Episode 63: Unlocking the Secrets of T Cell Therapy Resistance

Episode 63: Unlocking the Secrets of T Cell Therapy Resistance

Karie Dozer [00:00:04] I'm Karie Dozer and this is TGen Talks. For a patient diagnosed with multiple myeloma, a type of blood cancer, there are more treatment options than ever and traditional chemotherapies that cause debilitating side effects have been all but completely replaced by immunotherapies, treatments that help a patient's own immune system better fight the disease. But in many patients, a chosen immunotherapy drug can show great promise in early treatments, yet seemingly stop working altogether as time goes by. On this episode of the podcast, you'll hear about a study that found how these cancer cells were mutating to evade the very drugs prescribed to fight them, and how a new lab at TGen here in Phenix will soon be able to determine which drug to choose next for each patient's particular cancer. We are here at TGen in downtown Phenix for this episode, and our guest is Dr. Jonathan Keats. He's a director of bioinformatics TGen and he's the scientific director of the Judy and Bernard Briskin Center for Multiple Myeloma Research at City of Hope. He's also a coauthor of a research paper detailing these discoveries in multiple myeloma treatments. Welcome. A very busy. Jonathan Keats, thanks for being here with me on the podcast. Tell me, what it is that you do here at TGen?

Dr. Jonathan Keats [00:01:19] Well, as you mentioned, I'm a I'm a doctor, director director, which means I do a lot of different things. So my primary interest is I run a research lab focused on a blood cancer called multiple myeloma. So we spend a lot of time trying to understand what causes the disease, and particularly also now what causes drug resistance to many of the therapies that we have today.

Karie Dozer [00:01:40] What is multiple myeloma? It's not very common diagnosis.

Dr. Jonathan Keats [00:01:44] No, it occurs about one in about 20,000 cases a year in the U.S. or really from people, you know, one out of about 180 people will get multiple myeloma of their lifetime. So it's still considered a rare disease. It's the second most common blood cancer after Hodgkin's lymphoma. But it is a blood cancer that is really localized in your bone marrow. So unlike lymphomas, where people get a big lump and then people say, oh, I got a lymph node cancer or lymphoma or blood can't leukemias, which really historically meant I have white blood because you have so many cells in your blood. Myeloma is kind of the third child of the blood cancers that's very localized to the bone marrow. But it is just like leukemia. Lymphoma is a cancer of the cells that function our immune system.

Karie Dozer [00:02:32] And there's not technically a cure for it. There are treatments, but it's not a particularly good diagnosis, is it?

Dr. Jonathan Keats [00:02:39] You know, historically, I started in the field in 1999, and median survival was less than three years. It was one of the worst of the worst cancers. Today, actually, therapies have dramatically improved. So median survival is about ten years. The average patient who gets this disease is 71. So we're starting to get to the point where more patients that are in our clinical trials are dying of other causes than they are of their disease. But it's just kind of that 5050 medium. And we debate if we cure some patients today, we definitely have patients. In one of the studies that I run that after eight years, close to 200 or 2000 patients have never progressed in eight years. So is that a cure or will they progress at 15 years or 20 years? But people are definitely seeing dramatically alterations in their expected outcomes of this disease 

Karie Dozer [00:03:29] Why is it so hard to treat?

Dr. Jonathan Keats [00:03:30] A lot of it is the diversity. So we focus a lot on what we call subtypes of myeloma. So in pathologists will look at a slide and they see what my dad would call sunny side up eggs when he finally understood what I work on. And that's multiple myeloma. But genetically, when we look at it, we know it's about 11 different types of disease and it probably reflects a lot like what we see with other leukemias that we don't just say that everyone has leukemia. There's acute myelogenous leukemia and chronic myelogenous leukemia. The very different diseases that have different outcomes and different responses to therapy in myeloma, just because it's even more rare has not usually been broken up that way.

Karie Dozer [00:04:08] What is a typical treatment for someone diagnosed with multiple myeloma?

Dr. Jonathan Keats [00:04:12] So the average patient would get what we call an induction therapy to reduce the disease burden and then after that, a autologous transplant. So this is something where we actually come in and give you a very high dose of classic chemotherapy and then give you back your own bone marrow. So basically the drug, the high dose therapy was so high that it the goal is to eradicate the tumor. But we know we pretty much take you to the edge of survivable and we knocked out all of your bone marrow. So we give you back your bone marrow. And then most patients after that will be on what we call a maintenance therapy until they progress. So for some patients, that's a year. And for some patients that's three two years to a decade. 

Karie Dozer [00:04:55] The subject of your latest paper deals with resistance to treatment. It's not resistance to chemotherapy treatment, though.

