(Guest Lecture): June 2022 - Is CAR-T Cell Therapy the Answer or an Option?

I like the karaoke mic on this. All right. Okay. Thank you so much for having me here today and hopefully I can give you some answers about car T and it's interesting that Greg said you're seeing one end of it which you just talked about. Smoldering and I'm Gus, and this is the other end of it but I'm going to argue that maybe it shouldn't be the end but maybe earlier which would be great. So I'm Nina Sean from University of California San Francisco which is three time zones away but that is good for me because I like getting up early. Okay, so everybody knows that triple refractory multiple myeloma refractory to our traditional drugs, we may have heard bortezomib or Valcade, lenalidomide, irrevlimid, plus daratumumab or ecetuximab, those patients do really poorly and this is illustrated by this mammoth analysis you can see here, where patients who were either triple refractory, non triple refractory or penta really do poorly both from progression free survival and overall survival and this means that we have an unmet need and I really applaud many many of you and all the patients out there who are listening who have participated in clinical trials for us to understand this better. So, you know, then we talked about the unexpected stars of myeloma therapy I promised you six years ago I would not have been saying this, but it's true immunotherapy has completely changed myeloma, and I say it's like you know it's like Travis Barker and Pete Davis and like were they really going to get the Kardashians, who thought it right, but they got them. And it's true that we're it's not just lymphoma that has immunotherapy we have it too and it's actually becoming a huge player in our myeloma tool, so our toolbox so we have antibody drug conjugates by specific T cell engages and of course my favorite CAR T cell therapy which I'm going to talk about today. So how does CAR T differ from other therapies now I will be showing you a lot of data slides don't worry about the data this is just so you understand how we as the physicians come up and researchers come up with our ideas of how to treat treat patients but what does it mean for you. So, this is important for anybody who's considering going to CAR T therapy that there are two parts of it there's what's happens to the patient, and what happens to the cells, and that it has this sort of overlapping aspect first, the patient is identified you'll be identified there's all this testing very similar to transplant, the echo, etc. You have to stop your chemo therapy two weeks before we call a phoresis so many of you have had a transplant, and you know that you undergo this collection from your blood this is actually just a one day process, and it doesn't require the white blood cell stimulating drug the GCF or new pigeon as you may know it. Once that happens, and even getting that slot is a whole nother thing but once you get there and once that happens those cells get shipped off somewhere maybe New Jersey or wherever, and you wait for a couple of weeks and what happens to those cells is that those cells get engineered, the cells get incubated with this lentie viruses alternate virus that allows for the genetic code at this car this chimeric antigen receptor to be integrated into the DNA, and what does that mean for you as a patient that when these cells come back to you, they now have this nice protein on the outside of their cells that will recognize your myeloma cells, and we know that T cells are a very active way for us to kill viruses. So while you're waiting there, you know back at your home base, and these T cells are sitting in New Jersey being engineered, what happens, even though it only takes two weeks to actually engineer them and grow them. There's a lot of quality control right you don't want these cells to be growing out of out of proportion to what they should you don't want them to be sort of taking off and being you know cancerous by themselves because they've had genetic engineering you also don't want them to have infection right, these are living drugs that are growing, and anything that's living and growing can have an infection, all these things have to be cleared before these cells can come back to you and that takes a couple of weeks. It can take as long as four I've even heard now, thinking, like six weeks. And so, and it's hard because we as a new physicians and the and the patient like what am I going to do then. And we do things called bridging chemotherapy to help you to control your disease during that time if necessary. So that's what happens and then cells come back we give everybody lympho depleting chemotherapy, which is two days, three days excuse me a flu derby and cyclophosphamide, many of you had cyclophosphamide or site talks and this really just these two drugs combine and make room for these T cells that are a little bit foreign they're yours but they've been engineered, make room for your for these T cells to come in and do their work. So, two days later you get the T cells and then we watch and wait what happens we'll talk about that. Okay, I'm going to fly through a lot of this because I want to focus on what's important to you guys as patients. This is how the process goes that part right there, you can see that it's different now why is this important. Okay, so I'm telling you six years ago we didn't we didn't know any of this 2017 remember what that was that was a pandemic. So, a lot of things happened in 2017 and I actually think this world was totally different. But the other thing that happened in 2017 is we first heard about BCMA car T cell therapy for multiple myeloma that it made a splash and in this very small phase one presentation no one really knew about it was going to happen wasn't anticipated huge splash 100% overall response rate on herd of inpatient with seven eight lines of therapy so this is really really the data that started the whole force to get car T cell therapy developed and improved. This is the pivotal karma stay the karma one study that was for BB 2121 that's a BCMA directed car T cell therapy like we talked about. This was the phase two study that got this ultimately approved patients with three laps refractory myeloma at least three lines of therapy before we'll talk about what that means. But in this study the patient's median had a six prior lines that's a lot of lines for you guys know what all these different therapies it's a lot of different chemotherapies people have gotten. And eventually