Dr. Daniel Fowler, MD
National Institutes of Health (NIH)
Interview Date: September 25, 2015
How can doctors make both auto and allogeneic transplants better? Using allo transplant is the ultimate in immunotherapy because it replaces a faulty immune system with a healthy one, but it is not used frequently in myeloma because of the potential for fatality from graft vs. host disease (GVHD). Dr. Fowler has done intriguing work at the NIH over a decade to iterate on working solutions to improve the effectiveness of allo while also reducing graft vs. host and is now finding application of his immune therapy in the autologous setting. He discovered that new T cells from transplant donors actually had an impact to kill myeloma cells, not just replace bad stem cells. In the show, he describes that certain T cells have multiple functions. For example, a CD4 cell can both have two types of “helper” functions (Th1 and Th2). Th1 affects inflammation while Th2 kills cancer cells. By manipulating the levels of Th1 or Th2 with a drug called rapamycin, he can reduce GVHD in the allo setting or enhance the myeloma-killing effect of the T cells in the auto setting. Allo transplants are typically for late-stage myeloma patients who are already refractory to chemo, so he has developed both a low-chemo and a no-chemo allo transplant (called “zero-intensity” transplant) that is done as an outpatient service. He uses the rapamycin drug to reduce the inflammation, greatly reducing GVHD complications. He has then brought the same drug to the auto transplant setting, giving a standard autologous stem cell transplant and and then following it with a one-week regimen for four months post-transplant using this immune therapy. The immune therapy is going after all potential myeloma cells, not a particular protein target. To learn more about this fascinating work, click the clinical trials below or read the full transcript.
Clinical Trials Discussed in This Show
The Myeloma Crowd Radio Show with Dr. Daniel Fowler
Full Show Transcript
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom.
We’d like to thank today’s episode sponsor, Amgen, for their support of Myeloma Crowd Radio and all they do for multiple myeloma patients.
Now, before we get started I would like to share a way that patients can change their own myeloma outcomes. For the first time, myeloma patients and doctors have joined together to create what we call the Myeloma Crowd Research Initiative. We believe that as patients we can help accelerate a cure and selected high-risk myeloma as our target. So with the input from six leading myeloma doctors and five highly-educated myeloma patients and a very thorough review process, we have selected two critical projects that are immunotherapies that need our financial support. These are ways to use the immune system to fight myeloma.
We invite you to help raise funds for this proposal by creating your own fundraising page that you can share with friends and family. You can check out the myelomacrowd.org website for links to create your own page and to donate to this important initiative.
Now along those lines, immunotherapy is a very hot topic in myeloma and in our last show with Dr. Don Benson, we discussed the timing of its use and he mentioned that post-transplant may be the ideal time to use it. So today we have invited Dr. Daniel Fowler of the NIH to join us and he is doing work to do exactly that.
Welcome, Dr. Fowler, to the show.
Dr. Fowler: Thank you, Jenny.
Jenny: I will give a brief introduction for you before we get started.
Dr. Fowler is Tenured Senior Clinical Investigator at the Center for Cancer Research, National Cancer Institute or the NCI in Bethesda in the Experimental Transplantation and Immunology branch. He’s on the editorial board of Biology of Blood and Marrow Transplantation, the Journal of Clinical Immunology and reviews publications in the Journal of Immunology, Blood, Transplantation, Cancer Research, and the Journal of Immunology, just to name a few.
With his background in Immunology, he has received a T-cell patent and has one patent pending using PD-1, which I think we’re going to talk about a little later in the show. Dr. Fowler has received the NCI Directors Award in both Lymphoma and Mesothelioma and has deep expertise in changing allogeneic transplant responses for blood cancer patients. He’s now using this past expertise in allotransplants to combine an immunotherapy with transplant and we are looking forward to understanding what you’re working on better.
So welcome again, Dr. Fowler.
Dr. Fowler: Thank you. It’s a pleasure to be with you.
Jenny: We’ll begin with a question that we ended with on the last show that was about immunotherapies in general. So we spent some time talking about the timing of using immunotherapies in myeloma. And as a novice we may think that immunotherapies can’t be used very well when we have a low immune system like after transplant. But in our last show, the doctor said it might actually be a very best time for its use. And I know you have deep expertise in allotransplant minimizing graft-versus-host that you brought to this so maybe you want to start there and then we’ll ask the timing question later.
Dr. Fowler: Okay, starting with the graft versus host? Well, you bring up a good issue about timing and I think when most patients think about timing I would imagine they’re thinking would I receive this as my first regimen or second or third or fourth regimen down the line with a disease that relapses frequently as myeloma.
I think the answer to that is based as we always do on clinical trials or in practice is the risk/ benefit analysis. So with any immunotherapy, one first has to think what the risk is versus the potential benefit. And I think that if you have a strategy that’s very risky, one would not want to necessarily use that in a multiple myeloma patient with good prognostic features for example.
What you implied in your question was is there a time in the multiple myeloma progression where an immune therapy may work better or be more effective in treating the disease. And I think that’s a tricky question, I don’t know that there is an imperative there. I think there are multiple time points in a patient’s course where immune therapy may be used either upfront or in the later stages as a down-the-stream option.
As you mentioned, immunotherapy therapy is a very broad terminology. I think you may have addressed this in some of your previous episodes. Immune therapy may represent giving a patient a monoclonal antibody through an intravenous infusion. It may involve an autologous cell transfer of immune cells such as autologous being the patient’s own cells. Or in the other extreme, it may be an allogeneic immunotherapy where a brother or sister serves as the immune donor or even an unrelated donor. So when you talk about immune therapy it’s hard to say should it be given early or later in the treatment algorithm because of such a great variety of immune treatments that are possible.