Dr. Jonathan Keats [00:05:01] Multiple myeloma is very, very different. He's probably since the mid 2000s. Very few of the therapies that we use other than that high dose therapy I mentioned before is a classic chemotherapy that would cause you to lose your hair. Um, they're generally what we call novel agents or immuno oncology agents where we're using patient's immune system to fight the cancer. So the paper that we're talking about now is some of the newest and most cutting-edge therapies, where it's either a combination of where we take what we call T cells. These are kind of like you would equate it to the special forces in the military. We take those, take those out of the body. We train them to recognize the tumor cells, put them back in, and they rapidly go in and usually in less than a month, pretty much get patients to no detectable disease. And then the other type of drug that we use, which is probably a little bit easier to use clinically, is a drug where it's a specialized antibody that actually recognizes the tumor cells and recognizes the same kind of T cells and brings the T cells to the tumor and basically kind of artificially activates the tumor, the T cells to see the tumor as foreign and to kill it. And both of these classes now, like the car T cells, we're seeing clinical trials with 90 to 100% response rates. And then these what we call t cell engager therapies, 60 to 80% response rates in patients that normally would not survive more than three months at that point in their disease course.

Karie Dozer [00:06:33] So that's a great result for that patient. But sometimes that immunotherapy, that thing that worked so well the first time stops working why.

Dr. Jonathan Keats [00:06:41] The manuscript will highlight some of the different mechanisms. And again, like I mentioned, where we see there's many different types of myeloma we're appreciating, there's many different ways the cancer cell gets around these therapies. The most basic one is all of these are targeting proteins that are on the surface of the cancer cells. And the nice thing since the cancer we are working on is a very rare cancer. There's things on the surface of the plasma cells. These are the type of cells that we the tumor is derived from that are only on plasma cells. And those represent a very small minority of cells in your body. So the drugs recognize those unique proteins on the surface and target your immune system to that tumor. Now, for any protein on our cell surface, you have two copies of that gene in your body. So what we're seeing is the most common mechanism is that the tumors actually physically delete those genes out of the tumor. So we have things in cancer called tumor suppressor genes that prevent cancer. And the way cancers evolve is the tumor deletes those genes so that those genes can't prevent cancer any longer. In this case, these are two genes that are unique to plasma cells. We don't really think they're essential for the survival of the plasma cells, so the tumor cell can easily just throw them out and then the drug no longer has a gene to recognize. There's nothing on the surface that just goes by and says, Oh, there's nothing here. It's a nice stealth cloaking device to get rid of those genes so the immune system no longer sees the tumor.

Karie Dozer [00:08:14] So how did you find this? This activity by the cancer cell.

Dr. Jonathan Keats [00:08:18] So the driving force behind where we started things is we're one of the targets were targeting is a gene called BCMA called B-cell maturation antigen. Now, what's unique about that is as of today, there is now five different drugs FDA approved to target that same protein. So a lot of the work that we started here at Tejon and City of Hope was focused on patients who had previously seen one of the drugs against a BCMA targeted agent. And now we wanted to treat them, but with a different BCMA targeting drug. And the question was, can we is that target still there or has the tumor cell put a stealth cloaking device over itself? So actually, one of our very first cases was exactly that where we brought kind of the power of the T gen precision medicine approach. And a patient was waiting for one of these car T cells. So where we train the T cells to recognize the tumor and that takes about 6 to 8 weeks for it to come back. And in the interim, we were able to identify that that therapy was never going to work because the gene had already been lost. And in that patient's case, we were able to get them on to a different therapy that put them into a complete remission in under a month.

Karie Dozer [00:09:28] So do your findings direct you to the next best therapeutic treatment?

Dr. Jonathan Keats [00:09:34] So one, it'll tell you why something stopped working where what we learned also in this manuscript is that for sometimes the two copies of the gene have been deleted. No drug targeting. That gene will ever work again, but in some cases one copy was deleted and the other copy was mutated just so the drug couldn't bind. It's kind of like if you imagine putting a stop sign up on the cancer cell and then changing it to a yield sign. But what was important there and why it's important now that we have all these five different approvals for agents against BCMA is a mutation that stopped one drug from binding. Didn't block all of them. Maybe two of the five don't longer bind, but one of the other ones does, which is really again towards what we do here at T. Jan is trying to personalize everyone's care and now we can actually go in and sequence and predict which drug will work best for each patient, really specifically to what's going on in their tumor.

Karie Dozer [00:10:34] How many treatments are typically available to a patient with multiple myeloma? How many other options might they have? 

