Ivan Borrello, MD Johns Hopkins School of Medicine Interview Date: December, 2016 

The Myeloma Crowd Research Initiative is funding two immunotherapy projects. In this show we hear an update on the T-cell project being funded by the MCRI for Dr. Ivan Borrello's MILs (marrow infiltrating lymphocytes). Designed first for high risk myeloma patients, the treatment consists of a bone marrow T-cell sample being withdrawn and then grown up a hundred fold in the presence of their tumor. A few days after transplant, these tumor-specific T-cells are then given back to the patient. The MILs approach is now two years into a phase II clinical trial. Dr. Borrello gives us an update on this open clinical trial for high risk patients and shares how is also using the MILs with allogeneic transplant and other future combinations (like with checkpoint inhibitors) and in earlier settings. This immunotherapy can be used in almost 100% of patients with fewer side effects than other types of immunotherapy approaches like CAR T cells. 

Thanks to our episode sponsor

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 Takeda Oncology for their support of the Myeloma Crowd Radio program.

Our show today is the second in our update on the Myeloma Crowd Research Initiative or MCRI . One year ago, we selected two projects to fund because we believe that patients can help find and fund potentially curative research for myeloma. At the beginning of 2015 we created an expert Scientific Advisory Board (Dr. Robert Orlowski of MD Anderson, Dr. Rafael Fonseca of Mayo, Dr. Guido Tricot of the U of I, Dr. Noopur Raje of Mass General, Dr. Irene Ghobrial of Dana Farber and Dr. Ola Landren of MSKCC), then invited patient advocates to join together for the project. Together, we decided to go after solutions for high-risk myeloma because these patients have terrible outcomes even with the great advances that have been made in the disease. We also think that by addressing high-risk, the new discoveries will ultimately help all patients because we all become high-risk at some point in the course of our disease. We called for letters of intent and received 36 high-quality proposals from top investigators around the world. Our scientific advisory board then scored these proposals and selected a top 10. We then chose two projects and this is one of the two that we are now funding. With your help, we began raising funds. We are excited to announce that with your support we have raised over $400,000 so far for these projects. This is fabulous and we are so grateful to you. In 2016 we donated $100,000 to each project and today’s show is an important status update to see where the project is now and where it is headed. Additional funding will be given to the projects based on progress and need. Our ultimate goal is to raise $500,000 for the projects. With your support we could do this by the end of 2016. Take a look at myelomacrowd.org and find the donate or create a page button on the home page. You can join us to invite friends and family to make end-of-year donations towards a myeloma cure. Today we have with us Dr. Ivan Borrello from Johns Hopkins. Dr. Borrello just returned from ASH where he presented an update on this project in several sessions. Before we begin I’d like to share an introduction for Dr. Borrello. Dr. Ivan Borrello is Associate Professor of Oncology, Associate Professor of Cellular and Molecular Medicine for the graduate program, and Director of the Cellular Therapeutics Center at Johns Hopkins School of Medicine. Dr. Borrello and his team of researchers have focused on the development of tumor immunotherapy for blood cancers that use cancer vaccines as well as patient’s own immune system to fight their cancer. The particular treatments developed in Dr. Borrello’s laboratory are known as adaptive T cell therapy with MILs, which we will learn about today, and have broken new ground in the fight against diseases such as multiple myeloma. Dr. Borrello is the widely published author of many peer-reviewed articles and book chapters and a member of several national oncology organizations and professional societies. Dr. Borrello is asked to speak regularly at symposiums around the world. He’s received many honors and awards including the American Society for Clinical Oncology Scholarship Award, the Johns Hopkins University Clinician’s Scientist Award, the Kimmel Scholar Award, and the Leukemia and Lymphoma Society of America Clinical Translational Scholar Award. Dr. Borrello participated in a recent Myeloma Crowd Roundtable where I interviewed him about his MILs progress and the progress of his open clinical trials. Today’s show was recorded at that event. So let’s begin by asking you, Dr. Borrello to give an overview of MILs for those who aren’t familiar with the idea.

