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    • Myeloma Crowd Radio Episodes
    • Nov 07, 2019

    Full Show: Weighing Cancer Cells for Personalized Myeloma Therapy with Clifford Reid, PhD, Travera

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Clifford Reid, PhD
Travera 
Interview Date: October 23, 2019

Thanks to our episode sponsor

Summary

Can you tell how well a myeloma treatment might work on your personal tumor by weighing the cancer cells? Clifford Reid, PhD and CEO of Travera shares a new approach to “personalized medicine” in multiple myeloma. Cancer cells have different weights or mass at cell death. In this early clinical study, a small number of myeloma cells are taken from a bone marrow biopsy and tested against individual treatments typically given to myeloma patients. The cell weight is measured and can identify treatments that are more effective at killing the cells than others. It could also potentially test other FDA approved drugs not currently used for myeloma treatment. The study is open for newly diagnosed untreated patients as well as relapsed patients. This revolutionary approach could take the guess work out of picking a next therapy combination based on how well it will work for your individual myeloma tumor at a specific point in time. This is a truly remarkable approach that could identify better and more curative therapies for individual myeloma patients. 

To learn more, click here: 

Travera Multiple Myeloma Cell Mass Clinical Trial

 

Dr. Reid on Myeloma Crowd Radio

Full Transcript

Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We’d like to thank our episode sponsor, GlaxoSmithKline, for their support of Myeloma Crowd Radio.

Before we get started with today’s show, we’d like to share an update on the tool we created called HealthTree. We created HealthTree to help you as a myeloma patient better navigate your disease. You can track everything about your myeloma in a single place, you can see personally relevant treatment options, you can find clinical trials you’re eligible to join and soon, you’ll be able to find your twin or other myeloma patients with similar features and chat with them anonymously.

We’d like to announce that you can now automatically import your lab records from your online portal at a hospital if your facility has integrated with Apple Health. This includes over 900 hospital systems throughout the United States. It requires an iPhone or our HealthTree support team can also do this for you at your request if you don’t have an iPhone. Because many myeloma patients are being in several centers, this gives you a way to bring in all your lab data accurately and easily without having to do that manually. We’re super excited about that feature and invite you to join HeathTree and help track your myeloma in a single place.

Now, on to today’s show. I’d like to introduce Dr. Clifford Reid. He is the founding CEO of Travera. Previously, Dr. Reid was the founding Chairman, President, and CEO of Complete Genomics, a leading developer of whole human genome DNA sequencing technologies and services. Prior to Complete Genomics, he founded two enterprise software companies – Eloquent, an internet video company, and Verity, an enterprise search engine company.

Dr. Reid is on the Visiting Committee of the Biological Engineering Department at the MIT, a member of the MIT Corporation Development Committee, and an advisor to the private equity firm, Warburg Pincus.  He earned a Bachelors in Science in Physics from MIT, an MBA from the Harvard Business School, and a Ph.D. in Management Science and Engineering from Stanford University.

Dr. Reid is now working on a new approach towards more personalized myeloma treatment. As we know, each of us are unique as myeloma patients and our myeloma can change over the course of our care which makes things extra complicated. He is now testing how effective a treatment or treatment combination might be before it’s given to a myeloma patient through his work at Travera and we are very excited to learn about this new approach.

Dr. Reid, welcome.

Dr. Reid: Thank you for having my, Jenny.

Jenny: We’re excited to hear more about your program and what this can do. Maybe you just want to start by giving us an overview of this approach in general because it’s really a completely different concept in terms of trying to personalize medicine. We hear about personalized medicine all the time by targeting genomics with specific type of drugs or other types of things. But this is a really unique approach.

Dr. Reid: Great. Thanks so much, Jenny. I appreciate it. As I mentioned, I’ve been very engaged in the genomics sequencing business for many years as the CEO of Complete Genomics. As you’ve seen the results of personalized medicine for cancer be not quite what we had hoped and in particular, as you all know, there are no biomarkers for myeloma patients.

We’re taking a completely different approach. Let me tell you just a little bit about it. It’s based on two things. It’s based on a new invention and a new discovery. First, a new invention. This is an invention created at MIT which is simply a scale for weighing single cancer cells with exquisite accuracy about a hundred times more accurate than any other method for weighing single cells. That’s the invention.

Then the discovery is a part that was done by MIT scientists and Dana-Farber oncologists. What they discovered is that cancer cells lose a tiny amount of weight very quickly in response to effective cancer drugs. The amount of weight they lose is previously much too small to be measured, but that’s what the invention does.

Using the combination of this new invention and this new discovery, we can create a new cancer drug effectiveness test. What we do is collect patients’ live cancer cells expose them to many different drugs are now ex vivo in our lab, not of the patient, measure the weight response of the cells to each drug and determine which of the drugs will be effective for that particular patient at that particular moment in time.

Jenny: Well, that’s fascinating because as we know, myeloma changes over time so the disease that you have when you are first diagnosed is not necessarily the disease that you have after your relapse or even after a second or a third relapse because your disease might be changing. Some patients have disease that’s similar, but there’s quite a bit of genetic instability or genomic changes that are occurring. So to be able to weigh the cells and have that tell us, that’s truly amazing.

Dr. Reid: That’s the key point is that we don’t care about the genetics of the cells because as you said, the genetics are changing and we don’t really know everything about the genetics and how to map them to drugs. By just measuring the weight change of the cell, this is a drug independent and cell independent method of determining which drugs are going to work for which cancer patients.