Dr. Jonathan Keats [00:10:39] So today there's actually 19 approved agents since 2003, and these would be agents that we would consider non classic chemotherapies, all verging on what you might want to call a designer drug. They're scientifically informed, scientifically designed to be highly efficacious. So it is actually difficult now. So we with 19 approvals now of those we have six actual approved either CAR-T cell or T-cell engager therapies and that diversity is only increasing almost daily. We had two approvals last week in the field, So what is available for patients and physicians to use is changing rapidly and also makes it important for us to actually say what's going to work best for each patient, because deciding what you take off the wall in the patient that I mentioned before, had we waited and given them the therapy, that would never worked. Instead of being home for the holidays with his family feeling good, he probably wouldn't have made it through that time.

Karie Dozer [00:11:46] How long is a typical therapy given? I would imagine in the past? In the very recent past, it probably took quite a while to figure out that a particular treatment wasn't working before you had this information.

Dr. Jonathan Keats [00:11:57] Yeah, like generally 1 to 3 months before they would know. The advantage of multiple myeloma is because it is actually a tumor of the plasma cells, which are the cells in our body that produce antibodies. We actually have probably one of the best biomarkers for is the tumor going down or is the tumor coming up. But antibodies are extremely stable in our blood. So for us to really appreciate if a therapy worked, it sometimes takes 1 to 2 months before we even see it coming down. It is not working at all. Usually within a month you see it still growing up. So things that are not working at all, you can tell pretty easily. The problem is a lot of these drugs, even if they're not working well, they work well enough that over the four month or two you take 50% of the cells out and then they grow back. So you get a little bit of a delay or lag before you actually appreciate the therapy is no longer working.

Karie Dozer [00:12:50] So what now? What's the next step now that you know, you can find these treatments that aren't working so well and you can find them relatively quickly, what's that process like and what will you do with it?

Dr. Jonathan Keats [00:13:01] So now what we're really focused on here is at the T Gen is trying to translate these findings into our new teaching and clinical lab. So that lab is focused on building a whole genome sequencing test. So this is a case where we measure all 3 billion base pairs of our genome. We're actually going to sequence each one of those about 100 times to then understand what's gone wrong in the tumor. And we'll do that from the time it arrives to the time the physician has a report in their hand and 48 hours. And where that's so important now with these therapies is as more and more patients get exposed to one of these therapies through standard clinical care, should they progress on one of those agents knowing if they can go back on to one of those other drugs or which one they should go on to becomes imminently important for the patient's outcome. These drugs aren't cheap, so it is really important to get people the right drug that's going to be the right one for them.

Karie Dozer [00:14:04] Who will man this laboratory? What is the most important part about getting that information right?

Dr. Jonathan Keats [00:14:08] So we have a team that's building it. My team is involved in building up a lot of the informatics. One of my other roles here, teaching as the director and by informatics, we're building the infrastructure to do the analysis correctly and very quickly. We've been allocated about 3 hours of that 48 hours to get the analysis completed, will move patient samples will come in for myeloma. One of the important things is we have to purify the tumor cells out of the bone marrow. To be diagnosed with. Multiple myeloma generally means at least 10% of the cells in your bone marrow are these plasma cells, which normally be less than 1%. Frequently the sample we get isn't that good. But the nice thing, again, like how these therapies work, there's unique cell surface markers that are very unique to plasma cells. So we actually use another antibody to recognize. I saw the tumor cells and that antibody has a magnetic bead on it. And then we just basically run the cells over a magnet. It holds on to the tumor cells. And what's amazing for my side, I work on multiple myeloma for two decades now. When we do genetics on a myeloma tumor, it's on average 95% tumor cells. If you take our average other solid tumor, we average about 65%. So it's much easier to do this kind of work because it's a very pure tumor. Population makes it easier to do the genetic studies. It makes it a little bit cheaper because we don't have to sequence as deep to see things. 

Karie Dozer [00:15:38] But you're still sequencing 100 times, 100 times. I think most of our listeners think about this science as so precise that 100 times seems repetitive, duplicative, almost. But it's not.

Dr. Jonathan Keats [00:15:49] No. And a lot of it is sampling. And the easiest one is to think if you're pulling Eminem's out of a jar, if you think you have, we all have two copies. So if you imagine a jar that's half black, Eminem's half white Eminem's, and then you sprinkle in about 20 red ones to ever see one of those red ones, which is the cancer mutation, you have to start pulling a lot. So when we say 100, it's like pulling 100 M&Ms out. And hopefully when you do that, you see that you actually got six read M&Ms. So we know now 6% of the DNA is tumor mutated DNA.

Karie Dozer [00:16:30] When will this lab be open and how will that word spread?

Dr. Jonathan Keats [00:16:35] So the initial lab build out is targeted to be servicing patients as of January of 2024. Again, initially, it'll probably be primarily within City of Hope patients, just because that's where we'll have the most direct interaction with physicians. And there's going to be a little bit of education about how to interpret these reports. Not everyone's used to getting a report that was generated from all 3 billion base pairs of the human genome as opposed to one or two little yes or no answers. So there's also a little bit of work we need to do with treating physicians to make sure that the reports are usable for them in the short amount of time that they have to interact with a patient.

