the same problem.
Dr. Hofmeister: It could be. I’m not familiar with CD42. I am familiar with CD44. There is an antibody at Moffitt targeting CD44, and CAR T cells against CD44 sixth variant is already being looked at as a CAR T target in myeloma and that’s published. That looks interesting as well. We’re going to get into some of the same problems with that CD44 variant targeting. I really can’t speak to CD42, but CD44 variant targeting is expressed on a number of cells, so it will have many of the same hurdles as CD38.
Caller: Thank you very much for your time and thanks for the foundation.
Jenny: Okay. Thank you so much. Go ahead with your question.
Caller: Yes. Thank you very much, Jenny, for your work, and doctor as well. My question is a bit pragmatic. As a patient going into my fourth year, assuming that your work results in human trials in a year, a year and a half, what will the locations be or will it be a single location, and how much time do you think a patient would have to plan to be on site to participate in your trial?
Dr. Hofmeister: Right. We will likely try to mimic some of the experience at the University of Pennsylvania. It’s likely to be a single site, just here at Ohio State because our GMP facility is a wonderful location at Cincinnati Children’s Hospital. And so, many of our cells will be ideally driven down to Cincinnati, genetically modified, expanded, and then driven back up to be infused into patients.
Patients will be on campus a lot for that first four weeks. And literally for the first two weeks, it’s Monday, Wednesday, Friday at the very least, so it’s quite a bit for those patients in the first months is what is planned currently.
Caller: Right, and then the follow-up check-ups and so on, would we have to plan on being there for a period of months or can we come in and out of the campus?
Dr. Hofmeister: No. After that, it’s relatively minimal. What we plan at the moment is monthly for two months afterwards and then at six months follow-up from there and then the duration there depends a little bit on further communication with the FDA.
Caller: Great! Thank you very much. Thanks again, Jenny.
Jenny: Okay. Thank you so much. Okay. Our last question that we have time for, go ahead with your question.
Caller: Good morning. I’m in California and I just a few weeks ago was involved with the MMRF Walkathon with UCSF and over the weekend, I was involved with the IMF in a patient seminar. I also see that you have a site, which is endmyeloma.org.
My question is on the funding issue. With all these different organizations raising funding, how are you all working together or do you work together to come up with a plan? How does a person like myself who’s a myeloma patient want to — how do you say it — where do I focus my funds and my work to come up with a better resolution to myeloma?
Jenny: That’s a great question. Go ahead. You can answer and then I’ll answer from our perspective.
Dr. Hofmeister: Clearly there is a site to support this research alone at endmyeloma.org, but beyond that, I think the question when you invest in research that you’re interested in, I think that you want to invest in things you believe in. Invest in things where it really gets you jazzed about it. I think that the IMF, the MMRF, the LLS, there are a lot of 501(c)(3)s around that are funding excellent research.
I don’t necessarily think you can lose, but it’s really nice especially to be able to have some sort of connection with the research that you’re investing in and to know that the dollars that you’re investing go to the research you’re most excited about. And in some ways for you, maybe that might be at UCSF because you’re close and you’ll be able to communicate well with that research team. I don’t know. I think for me in my own investments in research, it’s what I get most excited about that I want to put my resources towards.
Caller: Thank you very much.
Jenny: Okay. Just to comment on that, we, coming into this with the IMF and MMRF having provided research dollars and patient education and support for many years, we looked at this as how can we fill the gaps of what’s not being done. The IMF focuses quite heavily on patient education and they have wonderful seminars like you said you just attended.
MMRF is focused primarily on research, but I think the appeal for this approach for us and the MMORE Foundation is that we do want patients to be able to see exactly where their dollars are going. And all of the dollars for the campaigns that we end up selecting, 100% of the dollars that are raised will go towards that research, so it was something that hadn’t been done before, and so we were looking to fill the gaps. But in addition, we have had conversations with multiple foundations to see how we can join together and collaborate a little more because I think historically that hasn’t really been done.
Okay. All right. Dr. Hofmeister, we’ve kept you long, but for a good reason.
Dr. Hofmeister: Absolutely. Thank you.
Jenny: Thank you so much for taking the time. We really, really appreciate it. We are very grateful for the work that you’re doing to cure this disease. We wish you all the best and we are just so thankful for your hard work.
Dr. Hofmeister: Thanks for having me on the show. It’s a great experience.
Jenny: Thank you so much for listening to Myeloma Crowd Radio and the new MCRI series on high-risk myeloma. Patients can help support this discovery of a cure and we are very excited to move forward in the Myeloma Crowd Research Initiative.