Jenny: That’s amazing. We did a show earlier with Dr. William Matsui and he was expressing the challenges of this older precision medicine approach where you try to match a genetic mutation with a particular drug. He was just saying how difficult that’s going to be and how long that will take to do and to identify.

I know nationally, they’ve run a study trying to do that in a variety of cancers for a particular mutation and the results weren’t that great. This is an amazing approach to be able to just weigh the cells. Can you go into little more detail about the process and maybe a little more detail about the new invention? Because it might be a little complicated to describe. I think patients would be interested in understanding how that works.

Dr. Reid: Sure. Up to now, the way you weigh cells is with a microscope. You take a picture of them, you find out their diameter and then you multiply by volume and density to get the weight. We don’t do that all. What Scott Manalis and his team at MIT invented is a MEMS device, this is a lab-on-a-chip that’s manufactured in semiconductor fabrication facility and what is built into this little chip is a diving board. It’s a little diving board, the fancy word for that is cantilever, and the diving board has a fluidics channel that runs down to the end of the diving board and back.

Every diving board has a natural resonant frequency and the natural resonant frequency is directly proportionate to the mass of the diving board. What we do is we take a single cell, we plow it down the diving board, and we measure the change of its resonant frequency and by making that measurement, we can extremely accurately measure the weight of the single cell without harming it

The accuracy of measurement is about one part in a billion. That means we can detect the change of a single cell diameter, the equivalent of the microscope method of about three nanometers. Now, what’s a nanometer? The wave length of visible light is 400 nanometers. This is a hundred times more accurate than any microscope can ever be due to the laws of physics. It’s an extraordinary invention that for the very first time gives us the ability to measure these tiny, tiny little weight changes measured in femtograms and picograms. No one’s ever been able to measure before, but it turns out, cancer drugs that work on cells causes them to shrink by a few picograms and for the first time, we can measure it.

Jenny: Well, that’s amazing. When the patient is donating a sample, are they donating a blood sample? Are they donating a bone marrow biopsy sample? Then I have a whole bunch of questions about how you process the samples.

Dr. Reid: All right. Let’s start with the sample itself. Unfortunately, there simply aren’t enough myeloma cells in peripheral blood for us to run our tests so we can’t do this yet with a blood sample. We do require a bone marrow sample.

Jenny: Well, that makes sense. Most of the critical tests are being still run on the bone marrow sample, we’re always hopeful, but that’s great. It’s I think well understood by patients that that’s going to be necessary.

Then you said you’re not necessarily testing genetics. It’s genetic agnostic. It doesn’t make sense. It doesn’t sound like you’re growing up a culture of these cells. When you get the bone marrow biopsy and you’re testing it against different samples, how many cells do you need? Is the bone marrow sample quality ever an issue because sometimes when we go in and get a bone marrow biopsy, they’re sending it for a genomic testing and they’re sending it for this and they’re sending it for that? How do you use that sample?

Dr. Reid: Your premise is exactly correct. We do not take the cells and then culture them, try to get them to grow up and proliferate in the dish in order to create more cells. The key reason we don’t do that is because you probably know there are many examples of drug effectiveness tests based on proliferating cancer cells in the lab. It simply hasn’t worked.

We now know that when you grow up cancer cells, because they are so genetically damaged to start with, they do not reproduce themselves faithfully. The culture that you grow up ends up living but it doesn’t any longer accurately reflect those cells as they exist in the patient.

Fortunately, our technology uses very few cells. We don’t have to grow them up to get enough cells to use. We can just use the cells that we get from bone marrow specifically, the number of cells that we require to test a drug for a patient is a thousand. That’s just one drug so we test a panel of many drugs and so we need only a few tens of thousands of cells to be able to do the test.

A typical bone marrow biopsy, first pull of a bone marrow biopsy, will have millions of cells, at least a million, and that’s typically the number of cells required to do genetic testing, but our test, because it’s a single cell test, we only need a very small number of cells so we can co-exist nicely with the genetic testing assays that require a lot more sample than we need.

Jenny: Then when you’re looking at the different combinations or treatments, I mean there are so many different options. You have 30 to 40 treatment combinations now that you can use. Are you testing them individually first? Do you then test them in a doublet or a triplet or a quad? I mean what’s your process to go through all the different myeloma therapies that are available to be tested?

Dr. Reid: There are two answers to that. The first is our clinical study that we’re running right now, and there, we are testing mostly triplets and quads because what we are testing in our study is the exact combination the oncologist plans to give the patient. We want to get the bone marrow, run that therapy or combo therapy against the cells, make a prediction of whether or not the drug is going to work and then have the oncologist give the patient the drug and within four months, tell us did it work or not? Then we’ll be able to calculate the accuracy of our assay.

That’s what we’re doing right now in our study. However, as we look forward, after the clinical validation study is done, we’re going to make this available to oncologists and their patients as a laboratory developed test. We’ve been talking to our oncology partners about what they would like to see, and for the most part, our oncology partners simply want us to test monotherapies. They want us to test each of lenalidomide, pomalidomide, dexamethasone, carfilzomib, bortezomib as monotherapies.

Then they will make the decision about which of those monotherapies to combine to give to the patient based on all the other patient considers. We can do both and we will do both but we think our study is going to be more about combinations and our commercial product will be more about monotherapies.