Dr. Borrello: We have developed this approach of adoptive T Cell therapy with non-gene modified T Cells that are coming from the tumor microenvironment which in the case of myeloma is the bone marrow. So we call these cells MILs, which stands for marrow infiltrating lymphocytes. The idea is that T Cells hone to where they are in touch with what they recognize. And so the highest likelihood of getting myeloma-specific in a patient is going to be in the bone marrow, which is myeloma resides. And in fact we have been working on this now for about 10-15 years and have shown that if we take the bone marrow out from patients and grow these cells up, these cells have a heightened myeloma-specific activity. So that’s the premise for the clinical trials that we’re conducting. The idea is that for patients who are interested in and eligible for the studies, they are going to bone marrow harvest of around 200 mls of bone marrow, which is approximately about a cup or 12 ounces of bone marrow. These cells are then activated in the lab, grown up, and then given back to the patient in the context of a transplant. So in our first trial what we showed was that there was a direct correlation between the ability to achieve a complete response and it correlated with the highest amount of myeloma-specific activity, which was encouraging for us because one it showed that we could take these cells, grow them up and that the in-vitro activity of these cells actually generated was then translatable to anti-myeloma activity in the patient. We are currently conducting a randomized trial specifically on the high-risk patient population. The trial is patients that meet certain eligibility which is defined by FISH criteria; 17p deletion, 4;14 translocation, 14;20 translocation, 14;16 translocation and 1q amplification. These patients then go on to get a bone marrow aspiration and then they are randomized in a 2:1 manner to get transplanted with MILs or without MILs. So 66% get the MILs and 33% don’t. And then they get Revlimid starting at around 2 months at 5 mg, which is a significantly lower dose that is what is normally given in the maintenance setting which is more around 10 or 15 mg. The rationale for the Revlimid that early on is to maintain this T Cell activation, taking advantage of its immunomodulatory properties. The funding that we are getting through the Myeloma Crowd Research Initiative is not to fund the trial. That’s already being funded. It’s really to try to answer a different question which is: of the patients who are responding, can we identify antigens that are specific to high-risk myeloma since this is what the trial is, and determine whether then we can ultimately make that identification and with that potentially go down to either developing either antibody targets or enriching for T Cells. Because right now what we’d like to do is see what the long-term overall efficacy is of the transplant itself, we are in the process right now of still collecting a lot of these samples and have not actually started with this analysis but hope to be able to do this in the next 3-6 months. Now that we have our first patients out two and a half years or so. The idea would be that within this next year we would do this initial analysis of screening of serum to identify antibodies and then once we have these antibodies to then go through to try to characterize the antibody responses to the two arm responses, specifically in the patients with high risk myeloma hopefully to see whether that is a response that is generated with the patients that got the MILs compared to the patients that didn’t get the MILs. There are several benefits of this trial. One, that it’s targeting a specific patient population and the second benefit is that we have this comparison between MILs versus non-MILs.

Jenny: And one thing you mentioned on the first show we did is that you’re growing up these T cells in the presence of the patient’s own tumor. Do you want to explain a little more why that is important or what you’ve found so far in your trial?

Dr. Borrello: Yes, so what we’ve shown from previous work, actually, is that we believe that it’s the tumor microenvironment that’s actually very important in terms of maintaining tumors alive. That’s clearly been shown, but also in terms of maintaining the T-cell specificity towards the myeloma. And so we made a conscientious effort in developing this clinical study to not isolate out the T-cells but to grow the T-cells in the context of the bone marrow microenvironment, and specifically within the context of tumor because we’ve actually done experiments showing that it’s the presence of tumor that keeps these T-cells more tumor-specific. So we did what we call criss-cross experiments where we took MILs and grew them in the bone marrow or took MILs and isolated them and then grew them or conversely took peripheral blood T-cells, grew them in the blood or grew them in the bone marrow and we were able to show that the best tumor-specific T-cells were the MILs that were grown in the bone marrow. Once we took them out, we lost a significant amount of tumor specificity. But interestingly, I think underscoring some of the unique aspects of of MILs, merely taking T-cells from the blood and putting them in the bone marrow did not restore a significant amount of tumor specificity. What I think this tells us is that one, we need tumor or the presence of tumor will make them more tumor-specific, but that intrinsically there is something unique about these T-cells in the bone marrow that is very differnet than the T-cells in the blood that we belive is one of the major reasons why they are a better source of T-cells for adoptive T-cell therapy.