Jenny: That makes a lot of sense. And we did talk about how there are the cellular therapies which you’re saying is transplants and certain things like CAR T-cells and then monoclonal antibodies are a whole separate category. So now there are a lot of different choices, it seems.
Dr. Fowler: Right.
Jenny: Well, would you like to try to explain your experience with the allotransplant approach in trying to minimize graft-versus-host and what you’re learning from that?
Dr. Fowler: Absolutely. I think that’s a good place to start because my initial research more than 20 years ago now was in allogeneic transplant. After I finished my clinical rotations for training here at the NIH, I went into the mouse laboratories for about five years looking at the role of T-cells, the immune T-cells in allogeneic transplantation.
So when one looks at allogeneic bone marrow transplant or otherwise known as allogeneic peripheral blood stem cell transplant, the realization around the time I started in the early 1990s was that although the stem cells are important for providing a new blood system for the patient after very high doses of chemotherapy, there was increasing realization that the T-cells, the mature T-cells in the blood stream, that were at some point in our history were thought to be going along for the ride along with the stem cells, it was actually the T-cells in the transplant that were contributing greatly to the curative effect of the allogeneic transplant. So it was a donor, not the patient’s own T-cells, but a brother, sister or unrelated donor for example, T-cells that when introduced into the body that could recognize in this case some multiple myeloma cell as being foreign and cause an eradication of the multiple myeloma.
Now the situation is that’s the good side of the equation. The other side is that the same T-cells, when they go into the body, can recognize not only the myeloma but the other normal tissues, in particular the skin, any part of the intestine and the liver as being foreign. And when this T-cell targeting occurs, then one has what is known as graft-versus-host disease, GVHD, and it’s still one of the top causes of lethality after a bone marrow or stem cell transplant. It’s a huge limitation. We talked about the risk/benefit ratio so when you have a treatment such as allogeneic transplant that can cause lethality in patients, even if it’s not a huge percentage of patients, then it gives pause to practitioners and patients for applying that treatment especially early in the treatment algorithm. So GVHD is a big problem.
The other problem with allogeneic transplant, this is particularly true in multiple myeloma patients who do not always have the best kidney function and therefore are not as adept at handling many of the medications that are administered after transplant and also handling the high doses of chemotherapy and radiation that are often given with transplant that it becomes a procedure where the patient is debilitated for a significant amount of time with low blood counts and infections can ensue and the immunosuppressive drugs that are used to prevent GVHD can further predispose to infections and therefore this adds to the morbidity and mortality of transplants.
So when one thinks about allogeneic transplant, it’s not only the GVHD but it’s the conditioning regimens, it’s the immunosuppressive regimens to prevent GVHD and the infection risk which when you add all those up, it gives a lot of pause to using allogeneic transplants especially in a disease like myeloma where there’s an increasing, thankfully, number of effective agents. So that’s how we look at transplant early on in our animal models and that informed us when we went to do our clinical trials is that there’s more to the equation than simply trying to prevent GVHD that one must have an eye toward improving all of these different aspects of transplant.
The research that we started with, it’s well-known in immunology. This was some groundbreaking work being done at NIH in the early 1990s. The T-cells, for example CD4 cells, CD4 are the cell component that in HIV patients when the value becomes low, they would go on to develop infectious disease and that’s why you take the medication that try to keep your CD4 counts high. Well these CD4 cells, they can exist in different functional subsets. So if you look at a CD4 under the microscope, it doesn’t tell you too much, you say “Oh, that’s an immune cell.”
But when one looks deeper into the immunology, one can now see that the CD4 cells exist in at least four different functional subsets. In these subsets, the first two that were identified were called T-Helper 1 and T-Helper 2 or we call Th1, Th2. The Th1 and the Th2 are kind of the yin and the yang, so to speak, of the immune helper response. The Th1 making a portfolio of cytokines, so these are molecules that the cell makes that tells other cells in the body to move into an inflammatory state so they’re pro-inflammatory in that respect. And in general they will cause graft-versus-host disease, which is a disease of inflammation and they can also kill tumors more readily because that also requires a very aggressive T-cell response.
In contrast, within that same CD4 pool of cells, there is the T-Helper 2, Th2 subset, and these cells in contrast produce anti-inflammatory cytokines and it was described in infectious diseases that there was a Th1-Th2 balance. So if the animal had a balance of Th1-Th2 cells, you could still cure the infection but the mouse would not get so sick from inflammation. So we initially hypothesized that in our mouse allogeneic transplant models, the same thing might occur. For example, if we did the bone marrow transplant and there were a sufficient number of Th2 cells in the transplant graft, that those Th2 cells could balance out the Th1 cells and we would get less GVHD. In fact, we found that and other groups around the world have found that as well is the GVHD can be controlled by controlling the balance of the T-cell function. So it’s not just how many T-cells are in the body but what are their functional characteristics.
Jenny: That’s totally fascinating.
Dr. Fowler: Yes. When you look at the immune system, every system that you find, there are a lot of backup plans. There is a plan for the immune system to do this and then there’s always a counter-regulatory aspect of the immune system that is supposed to keep things in check. And when things are out of check, then disease can occur.
Now unfortunately, the body is trained towards limiting inflammation and when you have cancer, you need a very strong T-cell response to eliminate the cancer. But the body has all of these built-in systems to limit inflammation so that otherwise we would have much more autoimmune disease which is already a problem. Diseases like lupus and rheumatoid arthritis and MS, these are autoimmune diseases where the T-helper balance is skewed toward an inflammatory state.