Jenny: Great. Well, I want to come back to your clinical study because I want to learn more about that and how you’re doing that and who you’re including and things like that, but let me go back to some questions.

When you’re doing this testing, how long do you need to keep this bone marrow sample alive and I know when you were talking earlier, and I’ve heard this from other investigators before, sometimes you can take myeloma cells out and they don’t stay alive very well without the bone marrow microenvironment, so what’s the relationship with the bone marrow microenvironment in your test? How long do these cells need to stay alive?

Dr. Reid: It’s a great question. One we’ve investigated pretty thoroughly. If you leave the cells in the bone marrow, they’re happy and healthy for many days. Amrita Krishnan (at City of Hope) does infusions and leaves them in marrow at room temperature for two days and they’re just fine. We use that fact to ship cells overnight. When a patient gets a biopsy, we leave the cells in the marrow and then we ship them overnight to our lab in Cambridge, Massachusetts

In our lab, when we open the overnight shipping container in the morning, the first thing we do is purify the cell using CD138 positive markers, we take them out of the bone marrow. At that point, the clock starts ticking. What we found is that myeloma cells mostly die at 36 hours after purifying them. That again would defeat most assays that take many days to grow up cells and it just wouldn’t work, but fortunately, our technology is same day.

We make all of the measurements the same day that we purify the cells. We purify the cells in the morning, we spend the workday making all the measurements we need to make then we do the computer analysis, produce the report, and can actually have it back to the oncologist at the end of the day.

That one-day process enables us to use the purified myeloma cells while they’re still relatively happy and healthy. If they took three or four days, it wouldn’t work.

Jenny: That’s really remarkable. I have never heard of a process that fast. That’s truly amazing. Also, when you first started talking about cancer cells and they are weighed, you were talking a little bit about cancer cells dying of maybe natural causes versus dying because of cancer therapy and there’s tiny weight difference. How do you tell if they’re dying by these natural causes versus dying? Is it just the weight? Are there other indicators or is that the thing that you’re tracking?

Dr. Reid: We actually apply sort of a control to every single test that we do just to take that factor natural cell death out of the equation. Here’s how it works. Whenever we’re going to test a sample against a drug, we take the sample and we split it in two, and what we do is we apply the drug to half of the sample and we do not apply the drug to the other half of the sample, and then we measure the weight change of the cells and each half of the sample over a period of a few hours and the number of hours depends actually on the kinetics of the individual drug ad we know how fast each drugs works.

At the end of that time, a few hours, we compare the weight changes of the sample with drug and the sample without drug. If the weight changes are basically the same, then the drug did nothing, but if the weight changes are measurably, markedly different, then it means, Aha! Everything else was the same but this drug caused a significant weight change in this half of the sample. Therefore, this drug is effective for this particular cancer at this moment in time.

Jenny: Okay. That’s really fascinating. Then when you measure the weight change, is there — let’s say you’re comparing different drugs. You’ve got maybe bortezomib or maybe dexamethasone, is the depth of the weight loss significant? Let’s say you’re comparing all the proteasome inhibitors together and one has a higher weight loss than the other, is that how you prioritize?

Dr. Reid: It’s a great question. The answer is we don’t know and it’s an open topic of research. We, right now, our test returns kind of a yes/no value, sensitive resistant. The drug is either over threshold and it is causing these cells to lose weight or it’s not over threshold and it’s not causing the cells to lose enough weight for us to say that’s a good drug.

In the future, as we get more and more data, we’re going to be able to drill into the question you ask. How much does more change weight mean compared to less weight change? Is double the weight change mean double the effectiveness? Are any of these weight changes correlated with duration of response? It is something, a critically important question we want to be able to answer, but we’re a young company. We haven’t run enough samples yet to be able to have the data to power the answers to those questions. It’s an important part of our future to figure that out.

Jenny: Another question. Some of the drugs from what I’ve heard from some of the myeloma experts, they take time. They have a delayed response. Have you seen that in any of your testing – like some of the IMiDs I’ve understood have more of a delayed response. Have you seen that or not? You just see the weight loss or you don’t see the weight loss.

Dr. Reid: Yes, another great question because in patients, obviously, the IMiDs have very delayed responses but in the lab, they don’t. In the lab, one thing to keep in mind is that our drug delivery in the lab is perfect. We are putting know concentrations of drug exactly on to the surface of the cell for known durations and it turns out that if the cell is going to take up the drug and metabolizes it. It all happens pretty quickly.

Now, in a patient, of course, drug delivery is highly imperfect, and so it could take a long time for molecules of drug to get to the relevant cells. We’ve run about 30 different drugs now across the whole variety of different categories and we’ve done timing studies and we use cell lines for these tests so we’re able to run four-day, five-day, six-day tests.

We find there simply are no drugs that take more than 24 hours to act, or at least we haven’t run into one yet. Maybe there are, but we’ve done the 30-week testing. We just don’t find any. It kind of makes some sense too at the cell biology level. If the cell is taking drug across the cell boundary, why would it take three days for the drug to work?

The longest we expect it to take is the cell cycle. Any cancer cell, typically, they divide in sort of 36, 40 hours or so, so you could imagine hitting a cancer drug to a cell right at the beginning of the cell cycle, it might be that that cell won’t respond for 40 hours, but that’s about as long as it can get. We’re really happy with this discovery and credit goes to our partners at Dana-Farber who found out just how quickly, at least most cancer drugs, that the ones we’ve tested actually act on cells in a laboratory dish.