Jenny: And when did you start the clinical trial and when do you hope to end the clinical trial that you’re currently running?

Dr. Borrello: Right. So this current clinical trial we put the first patient on in November of 2013. The idea is that 90 patients are going to be treated. We are currently up to 74 patients or so. We have now opened the trial up at other sites: Moffit in Tampa, Mayo in Jacksonville, and also Northside Hospital in Atlanta is going to be opening the study in the next few weeks. We’ve enrolled 72 and of those 72, I think 8 or so have dropped off either because their disease relapsed during that period of time or other things. I’m hoping to finish accrual up to the study sometime at the end of this year or hopefully first quarter of next year. The first analysis of this is going to be when half of the patients are at least 2 years out from transplant. Based on our accrual, that mid-time analysis is going to occur in the summer of next year.

Jenny: And do you have to wait for results to finish accruing or how does that work for clinical trials? Because I think one of the things we can talk about is participation in clinical trials because that’s a focus of this show.

Dr. Borrello: One thing that’s very interesting about what we have, I mean I don’t have any clinical data because ultimately, the randomized trial because of the way it was designed is that we are not going to look at it until at least 50% of patients are at least two years out. But the things that we can say are that we are able to grow the cells pretty much on everybody. We’ve had out of 40 or so patients that have been treated with MILs, I think one expansion failure. This is something that with CAR T cells people don’t talk about. Even with TILs. What’s the denominator of patients that are actually eligible for this? So our denominator is virtually 100% of patients. The other thing to mention is that it is a relatively safe procedure. The way we do transplant at Hopkins is that we do them as outpatients and patients get hospitalized if they develop some sort of complication. The most common complication in the transplant setting is fevers – the absence of white cells, or neutropenic fevers. What I can tell you that we are seeing is a higher incidence of hospitalization from neutropenic fevers in the patients that are getting MILs and slightly higher incidences of rashes and of diarhhea. But all of these symptoms are self-sustained and we have never had to treat anybody. So this is very, very different from the cytokine release syndrome that patients treated with CAR T cells are getting that is often ending them up in ICUs and I think up until now has really relegated that kind of aggressive T cell therapy to patients that are multiply relapsed that have very few other options. If this data turns out to be positive, and as we’re doing this we’re basically doing this in the up-front setting, I think this is one of the distinguishing features of MILs related T cell therapy compared to CAR T cell in its current formulation.

Jenny: And this might not be something you are measuring in this clinical trial, but in terms of recovery from the transplant, have you seen a difference in the patients on the MILs arm and not the MILs arm? And then do you also want to talk about offering the MILs if patients relapse?

Dr. Borrello: Yes. So the thing that we’re seeing is that the immune system of the patients on MILs are having their immune system come back quicker because they’re getting an immune system. We’re seeing very few opportunistic infections and I think we can say that we’ve seen fewer in the MILs/transplanted patients compared to the non-MILs patients. Certainly quality of life I think (it’s not something that we’re formally measuring but we would like to measure) I can tell you that once a patient is a month or so out, they seem to be doing well. If they are doing significantly better than patients that haven’t gotten MILs, I honestly can’t formally tell you that. But the other point you mentioned is an important one. This is a randomized trial where one third of the patients are not getting MILs with the transplant. But what they are going to be able to get are MILs at the time of relapse. The protocol that we are in the process of finalizing is I think also very intersting because it’s different. The idea would be to combine MILs with PD-1 blockade and Revlimid. This really builds upon several pieces of data. One is the fact that there is now evidence to suggest that PD-1 blockade alone does not work effectively in myeloma. And that the only way it does work is when it’s combined with an iMiD. But then the other aspect of this is one of the benefits of adoptive T-cell therapy is that it allows you to regulate a lot of these components of how and when to come in with defined therapies. The trial that we’re designing we’re going to be giving the PD-1 before we give the MILs. The idea is that we’re going to block PD-1 on the T-cells before they even have a possibility of encountering the tumor and therefore becoming energized. We hope that that one intervention alone can even further augment the overall efficacy of MILs therapy, not to mention the PD-1 that they’ll be getting every 2-3 week intervals post transplant.