Karie Dozer [00:17:17] What could this mean for doctors researching other types of resistance to other types of tumors? Is there a way to layer this knowledge upon other fields of study, other cancer research?

Dr. Jonathan Keats [00:17:29] Like there's been a huge revolution over the last almost ten years now of what we call immuno oncology. So early days, especially people who have no family members who have skin cancer or lung cancer, a lot of people are getting what we scientifically called checkpoint inhibitors. So tumors have developed ways to tell the immune system like, hey, ignore me, leave me alone, I'm fine. And then we were able to give them antibodies that would block those little talking points. And now the immune system recognizes a tumor. And it's why I like the outcome for lung cancer has changed so dramatically in the last decade. So some of the learning that we've seen from how these immune based therapies work, I think will translate to a lot of cancers because though those checkpoint inhibitors were there in solid tumors in the blood cancer space, these more directed immune therapies where we're actually not just letting the immune system do its job, but actually saying like, hey, you get over there and do your job. Those ones are a little bit more directed, which means there's more opportunity for the tumor to try and have an incentive to get away from it. And I think that concept that we're seeing here in the diversity of types of events that really highlight the power of whole genome sequencing, that you can do one assay to see a mutation, you can do another assay to see a copy number of deletion, you can do another assay to see what we call a translocation where the DNA breaks apart and you can do in a clinic, you can do those three different assays, but a lot of clinics only do one, maybe two of the three. With what we're now doing in this rapid whole genome sequencing lab. That one test gives you all those answers and not just on genes that you're focused on today. It does it across all genes so that when we have a therapy tomorrow against another gene, which we do have in the clinical trial pipeline, we don't have to redevelop new tests. We just the one test, it's like if you follow the Lord of the Rings, the one ring to rule them all, it is the one test that from a genetic perspective, there won't need to be another test. We can do it faster. We can do it more accurately in the future with better instrumentation. But we won't have to rehash the entire system ever again.

Karie Dozer [00:19:43] What have I missed, if anything, about this paper, about this rapid sequencing clinic that will open here? Anything that I didn't ask that you want to make sure people know?

Dr. Jonathan Keats [00:19:52] I think the number biggest one is, again, if there's people that are family with multiple myeloma therapies have changed dramatically and continue to change dramatically with every day. And I think the most important thing for my side that came out of that paper was we do need approvals of drugs that target these same antigens, but not so much that we need ten drugs. We want ten drugs that recognize ten different parts of those proteins because we're now appreciating so much that if the tumor goes this way to get around this drug, it makes it still sensitive to this one. I want to have as many drugs on the shelf. I want to look at a patient and use our best interpretation of what's going on to go. We're going to pull drug 12 and 30 off the shelf because this is what works best for you. That is the lifeblood of what we do here at T Gen, and that only works with the drugs on the shelf when we can use it.

Karie Dozer [00:20:46] You've been doing this for 20 years or a little more. How would you characterize the difference between the field and hopes for patients with multiple myeloma when you started and their hopes today?

Dr. Jonathan Keats [00:20:58] So the best one in like transitions that I've seen working with a physician when I was still in Canada who treated myeloma for probably 30 years at that point. When one of our new what we called novel agent drugs was in clinical trial, I happened to be in the clinic with him that day, and he was on the phone yelling at the lab about messing up because three patients had no detectable tumor. And he's like, You guys are messing up. It's not possible. And I asked him like, well, what else could be going on? It's like, well, they're all on that new clinical trial. And to see a physician who had spent his entire life treating this disease and not even thinking that the drug could be doing.

Karie Dozer [00:21:39] Possibly working.

Dr. Jonathan Keats [00:21:41] Now, he flipped forward to 2023 more junior people who are in the same boat. If that new drug doesn't put more than 60% of people into complete remission in under three months, they think it's a bust. So that's been the most impressive thing, I think. And again, for families and patients out there, the only thing I usually say is seek out specialty centers that have clinical trials going because the things that are in the pipeline today that are available to you even as control arms for some of these trials are therapies that we didn't even fathom would be possible in 2010.

Karie Dozer [00:22:20] Pretty encouraging news for anyone with that diagnosis. Thanks for your time today and congratulations on the results.

Dr. Jonathan Keats [00:22:25] Thank you.

Karie Dozer [00:22:26] For more on TGen’s research, go to tgen dot org slash news. The Translational Genomics Research institute, part of City of Hope, is an Arizona based nonprofit medical research institution dedicated to conducting groundbreaking research with life changing results. You can find more of these podcasts at tgen dot org slash tgen talks, Apple, Spotify and most podcast platforms. For TGen Talks, I'm Karie Dozer.