Jenny: That’s amazing. Well, it’s truly stunning, the discovery and then the application of it. I was reading your published papers and sometimes, instead of talking about weight, you’re talking about mass, what’s the difference in cancer cells between that mass and the weight? Is there anything significant about that.

Dr. Reid: No. There really isn’t. I mean this is just jargon from the scientific community. I’m a physicist by training and Scott Manalis, the professor who invented all of this, is really a physicist by training. We’ve all brought our physics skills to the world of biochemistry and cancer. In the scientific community, whenever you refer to weight, you typically write it as mass and that’s kind of the accepted approach. But as soon as we leave the scientific community and start speaking to patients or oncologists, then we say weight instead of mass but it really makes no difference.

Jenny: So we’re funding the Myeloma Crowd Research Initiative, a 3D tumor modelling project  with the same hypothesis of instead of trying to target these things genetically and use precision medicine that way, let’s test it again with all these different methods.

It’s really exciting, in my opinion, to see different approaches to this same idea of testing the drugs before the patient gets them and not after. I think it’s fantastic that there are multiple people going after it from different approaches, but how does this compare to a 3D tumor modelling using organoids or other types of “personalized medicine”. (That kind of has a connotation to just going after genetics, so that’s not really what I mean.)

Dr. Reid: Organoids, it’s a fascinating and exciting area about organoids and really serious progress being made to be able to grow up organoids whether it be tumors or human organs, but keep in mind, the thing about organoids, if you go down to the fundamentals of organoids, they are really another form of cell proliferation. Organoid-based tumors really are another form or growing up the tumor cells.

We run into the same problem that the two-dimensional proliferation assays run out and that is are the cells that are growing up similar to the cells in the patient? There have been some initial results on that, and it looks like it’s going to be really hard and indeed, may not be possible to grow organoids that faithfully reproduce the behavior of a particular cancer in a particular patient.

That’s not saying organoids are useless, they’re incredibly useful, incredibly valuable because what they really are is a new drug development tool, a tool that can identify new drugs, new compounds and their behaviors not just against cell lines but against intact organoids that have tumor microenvironment with them.

I think they’re going to be very important in the drug development world but I personally think they are not going to be successful at least any time soon at personalizing therapies to individual patients.

Jenny: Well, it’s tough because you really to have that bone marrow microenvironment be part of it, like you were saying, because that’s what the myeloma cell, that’s why it’s living in the first place because it has this really supportive soil around it. I hear them talk about myeloma experts talk about it like well, you have to not just look at the weed, you really have to look at the soil that’s helping this weed grow. (Editorial note: the MCRI project we are funding is using organoids in the context of the bone marrow microenvironment)

Dr. Reid: We agree with that wholeheartedly. In fact, we just want NSF SBIR (National Science Foundation Small Business Innovation) to work on exactly that problem and specifically, right now, what we do is purify then drug and we are doing exactly what you just described as taking the tumor cell out of its microenvironment and then applying the cancer drug to it. Under NSF SBIR, we’re running experiments now to drug and then purify.

Take the myeloma cells in their tumor microenvironment. Again, split it in half, apply drug to one half, don’t apply drug to the other half, incubate for the few hours to allow the cells to respond to the drug and then purify and measure your weight, and we’re very excited to run that experiment and it feels just like a better experiment in a lot of ways than we’re running now. It’s trickier, sample handling, there’s a lot of work that needs to be done to make sure that it all happens but during the course of next year, we’re going to do exactly that.

Jenny: That’s amazing. Outside of this study that we’re going to talk about in a minute, a patient could get a bone marrow biopsy taken and ship it to you, and then have you run a test or you’re developing basically a tool that each facility could have and they can do this themselves, right?

Dr. Reid: Both of those things although those are commercial operations in our future. We’re still in the research and development stage. We’re not offering a commercial test but yes, as I look out at our commercial future, there are two forms that will offer this testing.

The first form is the laboratory developed test, and that will be the laboratory that we’re running right now in Cambridge Massachusetts near MIT which is in a CLIA lab and we will enable patients to have bone marrow samples taken, shipped overnight in the marrow to us, we’ll just pull it out of the package in the morning, run the tests over some set of drugs during the day, and then get the results back that evening.

We’ll do that out of one laboratory. It’s starting in Cambridge, Massachusetts. Eventually, we’ll probably move to a much less expensive place to run a laboratory. So right now, we’re still tied to the hip to MIT and the research environment there. This is the right location for us while we’re a small company.

But as I look at into the future, not only will we move our lab to a much less expensive facility, in fact, if you’re familiar with Foundation Medicine, they also happen to have started in Cambridge, Massachusetts, and they’ve now moved their laboratory for testing to Research Triangle Park in North Carolina. That’s a path we very likely might follow. But the other thing we’re going to do is over the next three years or so, we are going to repackage this technology for delivery to clinical labs.

Right now, our technology is not packaged for delivery to Mayo or to City of Hope or any of the other hospitals, but we are going to a repackaging process which is both a technical process and an FDA approval process. We will have our second generation of instrumentation easy enough to use and to maintain for clinical labs around the US and around the world to run them and also, we’ll take it through the FDA in vitro diagnostic (IVD) device approval process.