So that’s kind of the challenge in general with immune therapies. At least some of the T-cell therapies like allogeneic transplant is that if one pushes too far into a Th1 state you may get effective cures but then you’re limited by your toxicity, the inflammation in the body including GVHD which is an inflammatory state.
So based on these results in 1999, I wrote a clinical trial here at the NIH Clinical Center where we were going to do allogeneic stem cell transplant. And in conjunction with the transplant, in addition to collecting the donor stem cells and T-cells, we took other T-cells and we manufactured in the blood bank here at NIH, cells that were polarized towards the Th2 phenotype. So they looked more like a Th2 cell than they otherwise would have because when we put the cells in the incubator we can add different molecules to train them to become a Th2 cell. We know that these cells do not exist in the steady state body to a high degree so that if we want more of them we need to put them into culture and manufacture them. So that’s what we did at that time in 1999 when we started the trial.
We transplanted about 50 patients and did different treatment cohorts, different doses of these Th2 cells and overall, I was a little depressed because we did not find our anticipated effect that we would get less GVHD if we added more of these cells. It appeared to be initially some glimmering hope but then as we did more patients, it looked like we did not have a robust phenomenon, a robust reproducible treatment.
In parallel with that clinical trial, which we learned a lot and some of the patients are still living, so we didn’t do any worse than regular transplant, but we were doing some additional studies in our mouse models. I was thinking that when we put in these Th2 cells we always give the patient immunosuppressive drugs after the transplant and the drug that we were giving at the time was cyclosporine. So I reasoned that while we’re giving these cells to cause this effect and then we’re putting them into the patient who’s being treated with these immunosuppressive drugs and maybe that’s counterproductive because we need the cells to be able to run free in the body, not be suppressed.
And that led us to study whether other immunosuppressive drugs would be favorable for the type of cell therapy that we were doing. And we evaluated cyclosporine and we also evaluated another drug called rapamycin. And that’s the drug that we then invested our laboratory efforts in because we found that in contrast to cyclosporine, which always led to a decrease in our Th2 cells, when we cultured the Th2 cells in rapamycin (which is also known as Sirolimus, it’s an FDA-approved drug, a tablet). When the Th2 cells are exposed to Sirolimus there was always a population of cells that could become resistant to the rapamycin. We then studied this phenomenon, it’s called rapamycin-resistance so we called the cells that we grow in rapamycin T-rapa cells because they are T-cells that are more or less bred to be resistant to rapamycin.
And when we looked at the cells that were growing in rapamycin, they looked very weak initially. They weren’t making a lot of cytokines and we can only grow about 10% of the cells that we otherwise would have grown. But luckily we went on and studied them and when we transplanted those cells into the mice, the cells were much more powerful, on a scale of about five or ten times more powerful than the T-cells that we were previously studying.
Now rapamycin is a drug that causes starvation. It was discovered on Easter Island, which is down in South America, I think off the coast of Chile. Very fascinating culture down there, the Rapa Nui indigenous tribe there. It’s a natural product, it was found in the soil. It’s made by a bacteria and it has antifungal properties but it also had these immunosuppressive qualities and therefore have limited capacities to serve as an antifungal drug. Later on more recently, there’s been a lot of interest in Sirolimus and other drugs now similar to Sirolimus for treating cancer because cancer cells will also be susceptible to this drug and can slow down the proliferation of cancer cells.
So that’s what we are studying, these T-rapa cells. And the things that we found, so rapamycin, it blocks a molecule in the cell called mTOR, the mechanistic target of rapamycin. And mTOR is in the middle of the cell and it serves as a central gatekeeper. And when a cell, whether it’s a myeloma cell or a T-cell, is exposed to rapamycin, all of the external signals, the cell surface signals that tell the cell to grow are blunted because rapamycin’s blocking their transmission. The cancer cell or the T-cell that’s being activated by all these growth signals, which we cannot control to a large extent, the body’s constantly making growth factors. But when rapamycin is onboard, that central gatekeeper, the mTOR molecule is blocked so all of these different surface signals don’t get through to the cell so it goes into a starvation state.
What we had generated when we’re using rapamycin in the petri dish or in the incubator is the cells that are being starved, the T-cells that we’re growing and we’re starving them at the same time, they have to up-regulate other molecules in the cell that cause them to be actually more powerful. It’s almost like an evolutionary concept as you’re starving the cell, you’re putting a stress on the cell, and if the cells are indeed going to survive then they need to up-regulate other molecular pathways to overcome that starvation.
And that’s what we found with the rapamycin is when we manufacture our T-cells in rapamycin at the end of the culture when we go to put those T-cells into a mouse or now into our clinical trials, we have a T-cell that’s more able to mediate effects upon their transfer.
Jenny: Okay, that’s fascinating. Now let’s talk a little bit about this clinical trial that you have because now you are using this in multiple myeloma and you are using it with autologous transplant, right?
Dr. Fowler: Right.
Jenny: So if you want to explain the approach?
Dr. Fowler: Absolutely. Let me first summarize our allogeneic clinical trial and then we’ll finish up with the autologous.
The allogeneic, in that case what we’re doing is harvesting the T-cells from our stem cell donors and we put them into culture with the rapamycin. Usually with allogeneic transplant, a pretty big preparative regimen is given before the transplant. Now by preparative regimen that means chemotherapy and-or radiation that is used to make space for the new stem cells and the new immune system. Initially in transplant this included so-called ablative regimens, and more recently over the last 20 years involves what’s called reduced intensity conditioning, which is still pretty potent cocktail of chemotherapy, but not quite as high as it used to be.