Jenny: You’re looking for patients to join to finish up the trial. How much longer from the time you finish accruing patients until the trial is closed and what is your next step?

Dr. Borrello: The time until it’s closed is going to be in large part driven by events. If we get a lot of relapses on the standard transplant arm, and very few relapses on the MILs arm, then obviously we’ll get an answer much quicker than if it looks like the difference is significantly smaller. In terms of the next step, a lot of it is going to be dicated by what we are going to see. If we see a dramatic difference, then one thing we are planning on doing would be to think about a Phase III trial or maybe even doing something to try to get this into patients earlier. If in contrast, we don’t see that kind of difference then we have to go back to the drawing board and figure out what went wrong and how can we improve upon it.

Jenny: You recently started a company around this idea. So it seems that you think it has a lot of promise in many different applications?

Dr. Borrello: Yes it does. Based on this MILs technology, I’m a co-founder of a company that’s called Windmil Therapeutics and the idea is to build a therapeutic platform around MILs therapy. For obvious reasons the myeloma program is the furthest along in large part because that’s the disease that I see and that’s where we’ve conduced the largest number of trials. But we are also looking at examining these cells in a variety of different diseases in large part based on the biology of what the bone marrow is and what the T cells in the bone marrow can actually be. We are looking into a possiblity of deploying this in the solid tumor arena which may sound a little bit counter-intuitive. But it’s based on data that we are currently in the process of finding. I’m really hopeful that this will open up a whole new line of research.

Jenny: Let me ask a follow up question from what you just said. You said you are thinking about using it in solid tumors. So how does that work if you are pulling something out of the bone marrow and myeloma is a blood cancer. Are you looking at other blood cancers or for other types of myeloma transplants?

Dr. Borrello: We currently have a trial where we’re giving MILs following an allogeneic transplant where in contrast to what the “standard of therapy” is, that you would go back to your donor and get something called DLI (donor lymphocyte infusion), in this case we are going into the patient and we’ve been able to show that we can take bone marrow out of the patient and grow up these T-cells which are actually of the donor and in so doing, give them back a product that is significantly enriched for tumor-specific T-cells and dramatically depleted T-cells that would normally cause graft vs. host disease. The idea of the allogeneic transplant setting is that we would hopefull be able to get around the need for tracking down the donor and getting these T-cells from the donor. But more importantly, eliminating the toxicity and improving the overall efficacy of this approach. We have now treated about 7 or 8 patients at Hopkins and what we’ve been able to show is that we are seeing no graft vs. host disease. This is a classic phase I trial where we are starting off at a low dose and gradually increasing the overall dose. The first patient that was treated was actually a patient of mine with a plasma cell leukemia who got a very nice initial response that lasted over a year. Now the idea is for her to go back on the trial at a higher dose and see if we can potentiate that response even longer. But as you know allogeneic transplant is really used more in other hematologic malignancies – leukemia, lymphoma and so we have patients in those settings as well. The challenge with leukemia oftentimes is that when the disease relapses, it relapses very quickly and so we’ve had problems growing T-cells from patients in which the bone marrow is 80-90% tumor (leukemia). Whereas in the myeloma setting it tends to be a much slower process and allows us a slightly easier leeway in terms of actually growing it. But nevertheless it is a challenge that we can easily overcome.

Jenny: Dr. Borrello, thank you so much for joining us today. We’re excited about your progress and your project and can’t wait to hear more about your upcoming findings and we know we’ll hear more about that in the future. Thanks for listening to another episode of Myeloma Crowd Radio. We look forward to helping you understand more about what research is happening in the new year.