We’ll have an approved IVD which gives us the regulatory power to sell these instruments to every cancer hospital to be able to run same day tests both US and around the world.

The first path to market is our CLIA lab in either Cambridge or North Carolina, and then the second path to market is being able to deliver these instruments to every cancer facility in the world.

Jenny:  That would be so amazing because sometimes, just having patients have access, local access, is just huge. That’s a big issue for myeloma patients even when it comes to genomic testing or things like that. That’s fantastic that you’re working on that.

Let’s talk a little more about the study that you’re running and then I’ll come back to some other questions that I have. This study you were saying is going to be run in Boston at Dana-Farber and MIT and patients consent samples. How many patients are you going to accrue for this study? How can patients join the study and what’s involved in that whole study? What’s your target for number of patients?

Dr. Reid: Sure. So we launched the study a while ago last year, although it’s taking a very long time to get through all of the MTAs and IRB approvals and all of that, we finally have achieved IRB approval from all six of our study sites. Let me just kind of list the study sites, you know, which cities these are in.

We have two study sites in Boston and that’s Dana-Farber and Mass General. We have two study sites in New York which is Weill Cornell Medicine and Mount Sinai. We have one study site at Emory at Atlanta and then we have one study site at City of Hope in Los Angeles, so those are the six sites.

The process of entering the study is really mediated by the oncologist so the oncologists are study leads at each one of those sites, and the other oncologists at the sites too have been briefed on the study. We’ve trained them, we’ve done the site initiation, they have shippers that we have provided to them for shipping us bone marrow overnight.

Whenever a patient comes in that meets all of the inclusion/exclusion criteria of the study and which in the judgment of the oncologist is a good candidate for participating in this study, that the patient consented to participate in the study, and the we get bone marrow the day after the biopsy of the patient.

The inclusion/exclusion criteria of the study – we are looking for later stage patients, we’re not doing any naïve patients. These are typically third or fourth relapse patients and what we’re doing is testing whatever combination of therapies that their oncologists are going to give them prior to the patient getting those therapies.

We still full appreciate that these third or fourth relapse patients may have and probably have been exposed to all of the dominant, the popular multiple myeloma drugs, but I think the oncologists are particularly interested in discovering re-sensitivity that has emerged as you said. We know these cancers are heterogeneous and what very possibly has happened is a year or two or three ago, a drug knocked down a population of cells and that’s great getting remission, and then that population of cells may have grown back up and actually be sensitive again to a drug that worked for a while then stopped working.

We can figure that out without putting the patient back on the drug and incurring all the toxicity and not knowing what’s going to work. That’s sort of the nature of the study. We’re doing that for 100 myeloma patients and I certainly hope to have the study completed in 2020 next year.

Jenny: I don’t think it would be hard to find enough patients to do that especially at those facilities because those are some of the very top facilities in the nation for myeloma and I think this would be so fascinating to patients to join these studies.

I love the idea of not wasting time on drugs that are going to be ineffective or not work, so how many different treatment combinations can you test for once you get the sample because by the time you’ve relapsed three or four times like you said, you’ve probably been on everything, you’re probably penta-refractory at some point and so how are you putting those in combination I guess?

Dr. Reid: Here’s what we’re planning to do when we launch our commercial laboratory developed test. What we will do is as you know correctly, behind your question is there’s just too many combinations to test. If you try to do every possible one, five or six drugs, you end up with hundreds and hundreds of combinations in it, kind of in some cases, tens and thousands of combinations. It makes no sense.

Here’s what we want to do. We want to do two things with our laboratory test. First, we want to test for re-sensitivity. We think that could be done just by testing monotherapies. It really is just testing five or six drugs but the drugs that a US oncologist is likely to prescribe. There are many more than those approved for myeloma, but they’ve kind of fallen out of fair.

We’re going to test for those popular drugs. But we’re going to in addition, test for a whole set of drugs that are FDA approved but not FDA approved for myeloma. There are over 500 FDA approved drugs for cancer and there are actually 84 FDA approved targeted drugs for which there are no biomarkers to associate to a myeloma patient, but we have a method.

Our method is to go into the genomics literature, and to the extent that we have sequence data from a myeloma patient whether it’s Foundation Medicine or University of Michigan or whatever we have, go into the genomics literature and say, which pathways are being disrupted by the mutations in this particular patients, genomes, like cancer genome. If we find a pathway, maybe it’s disrupting the EGFR pathway.

Why don’t we go try the EGFR drugs in our laboratory tests? No oncologist would say, “Hey, that pathway’s disrupted. We’re just going to give you an EGFR drug.” That wouldn’t be smart. But there right now are nine FDA-approved EGFR drugs. We need so few cells for patient. Why don’t we just test all nine of them? And probably none of them work but possibly there is some other pathway even if the patient doesn’t have any EGFR mutation, there’s some other mutation in that very long and complex pathway we call the EGFR pathway that causes one of the EGFR inhibitors to work for a patient. That information is gold and there’s no way to get to that information today.

We’re looking to step outside the box not just test standard of care drugs, but test a much broader set of drugs that we have some reason to believe might be active for this patient.