And when we started looking at these rapamycin-grown cells, we were using a more conventional reduced amount of chemotherapy and what we found is that even in that setting of reduced amount of chemotherapy, the cells were not safe enough. They were a bad mixture of chemotherapy toxicity, low blood counts and a very powerful immune system so patients were getting a lot of side effects from that. And that led me to reduce the amount of chemotherapy by 75% and also move the experimental T-cells until two weeks after the transplant to let things calm down.
So by reducing the chemotherapy 75% it turned the allogeneic transplant mostly into an outpatient type regimen because the drugs are not the dose that requires inpatient therapy for most of the patients. There were still some low blood counts, it wasn’t a trivial amount of chemotherapy but much reduced burden relative to where we started out. So we published that article in 2013 in Blood journal where we showed that regimen and we were on pretty good track with that. We were getting good responses in some of our patients, about half of the patients we had satisfactory effects against a whole variety of different tumors including some with multiple myeloma.
But I knew that that wasn’t the place where we wanted to rest. We had done about 40 patients and if you look at the main limitation in that study it was still tumor. So patients were still not adequately being treated for their lymphoma or myeloma or leukemia. So we made some additional changes into the manufacturing of the T-cells that made the cells even more powerful.
And what we saw then was our GVHD rate increased. Not to a crisis point but certainly to a point where we had about the same percent of patients having overall survival but if there was a death on the study it was more likely to be due to GVHD now. So we weren’t happy with that. We were intrigued that we had a cell that was very powerful in some patients that cause very dramatic tumor reductions but the safety wasn’t where it needed to be.
Given our previous experience, we further reasoned that we could further lower the amount of chemotherapy before the transplant to further improve the safety. So we thought we had a very active T-cell but we had too much chemotherapy before the transplant. So in the last approximately 15 patients, we’ve totally eliminated the amount of chemotherapy that we administer just before the transplant. So we’re fond to call it the zero-intensity transplant. Instead of reduced intensity, what we try to do is the patient may get chemotherapy at their private doctor’s office or university and then when they refer here for transplant, we would give them hopefully a two-week rest period where they don’t give any more chemotherapy and then when they go into the transplant, we don’t give the preparative chemotherapy. We simply put in the stem cells and then two weeks later put in the activated T-cells.
Jenny: Well, that’s revolutionary. I haven’t heard of that before.
Dr. Fowler: We’re very happy with this, it’s very preliminary results. Like I say we’ve done about 15 patients and we’re still learning how to do this. But we think it’s definitely a strategy that we’re going to invest in and the patients that are successful with this strategy are having greatly reduced side effects.
So that’s what we’ll be working on is basically shifting the component of treatment away from the chemotherapy which patients that are referred for transplant in general, if they were going to be cured by chemotherapy that are going to happen, they are already chemotherapy-resistant to some degree. So the rationale is why are we giving even more chemotherapy, let’s try to limit that and focus on administering more powerful T-cells.
Jenny: And this clinical study is for myeloma patients as well as other blood cancers?
Dr. Fowler: Yes. It’s open to multiple myeloma patients, it’s also open to patients with Hodgkin’s disease and non-Hodgkin’s lymphoma and the acute and chronic leukemias.
Jenny: And that’s open now, right?
Dr. Fowler: Yes. We anticipate keeping that open and extending in to new protocols and keeping the development of this new strategy long term.
Jenny: Well, a no chemo transplant sounds really amazing.
Dr. Fowler: I don’t want to give you the impression that patients could just come off the street and do it. These are all patients who’ve been relatively heavily treated in the past so their immune systems have already been beaten down to a significant degree. But that’s an important finding that because of that we don’t need to do too much more preparation. We can still get the transplant accepted into their body without it being rejected and if it can do that, we can hopefully do the transplant safer and still get the disease remissions that everyone’s after.
Jenny: And in terms of allo, what percentage of myeloma patients, do you believe, get an allotransplant versus autologous? It’s much smaller than autologous, I’m sure, but I don’t know.
Dr. Fowler: Yes. The thing is allogeneic transplant in general because of our history of using very high dose conditioning, because of our history of graft-versus-host disease, when the practitioner is thinking “Do I refer my patient for myeloma for transplant?” they may remember back to when they were training when they were giving a lot of radiation. So there’ve been a lot of improvements in the way transplants administer, but at the same time there are advances in the different medications, the drugs and antibodies.
So it’s nice in the way there’s been developments on different sides of the equation but in general, allogeneic transplant I think is being relegated to consideration in a very late stage of myeloma, which I don’t think is unreasonable. I think when you’re a myeloma patient, if I were in that situation I would want to play out all of the therapeutic strategies that are available as long as they have a good safety profile and have a chance of quality of life. And then the other thing is that you’re not losing your future option of going to allogeneic transplant if the other strategy stops working.
Now what I would hope is that we would develop a strategy of allogeneic transplant that is so safe and so effective that people would start to say well in the past we reserved myeloma treatment for after four or five different regimens, but now that it’s so safe let’s try to move it up in the treatment algorithm. But I don’t think we’re there yet, certainly not in the standard transplant approaches. There are probably too many good treatment options to make that conclusion at this point.
Jenny: Yes. And if that’s the case, you might want to consider something completely different like this because your outcomes are going to not be what you think of as standard with allo.
Let’s move on then to your application of the same Th1 and Th2 within the autologous transplant because you have an open clinical study. Can you explain how that study is created and how it works?
Dr. Fowler: Yes, absolutely. So we spent most of our time working on the allogeneic strategy and in particular in our initial mouse models and then in these clinical trials which sequentially from 1999 up to the current point we’ve had many different iterations of this strategy to supplement our allogeneic transplants with so-called Th2 cells or the T-rapa cells now.
When we grow these T-cells in the incubator we add a cytokine called IL4 and that’s a cytokine that will cause the T-cells to move toward the Th2, the anti-inflammatory state. Now in the autologous setting, GVHD is not the prime consideration because it’s the patient’s own immune system going back. If you read the literature you can find a few articles out there where GVHD can occur with an autologous cell transfer. It’s very uncommon but the body’s own T-cells if they’re treated in certain ways can cause a GVHD-like syndrome, but it is not so common.
So what we reasoned in our autologous multiple myeloma protocol, when we’re taking the T-cells, this time from the patient’s own body and putting them in the incubator and culturing them with rapamycin, instead of adding IL4 we added a cytokine called interferon alfa. If you’re a historian of immune therapy, interferon alfa is one of the first cytokines that was associated with an antitumor effect. The reason interferon alfa is somewhat effective is it drives T-cells toward that Th1 phenotype, the pro-inflammatory tumor-fighting phenotype.
So because of those findings that we’re not so concerned about GVHD, it these known effects of interferon alfa, when we cultured our myeloma patients’ T-cells in the incubator, we would add not only rapamycin but now instead of IL4 we add interferon alfa to push the cells more toward the Th1 pro-inflammatory phenotype.
Jenny: So instead of pushing them to the Th2 you’re pushing them to the Th1 or you’re pushing both?
Dr. Fowler: Exactly.
Jenny: Oh, you’re doing more to the Th1. Okay.
Dr. Fowler: Pushing them toward the Th1.
Again, it’s kind of the yin and the yang. For the allo, we’re concerned more about GVHD, we push toward the Th2. For the autologous, because we’re concerned more about the tumor and the GVHD is not so much a concern, we push the cells toward the Th1.
In multiple myeloma, as you know, autologous bone marrow transplant or stem cell transplant has been used as one of the standards of care for getting a durable remission and is usually applied in the earlier stages of myeloma treatment and the strategy is largely based on high doses of chemotherapy, for example, drugs like melphalan can be administered in very high doses and eliminate the stem cell pool. This is a strategy that was developed to not only treat the multiple myeloma but then to improve the safety of that, the cryopreserved stem cells from the patient are reintroduced.
And that’s what the autologous stem cell transplant is predicated upon is mostly high-dose chemotherapy followed by a stem cell rescue. There’s not a huge amount of evidence that the stem cells themselves are mediating additional therapeutic benefit outside of rescuing the patient from the stem cell defect and the need to repopulate their blood counts. There are certainly to be some argument about that, maybe some cells are important as they reconstitute natural killer cells and so forth may also kill multiple myeloma cells. But in general the feeling is that an autologous stem cell transplant gives the patient an opportunity to receive very high doses of chemotherapy to reduce the multiple myeloma burden and the stem cells are mostly a rescue attempt.
So that’s the standard stem cell transplant. Unfortunately most patients with multiple myeloma will relapse after the autologous procedure at some point. It’s certainly very effective treatment for giving long terms survival but if you look at the survival curves and relapse curves eventually most of the patients will have a relapse. The angle that we took on this current protocol that we started here at NIH, I think it was starting around 2011, was that before the patient would go for their stem cell transplant, we would harvest their immune system, we would purify it and put it into the incubator with the interferon alfa and the rapamycin and then we would cryopreserve this Th1 type immune system. And then after the patient recovered from their standard of care stem cell transplant, autologous, we would administer back to them their own T-cells but this time it will be T-cells that were activated in the incubator under these conditions.
So that was how we started this protocol. Because it was phase I study where we didn’t know the dose of these T-cells that would be safe, we started only with patients with very high risk multiple myeloma based on their cytogenetics primarily. And we did just finish approximately a 20-patient part of that protocol where we evaluated different doses of T-cells and found basically that the cells were very safe when we administered them. We waited a month after the transplant at least to give the T-cells but we did not see any adverse side effects that we could attribute to these T-cells. They appear to be very safe; we didn’t find any autoimmune inflammatory diseases for example.
In the final part of this protocol we evaluated infusion of these T-cells with a very light chemotherapy regimen. This is a regimen that we developed here in my lab. It’s two drugs, one drug is called pentostatin and one drug is called cyclophosphamide (Cytoxan). And we developed a way to give these drugs in combination where we eliminate or drastically reduce the patient’s T-cell count but we keep the other count largely preserved. For example, the neutrophil count, we do not see significant reductions in that. And by giving that regimen, before we give the T-cells we’re able to bring down the patient’s T-cell counts and then when we put in our specialized T-cells, they — at least we hypothesize — will have a more advantageous environment to grow in so the cells will have more of an ability to proliferate in the body because we’ve eliminated some of the patient’s immune system. But it’s a way that we can give chemotherapy, hopefully make the T-cells work better in the body and to do that safely in an outpatient setting by using chemotherapy that specifically can target the T-cells and leave the other blood counts more or less alone.
Jenny: And so you kind of have three phases to it. So you do the stem cell transplant and then a month after you do this other light chemo and then give your therapy. Is that correct?
Dr. Fowler: That is correct. We did the initial 20 patients and we worked through some of these variables as far as what dose of T-cells and what type of chemotherapy we could give. And at this point we recently amended the protocol and now we’re looking at very standard regimen is going to be the same in each patient and in that regimen is we will give the T-cells and we’ll give these outpatient chemotherapy drugs in certain combinations, certain number of days and that’s the nature, the study now is more I would say kind of in a phase II or pilot-type nature. We already have a fixed dose of T-cells that we’ve identified that we’re going to focus on that’s safe.