Jenny: That’s a very personalized and unique approach because I think that’s where cures are found. Right now, the majority of myeloma patients are relapsing on the standard of care therapies and they’re helping patients live longer which is fantastic and there are subsets of patients who potentially could be cured by being in remission for really long periods of time. But there are many patients that are really, really struggling. So I love that approach to try something that you wouldn’t necessarily think of.

To try run a clinical trial like that would be probably disastrous just because you’d be trying all these different drugs on patients and having their myeloma continue to — probably continue to grow in most but have one or two that’s like, aha, we found it. This is fantastic that you could do this ahead of time before you give the therapy, see if it’s even a viable option with very particular myeloma that’s fantastic.

Dr. Reid: We almost think of this as sort of a one-day synthetic clinical trial. It’s a clinical trial that you try drugs against your cancer cells but you don’t have to put them in your body and incur all the toxicity and you get to try more than one. You get to try maybe 20 different drugs, and so it’s a one-day synthetic clinical trial on 20 drugs. That’s a very attractive feature if we can accomplish all of the goals that we’re setting up to accomplish.

Jenny: Better than speed dating. They’re similar in some ways. 🙂

Dr. Reid: We’re going to stay away from that analogy.

Jenny: How was this idea sparked?  You talked about at the beginning of the show that this was both an invention and a discovery. But how did this come about?

Dr. Reid: The idea was sparked — I mean it’s classic MIT. First, you invent the tool then you figure out what to do with it. It’s kind of how brilliant technology organizations work. Scott Manalis and his team invented this tool, invented the tool more than ten years ago.

It’s been around for a while and they immediately say gee, now what do we do with it? The first thing they did with it was a lot of really basic cell biology having nothing to do with cancer because no one is ever going to be able to measure these tiny weight changes in cells. I thought – wow. What happens in apoptosis? What happens when they’re put in different growth environments? Really interesting cell biology.

Then someone had the brilliant idea – gee, I wonder if this could be used for bacterial testing of antibiotics. Antibiotics in an ICU to do a test of an antibiotic against an infection for a very, very sick patient takes multiple days because they have to grow up a culture of the bacterial cells.

The good news is bacteria grow really well in a dish where cancer cells grow really badly. But still, if it takes two or three days, that can be the difference between life and death for a patient. They said gee, I wonder if a bacteria loses a tiny bit of its weight in response to an effective antibiotic. They ran that test, it turned out that it worked perfectly. That is 510(K) FDA approval process right now and will be a commercial product very shortly.

Then of course once the bacteria worked, a bunch of smart oncologists looked at it and said okay, could this work in cancer? That’s what sparked the idea.

Jenny: Yes, that’s fantastic. I mean this invention came out of MIT. You’re obviously doing this in tight partnership with MIT and we’d expect that continues as you progress down all these different steps and developing this as a commercial test.

Dr. Reid: Yes, indeed. MIT is very central to our future, our best partner. Scott Manalis, the inventor of this core technology, is a consultant for the company, he works for us a day a week and a close personal friend.

Scott continues to do research in this field so MIT exclusively licensed the technology to Travera for cancer and immunology. MIT by policy, always retains the right to continue to do research and development around all of the technology they develop.

Scott has recently won a $10 million NCI grant to continue to do research of applying this technology for cancer. He’s part of the Koch Institute for Cancer Research at MIT. Anyway, Travera as a company, and MIT as an academic institution, are sort of independently funded by venture capital and by the NCI, but we get access to the rights of all of the research and development that Scott does. We’re extremely happy with our ongoing R&D partnership with MIT.

Jenny: That’s amazing. This is a whole new area of such exciting research. In myeloma there are a lot of different types of clones and somebody described it like a friend group. You have a more aggressive friend and you have a passive friend and sometimes, the passive friend is leading the group whereas sometimes, the aggressive is leading the group.

You have these multiple clones or a lot of heterogeneity, they call it in multiple myeloma. Is there any way of telling which clone might be the most aggressive or which treatment combo might best hit that driver clone or does that just not matter because you’re just identifying what’s the best therapy for this person at one time.

Dr. Reid: This is the key strength of our test. You described it well. It’s what’s the best therapy for that particular patient at that particular time. Our approach is to run the test, find the drug out of a list of potentially dozens of drugs that works the best even if we don’t exactly know why that drug works the best because there’s so much unknown about cancer drug metabolism and about the genetics of cancer that it’s good enough from our perspective to find a drug that works even without being able to fully understand the mechanism of action.

Then if you think about what we can do with this test, it is to use it iteratively. Let me describe that. This is how to address heterogeneity. Take the patient’s sample, run a panel of drugs by that sample, find the drug that works the best which for whatever reason is going after the dominant clone, that’s going after the majority of the cells but by no means, all of the cells because of heterogeneity. It just works for the majority of cells and that’s what shows up in our weight measurement that it’s working on more cells than any other drug.

Work with the oncologist to give the patient the drug and then at some point, a month later, two months later, three months later, whatever the oncologist decides, we run the test with the same panel of drugs. Now, if that first drug given was effective, it won’t work the second time because it will have wiped out that clonal population.

Now, there’s a second drug that works the best because it’s picking up the second clonal population which very likely has grown up into the kind of ecological niche opened up by the elimination of that first clonal population. Now, you can see the algorithm. Iterate until you run out of cells and we can just kind of walk down those clonal populations.

As soon as you don’t have any — you’re down at MRD, you don’t have enough cells to run a test, fine. You call that remission. Then just monitor and if the population grows up again, whatever clone it is, just run a panel of drugs and hopefully find one that knocks out the new clonal population.

It’s the power of being able to test many drugs that can pick up the many different clones of cancers that we all know very unfortunately know are the rule not the exception. High heterogeneity defines cancer, it’s how cancer works and we think we may have a solution to addressing this heterogeneity that could be the first solution.

Jenny: It’s really amazing because it’s so frustrating to a patient to have relapsed multiple times and feel like you’re running out of treatment options and you’re kind of guessing at that point, well, whichever combination we have at use, let’s try that, or maybe we go back to what we used before because it seemed to work at the beginning and meanwhile, you’re kind of running out of time. This is a fantastic approach, in my opinion, to just do it quickly, identify what works, identify what doesn’t and move it forward, it’s just great.  

Dr. Reid: And casting the net broadly. I mean I think that’s the attribute that we’re able to do. In fact, now, I’m speaking about some speculative things in the future but there are a lot of approved drugs for multiple myeloma. I think there are 21 right now.

Many of them have been obsoleted because they don’t work as well in a population as the existing, as kind of the top five frontline drugs. That’s a statement about a population. It’s not a statement about an individual. Wouldn’t it be interesting — and these are drugs that are approved for myeloma so it works for somebody at some point in the past, it just didn’t work for enough people.

Well, if you’re the somebody, you want that drug. If it works for 1% of patients, but you’re the 1%, let’s get you that drug and we may be able to bring back into clinical practice these FDA approved drugs that were shown to be safe enough and effective enough to give to patients, they just don’t work for many patients so we don’t use them but if you really have personalized medicine, you don’t care about the population behavior of these drugs, you care about the individual behavior about these drugs. That’s what we care about.

Jenny: Right. That’s what Dr. Matsui kept saying. He said, we don’t care what the genomics looks like necessarily. We just care how the disease is behaving. We should be focusing more on that because it’s going to be a faster approach to a potentially personalized curative idea for that particular patient which is what you’re saying.

So I will need time for caller questions, but what are your next steps? Where do you go from here?

Dr. Reid: Well, the clinical validation study is about 80% of everything we do right now at Travera. We run a very small test at Dana-Farber. We did it with nine patients and with the Nikhil Munshi, MD, who I’m sure you all know, one of the leading myeloma docs in the US.

Jenny: Yes, he’s great.

Dr. Reid: He sent us nine bone marrow samples and we made our predictions about which combos would work and not work and we predicted that six of his patients would be sensitive to the combo who’s going to give them and three of them would be resistant and we got nine right. It was a fabulous study. It’s published in Nature Communications, but it’s only nine. Scientifically, we were thrilled. Clinically, that’s not enough to use to launch a commercial test.

We are running this hundred patient study right now and the vast majority of our effort is just bringing that study to fruition. The other thing we’re doing is in parallel. We’re setting up a CLIA lab so that when that study is finished and we’re hoping against hope that the quality of the results are at least similar to the quality of the results that we got back from the nine patient.

We certainly don’t expect it to be 100% accurate, no test is, but if we can show it’s really as good information for an oncologist and patient to make decisions about drugs, we’re going to launch it as a commercial product.

Our next step is to finish the study, set up the CLIA lab, and get ready to make this available to patients.

Jenny: Well, we’re excited that you’re going through this process. It’s just truly amazing. To me, this makes a fundamental paradigm shift in the way you think about applying myeloma drugs in the clinic and kudos to you for doing that because it’s much needed.

Dr. Reid: Thank you very much.

Jenny: I just feel like research needs to move faster and this is the way that they could move much, much faster.

Dr. Reid: I agree with that. You noted at the beginning of this discussion that personalized medicine has become synonymous with genomics.

Jenny: Yes, and it’s not.

Dr. Reid: There are many other ways to do personalized medicine and it’s a little bit unfortunate that so much of the research funding is genomics in nature, it’s just everyone’s kind of on that bandwagon and that’s what NIH funds and that’s what researchers do research on and there are many other ways to personalize therapies to patients, not just ours.

In fact, there’s a whole new professional society called The Society for Functional Precision Medicine that’s bringing together researchers and commercial companies who have a fundamentally different approach to personalized medicine. It’s a very small effort. It’s underfunded effort but I think it’s going to be very important for the future personalized medicine in cancer.

Jenny: I completely agree. There are other things like having an immune system signature or understanding the microbiome that it’s all these different factors that are coming together so it would take decades to research it in detail. It would be so much faster to just okay, well, let’s just deal with what we have to work with right now and here are your myeloma cells at this point with the microenvironment, what do we do today?

To me, this addresses an urgency issue that myeloma patients have who are trying to make these critical life and death decisions. It’s super exciting.

If you have a question for Dr. Reid, you can call 347-637-2631 and press 1 on your keypad.  

Jenny: Please go ahead with your question.

Caller: Hi. This is Jack. Really have enjoyed the questions and the answers from Dr. Reid. Can you share why because this process we’ve seen the work across other cancers, what made you target myeloma initially?

Dr. Reid: Hello, Jack. Thank you for the call. We targeted myeloma because it was really the Dana-Farber researchers who drove the initial testing and one of the key considerations is how do you get access to live single cells for cancer.

Just you know, we probably know the history of the Dana-Farber Cancer Institute, Sidney Farber started in pediatric blood cancers in large part because it was so much easier to get access to the cells than in solid tumors and that really was the driving force behind starting in multiple myeloma.