The other important thing that I wanted to mention, we are continuing our effort to rebuild the immune system after an autologous stem cell transplant that’s based on what I just outlined. And we opened another arm of the study where we would do the T-cell therapy in isolation. In other words, it would not be linked to any stem cell transplant. That is if these T-cells indeed are effective in fighting multiple myeloma, then we would not necessarily have to link them to a stem cell transplant. And we’ve recently opened that part of the study, with that study we’re seeking to accrue patients who had at least two prior treatments for multiple myeloma. And for whatever reason they may not be a transplant candidate or maybe in the past they’ve had a transplant and now have a relapse, they could be potentially eligible to receive the rapamycin T-cell therapy alone. And we’ve written into the protocol where we infuse one dose of these T-cells approximately once a month for four months.
So we’re looking to have a very gradual type of immune therapy where it’s not a one-shot theory where you give a lot of chemo and hope for the best, but we’re trying to use it like chemotherapy was developed in the past where you give a cycle and then you wait a month and then you recondition the patient and give another cycle of T-cells, because we know in multiple myeloma and all of the other tumors as well, there’s a very high mutation rate in the myeloma. It can change very rapidly the antigens that are important and the job the immune system has to do is a very tall task because the tumor is changing as we treat. We might select out different types of multiple myeloma cells that are resistant to the treatment and therefore that’s kind of a built-in part of our strategy is we’re going to make the treatment less toxic but provide a longer course of treatment with multiple interventions and restaging of the disease as we treat the disease.
Jenny: So in this other arm are you giving the same light chemo once or you’re not using at all, you’re just doing it for four months?
Dr. Fowler: No. We give the pentostatin, which is an intravenous infusion. We give the drug on a Monday and a Thursday and we give the Cytoxan tablets on a Monday through Friday and then the next Monday we give the T-cells. So it’s a five-day regimen and then two days of rest on the weekend. This is all as outpatient. And then the cells are administered again as an outpatient usually on Monday. We like to think of it in that term.
Jenny: And then you do that every month for four months?
Dr. Fowler: Yes.
Jenny: Okay, that makes sense.
Dr. Fowler: Yes. That’s our goal now for patients having a side effect where they want to take a vacation. We have a little leeway and it doesn’t have to be exactly that, but that’s the idea.
And we also built in if a patient is not responding we can double down on the chemotherapy to make it a two-week regimen because we have evidence that if you give even more immune depletion then the T-cells that we give they’ll have even more potential to cause an effect in the body. The effectiveness of the T-cells, adoptively transfer T-cells, is highly dependent on the state of the immune system in the body. So we start off with a five-day regimen, if the patient is doing well we are going to continue. But if we have a patient that is not responding then we’ll try to make even more space for the T-cells.
Jenny: And a question about how these T1 and T2 cells work because I know in a lot of immunotherapies, they have specific targets that they’re going after. For example, they’re going after CS1 or CD38. So these don’t have particular targets, how do these cells know what to go after?
Dr. Fowler: Yes, that’s an important distinction in the immunotherapy. These T-cells, the immune system can recognize a myriad of different targets and in multiple myeloma there may be dozens of targets that the immune system may want to focus on at any one given point in time.
So the cells that we’re growing have a full repertoire. They are not skewed towards seeing this thing or that thing. They are full repertoire and any selection of the cell towards targeting this mutation or that mutation must occur then in vivo and we’re trying to look at that to find out what antigens are they recognizing. But that is the distinction here; we are not pre-selecting a target. We’re creating what we hope is a more resistant cell through the rapamycin, a more inflammatory cell through the interferon alfa, and we’re still relying on the body’s normal way of presenting tumor antigens to tell those T-cells what they are able to see on any particular myeloma at any one particular point in time.
So in that way it’s very different from a CAR T-cell that’s going to interact with CD19 or BCMA that we’re also doing protocol here in our branch on BCMA CAR cells. So it’s very different from those types of strategies, there is a little more of a holistic treatment where we’re letting the body decide, the tumor decide, which antigens to focus on.
It’s not too dissimilar then to the anti-PD1 approach that I know you guys talked about recently. In that approach you’re relying on a similar unknown about what the cells are targeting. Because when you give an anti-PD1 or anti-PDL1, what’s being done is you’re removing a generalized break on the immune system so that whatever T-cells are in the body and potentially reacting to the myeloma, the brake is taken off and now those cells are more free to target the tumor because you’ve taken off the brake. The targeting has already occurred, the antigen specificities are already determined, you’re simply removing the brake and whatever T-cells are responding to whichever mutation, they are more free now to do what they are supposed to do without the brake being on.
So that’s also a more global strategy to immunotherapy where you’re simply removing the brake. I think our strategy here is very similar. These T-cells that are cultured in rapamycin and interferon alfa, they’re very active T-cells. Essentially their brake has been taken off during incubation of the cells. We’ve created a T-cell that has more ability to do things when it’s put into the body. So in a way there are a lot of similarities I think between this strategy here and the anti-PD1 strategies and then those are in contrast to the CAR studies or TCR studies where you’re really trying to focus the immune system on one particular antigen.
Jenny: That makes a lot of sense, thank you so much. We’re almost out of time but I’d like to open it up for caller questions. And I might have some additional follow up questions but I want to give time for that.
So if you have a question for Dr. Fowler, you can call 347-637-2631 and press 1 on your keypad.
Caller: Hi, thank you for taking my call, fascinating interview. I’m really interested in the allo transplant. When I was diagnosed in 2012 it was one of those things that my diagnosing physician kind of mentioned that someday potentially that was sort of on the table. Other oncologists that I’ve seen since then have mostly said that they don’t ever want to use an allo. At what point do you suggest doing an allo and where can I find more information about that clinical trial?