Having said that, Jack, your question embeds the other question. Shouldn’t this work in a lot of different cancer types and could you do it in solid tumors by dissociating the solid tumors down the individual cell? The answer to that is yes.

We are actually running to very small programs, very early stage, one in breast cancer with USC and the Department of Defense. One in Lung Cancer with the Boston VA to see if we can move this technology from the blood cancers into solid tumors. But as I said, about 80% of all of our work right now is in multiple myeloma because our focus is get this clinical study done and get the laboratory development test launched.

Caller: Fabulous and thank you.

Dr. Reid: Thanks, Jack.

Jenny: Okay, great. I have a follow-up question after Jack’s question. I know that some of the doctors talk about this precursor cells or stem cells that might be causing the regrowth or myeloma so is there anything that can be done to test different — and I guess there are some controversy as to whether those cells exist or not so maybe this is not a question for today, but tomorrow.

But can those types of cells, those precursor cells that might be behaving differently to standard myeloma therapies and not responsive to myeloma therapies, would you have any way of testing for that?

Dr. Reid: We don’t think we do. We know we read the papers on the theory. This is a little bit premature. Nobody quite knows if that’s true. It does make an awful lot of sense but part of that theory is that these stem cells are quiescent. They’re very quiet. They’re not being very active, they’re very hard to drug even if you could get drugs to them because they’re not metabolically producing quickly. But they can end up causing a bloom of cells.

If that turns out to be true, I do not despair because if you think about what we’re doing, we’re going after the bulk of the cells, and these quiescent stem cells are never going to be the bulk of the cells. But if what we can do is this iterative process that I outlined earlier and say whenever these quiescent stem cells wake up and they produce a bloom of cells, we can measure that with a blood test using a cell-free DNA test, just to understand tumor load then we can go run a panel of drugs and find out how to knock down the dominant clones until we’ve knocked it back down the MRD.

Then we just repeat that and kind of methodologically, what we’re saying is we’re really not setting out the cure for the cancer, we’re setting out to make it a chronic disease that has the patient feel healthy and happy every day for the next 30 years. For this century, that’s good enough.

Some century in the future, we should cure it. We should understand enough about cancer biology to know how to cure it. I don’t think we’re going to get through this century. In the absence of cures that understand this enormously complex biochemical process is going on in cancer, let’s turn it into a chronic disease then people feel good every day. That’s our objective.

Jenny: Well, it’s a great one because you look at other diseases like heart disease or diabetes and there’s no cure for those things either. If you think of cancer to a point where you can live with it, and it’s not going to kill you, that’s great. That’s amazing.

Okay. I have one final question. What can myeloma patients do to help accelerate your research?

Dr. Reid: The main thing they can do is for any myeloma patient who goes into any one of the six sites I mentioned, let me just briefly tell you them again. Dana-Farber, Mass General, Weill Cornell, Mount Sinai, Emory, and City of Hope. If they are a relapsed myeloma patient, they should ask about the Travera study. We have heard talking to the lead oncologists at all of those sites, a discussion between oncologists and a multiple relapsed myeloma patient can be a very stressful time.

People may just forget that we have a study running. We would be delighted and thrilled if the patients remembered on behalf of their oncologists and said hey, am I eligible for this Travera study? I know it’s running at this site. That would help us recruit patients into the study. Our patient recruitment has been slower that we had hoped this year even for the three sites we’ve had active. Any patient who says yes, I want to participate in that, will help us bring this product to commercial reality.

Jenny: Does it matter what kind of pull it is? Like if they’re having other biopsy for any other reason which relapsed patients frequently do? It’s not that big of a deal to get an extra pull. Is it okay? Does it have to be the first pull or is there any specificity around that?

Dr. Reid: We never get first pull. Our protocol is that we want second and we will accept third. We had so far 30 patient samples show up for various types of testing. There are cases where the third pull doesn’t have enough cells for us. Second is much, much our preference but if we get a third, we’ll try it and we’ll see and then we may just say sorry, we couldn’t run a test on this one. But we fully appreciate there are other tests, for the moment, higher up in the queue than our research study and so we don’t expect any first pull at all.

Jenny: Okay. Well, that’s something that the patients can also have some influence on. I think there’s just a patient education issue. I cannot see being multiply relapsed and not wanting to participate in this study in my opinion. I would jump at the chance to do that so to have more information about your particular disease and to be treated as an individual, that’s just stunning.

We will include a link to the study with the contact information when we share the show with the transcript so patients who are interested in the study can learn more information from those centers about how to join.

Dr. Reid, we are just so thrilled that you joined us today. This is a fascinating idea and one that I think could really move the bar quickly in myeloma so congratulations for all the work that you’ve done and it’s just a really amazing idea.

Dr. Reid: Oh, thank you very much and thank you for having my, Jenny. I really appreciate it.

Jenny: Well, we’re just so happy that smart people like you are working on these things. We have a lot that if we can support you on what you’re doing to make things go faster, we would just be happy to do that.

Dr. Reid: Excellent. I appreciate then.

Jenny: Okay. Well, we thank you for joining us again. We are thankful for our listeners to listening to Myeloma Crowd Radio. We invite you to tune in next time to learn more about the latest in myeloma research and what it means for you.

About Author

Jenny A

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

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