Dr. Fowler: Well, you can contact me. Maybe you can contact your organization there, your radio station and have you get in contact with me by email and then we could talk on the phone and review some of your records. It really is more of a personalized case-by-case decision and a lot of times, doctors they may not know what we’re doing here. I mean everyone doesn’t get a Twitter feed of what we’re doing here at NIH and so forth. It’s really a complicated decision that deserves a lot of review. I’ll be happy to go over your particular case.
Caller: Another question. So for Medicare patients, and I know that we have a lot of myeloma patients who are on Medicare, is that something that’s covered for this trial?
Dr. Fowler: Well, I’m very fortunate to work at NIH here in the Clinical Center, we don’t take insurance money. So we’re part of the Federal government and we don’t charge for any of our clinical trials. So all of the treatments are covered regardless of insurance policy or not. We even pay some of the travel to NIH and can provide some stipend for housing. We can’t cover all of those types of extra cost but to a large extent they can be defrayed. So yes, all the treatments should be available regardless of insurance status.
Caller: One last question, how much time is required for travel if one could do this trial?
Dr. Fowler: Well, in the transplant where we’re not giving chemotherapy prior to the transplant, almost all the patients are outpatient requiring only one or two clinic visits per week; we’re getting more liberal in terms of letting patients go. And traditionally with the transplant people would need to be inpatient for one or two months and stay in the area for at least 100 days to take care of complications. But since we’re hopefully not going to be having this degree of complications that patients be more free to come and go, get a lot of their care at their home physicians – that’s our plan to get people back into their community.
Caller: Thank you.
Jenny: Okay. We have another caller – go ahead with your question.
Caller: Hi! Good afternoon, Dr. Fowler. I’m very intrigued listening to your interview today with Jenny. It’s very, very complicated obviously. I’m a smoldering myeloma patient and I’m in a phase now where I’m just really trying to learn as much as I can so should I need to go forward with treatments someday I’ll be able to be more educated about what my options are.
Obviously your research is beyond the smoldering category but I was really sitting and listening to you about all of the immune system involvement and wondering if while the immune system might not yet be so grossly dysfunctional at the smoldering stage, do you and your fellow researchers ever imagine moving something like this into the smoldering myeloma patient cohort?
Dr. Fowler: I would say you have a great point. The philosophy when developing new treatments, they might be risky; one doesn’t know how toxic they’re going to be. Luckily with the treatment we developed it appears to be very safe. We haven’t seen any significant side effects in 20 patients so far treated.
I have thought about that that as we continue to develop and understand the T-cells especially if we have further evidence that they’re effective, then they can be brought earlier into the treatment algorithm. And as you’re saying the earliest treatment would be a smoldering type where maybe even small doses of T-cells to keep the T-cell arm of the immune system as robust as possible without causing autoimmune disease or some other problem, may be very effective in terms of keeping the myeloma progression at bay.
So I think it’s a great point and I would hope that as we develop these strategies that we can keep them safe and then other investigators can look at them and earlier or even preventative indications.
Caller: That would really be amazing if that were to come to pass. Dr. Fowler, you mentioned something though about the autoimmune aspects of it. Would your current trial for anybody even with myeloma, would they be precluded from this trial if they have existing autoimmune disorders?
Dr. Fowler: I think it would depend on the extent of that disorder. I think if someone had severe lupus or multiple sclerosis it probably would not be a good idea – that other experimental options would be more favorable to investigate. Maybe even an allogeneic transplant would be better as long as the donor were not afflicted by the autoimmune disease.
Caller: So the autoimmune disease complicates patient treatment, it sounds.
Dr. Fowler: Yes. I mean we haven’t run into too many problems with patients having both multiple myeloma and autoimmune diseases. These diseases are not rare but then again, they’re not the most common diseases either, so it’s not a huge barrier.
Caller: As a myeloma researcher, how would you guide a smoldering myeloma patient in this stage of ongoing research? There are not many, many trials out there for smoldering myeloma patients out there but there are several. Some of the newer ones that are just hitting the smoldering road or daratumumab or the monoclonal antibodies, just your research and what you’re doing with T-cells and the immune system, do you see these types of trials holding promise in this early stage? I realize that that’s a very hypothetical question and that’s what everyone’s trying to answer, but just from what you know, can you share some insight?
Dr. Fowler: I would say it’s a very meritorious area of research. I would say that if I were in your situation or investigators that are focusing on that, that is a very meritorious thing. We know that cancer will wax and wane in response to variations in the immune system. People that are immunodeficient, they have higher rates of cancer and so it’s not been unusual to predict that smoldering myeloma patients have a more robust immune system or immune system better able to kill cells as they’re trying to develop into full-blown cancer will be an advantage.
So if there are protocols that are seeking to target cells or rebuild the immune system or vaccinate patients, as long as you review the risk and potential benefit of these strategies, yes, I would say that’s a very good thing to be thinking about as well as maintaining your quality of life and nutrition and all these other factors that are very important for everybody to think about.
Caller: Well, thank you, Dr. Fowler, for all the research that you’re doing. It gives myeloma patients in my situation, a smoldering myeloma patient who’s waiting for the other shoe to drop, a lot of hope knowing that perhaps there will be curative approaches when we need to face these tough decisions to make. So thank you, thank you very much. And thank you, Jenny, for taking my call.
Jenny: Oh, thanks for your question. We have another caller, please go ahead with your question.
Caller: Thank you, Jenny and Dr. Fowler, very strong interview. Can someone have a transplant somewhere else and then come and get their rapamycin treatment?
Dr. Fowler: Yes, we’re working on that. That’s a very great question. We are collaborating with Hackensack University up in New Jersey and they have a very strong multiple myeloma program there and I have collaborations with the group there. And we’ve been able to do that to work with outside institutions including in the allogeneic transplant, they’ve been able to reproduce many of our results there.
So that’s our idea or that’s our vision that we’ll be able to have patients get their standard of care treatments at home and then we could do the experimental therapies here at NIH. Potentially if things start to develop and become more convincing then we’ll have other institutions do the experimental components. So it’s possible. We haven’t done that in a broad way right now so I would have to try to work with you on that. We have certain regulatory requirements in terms of monitoring data that’s being done in other institutions so there’s a little bit of a bureaucracy there so we have to do things in the correct way. But that’s at least our model, we’re not fully able to do that across the board for all patients right now but it’s something that we’re working toward.
Are you getting a stem cell transplant soon or are you thinking about it?
Caller: Yup, just thinking about it.
Dr. Fowler: We would like to be able to offer that, it’s kind of a regulatory hurdle. If not then we could offer the stem cell transplant here where we give the standard approach. And then as I mentioned, we do have the other arm as a protocol where we are giving the T-cell therapy independent of any stem cell transplant. So if you were going to get a standard care transplant at your institution, hopefully that will keep you in remission for a long time. If you were to relapse then you could potentially come on under the arm of the study.
Caller: Sounds like there’s a lot of flexibility in your program.
Dr. Fowler: Yes.
Caller: Thank you very much.
Jenny: Okay, thanks for your question. And our last caller, go ahead with your question.
Caller: Thanks, Jenny and thanks, Dr. Fowler. It’s a great interview, really appreciate your time. So a question, would you consider using the rapamycin approach with other myeloma non-chemo approaches?
Dr. Fowler: Can you clarify the question? I’m not certain I know where you’re coming at with that.
Jenny: I think what he might mean is other standard myeloma therapies — Velcade, Revlimid — all the standard.
Caller: Exactly, yes.
Dr. Fowler: I think whenever you combine things you can always end up with a toxic brew. These drugs like Revlimid, I’ve studied that in my own laboratory, they can have very powerful effects on the immune system. In fact, to some degree, how Revlimid can work is by activating T-cells so then you throw that into a T-cell that’s already activated, you could come up with some surprises or maybe some beneficial effects as well. In fact, I’ve tried to manufacture cells using Revlimid in the incubator as well, so it’s a very good question that you’re asking and there is some rationale for doing that.
It’s a matter of developing one thing to a very fine extent and seeing what the limitations are and then seeing if it’s advantageous and to overlay another immune modulation strategy like a Revlimid which can also have a direct effect on the tumor cells. So it does make a lot of sense. You have a bright future in protocol design, it sounds like.
Caller: I appreciate that, thank you very much.
Dr. Fowler: That’s a very good point.
Jenny: Thank you so much for your question.
Well, Dr. Fowler, my last question is I don’t know how at liberty you are to talk about study results but if you have interesting results or observations that you’ve seen so far, I would just welcome you to share them before we close.
Dr. Fowler: The allogeneic protocol we’re very happy with that because we’re now able to do the transplant and do it much safer and it’s obviously 15 patients, we need to do a lot of patients to make sure we’re still preserving our antitumor effect and improving the overall survival. And we need to treat more myeloma patients as well to get bigger numbers there.
In terms of the autologous treatment, we’ve done 20 patients and we’re submitting an abstract to a conference this winter and we think these are very good preliminary phase I results where we have identified a T-cell dose that’s safe; we’ve found some chemotherapy where when we give the T-cells with this type of chemotherapy, it also appears to be safe. It’s hard when you’re talking about tumor remission and progression-free survival. When patients are getting an ablative type of chemotherapy and a stem cell transplant, many of those patients will go on to live three years, five years without having a relapse and we don’t have a randomized control group in this study. This is all single-arm study.
Nonetheless, we accepted only patients with high-risk myeloma which have a pretty high chance of relapsing within the first year or two post-transplants especially patients with bad cytogenetic multiple myeloma. We have at last tally I think five out of our 20 patients have not relapsed; they are now out going on 2 ½- 3 years from the transplant. A couple of patients with very bad disease where some of my colleagues thought for sure this is not going to be a case that should stay in remission.
So there are some anecdotes like that. There’s certainly nothing that we can prove that these T-cells are doing something but we’re certainly doing no worse than what one would expect and potentially better. And it’s certainly enough evidence that we should move forward and try now that we’ve done the safety component of the study to move on to identify more definitive evidence that we’re actually providing the antitumor benefit and that’s what we hope to do over the next round of protocol implementation.
Jenny: And that’s terrific. Well, we are so grateful that you took the time today to explain what you’re doing because it’s just fascinating. And the research that has gone into it just shows that there are just decades’ worth of brainpower on these types of approaches by very talented people like yourself.
Dr. Fowler: We’ve been very fortunate, like you say, consistent research effort over a couple decades to grow as the field of immunology grows and our ability to try to bring these interventions from the animal models into the clinical trial and then back into the animal models. It’s been a back and forth interaction and we’ve been very fortunate here at the NIH to get this level of support and of course all the patients who have allowed us to participate in their care. So it’s been a very magnificent journey.
Jenny: Well, thank you for what you’re doing. We know that if patients join clinical trials in greater numbers, we could really hit the gas on some of the outcomes and some of the data that you need to be able to change things and move forward in a better way.
Dr. Fowler: Right.
Jenny: So, Dr. Fowler, thank you so much for joining us today, we really appreciate it and we wish you all the best with your research.
Dr. Fowler: Thank you very much. You know my contact information so if there’s any further questions, I’m happy to further help you out.
Jenny: Okay, great. Thank you so much.
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