on the right hand side you can see that 73% of patients responded really unprecedented data I want to remind you that in myeloma, we generally get FDA approval for around 30% response rate so this is really good. And furthermore there were several doses picked here and the dose. That's the top dose that 450 million dose and the third bar that ended up being the highest overall response rate of 82% and that's sort of how we recommend that these potential, these cells get engineered and dosed cytokine release syndrome or talk about it later, pretty well controlled the median progression free survival here that means how long did people last before something happened was 8.8 months, but actually if you look at the 12, if the 450 dose that's on the left hand side that top curve, the patients who got this T cell therapy at that dose had a median means 50% did better and 50% did worse of 12 months before anything happened to them. Now that doesn't seem like a long time in a way that if you think about it, this is one time therapy, and then nothing else. And that's I think the way that car T differs from what you would get really as a regular drug, a lot of you know you go to cycles and cycles of chemo this is a one time treatment, something that I really like, oh sorry I wanted to point out actually hold on for the, but on the right hand side you can see who did the best. The people that had the top curve are the people who got into a complete response or stringent complete response. And I want you to keep that in mind because we're trying to figure out who those patients are, because those are the patients we want to give this very complicated and expensive therapy to because they are have the most potential to benefit. Okay, that's IDA cell but you know there's also still to sell anybody who knows how Kim Kardashian got famous she was actually the friend of Paris Hilton, and at first Paris Hilton was super super famous, but then this brand showed up and next thing you know boom she's got an empire so I think that's possibly what's going to happen to sell to sell based on this data. This is the car to data presented by my awesome awesome best boss in the world Tom Martin this past year at Ash this was the updated data. This is also a BCMA directed car T cell therapy, a little bit different because the outside surface the part that binds to the myeloma protein is binding two parts of it and that might explain some differences that we see between this and some other car T cell therapies. This is what you have to know. You got patients with six prior lines of therapy. These people had a 98% response rate unheard of. That's the kind of data you see when you have newly diagnosed myeloma right 90 almost everybody responded, and not only that the depth of response meaning how much did they clear that and protein and those light chains, 95% of them had a VGPR very good partial response for better that means 95% of patients cleared at least 90% of their disease, which is great, because we know that deeper responses in myeloma usually equate to longer follow up longer responses. Now here, they did have most patients actually did have CRS or cytokine release syndrome, but it actually was generally well controlled there's also some alternate neurotoxicities and we don't have too much time to go into that, but there are things that we can maybe control with disease burden. What I want to show here is that we don't actually have the true median PFS, as of yet maybe we will this year in a few weeks, when we have our next conference in June, but at the two year mark over half of the people so 60% of patients were still quote unquote in remission or had maintained the response so this is probably going to beat to 24 months which would be great. Again, one time therapy and for 24 months patients don't have to come back and get chemo or anything else. There are some other side effects but I think this is something that really can give people back their lives and the reason I'm such a huge proponent of of car T self therapy, if we can get it to last, is that that's the thing it's like my mom was a marathon if I could just prevent the patients from having to come back to the infusion center every week or every month, we would have done something good for the patients. Of course we always talk about MRD negativity. If I had a dime for every time someone asked me about MRD I certainly would need to work as hard but people who get into MRD negativity they do better everybody knows that again deeper responses, people do better so if you can eradicate the most disease you possibly can which seems like some of this car T therapy can do, you have a better chance of having a longer, longer duration response so how does car T differ from other therapies. This box is how it differs right this is the whole process that I explained before that you have, it's a living drug, you give yourselves those get engineered, and then those get back so it's like more of an intense upfront payment of logistics and therapy and this sort of six to eight week period that you're really kind of tied to the specialty center, very similar to transplant. But look, there's nothing after the red box. That's the other way it differs right. That means that if you're done and you really have a good outcome and I've had patients who have this not all, but some do it's really remarkable that people get back to their lives and go see their grandkids graduate and all these other things that we really hope people can see as myeloma patients, this is what I think is one of the most important things, and I'm I'm not saying this is high to sell data but this is also true for cell to cell. This is a quality of life measure this is the mean change from baseline of scores. Basically, fatigue and pain those are bad symptoms you don't want those right, you can see here for both of these symptoms that both of these went below a threshold that blue dotted line is an important threshold we define, and both of those symptoms went lower from months, one, all the way out through months 912 and 15 after one treatment, so the bad symptoms are better physical functioning health related quality of life those are better and persistent as such. So people are certainly not having worse quality of life for this one time treatment. And then there's the, I think the secondary subscales we just published this in one of our articles, the qlq c 30 secondary subscales. This is what I think makes people makes patients, people, not just patients right, the things that make you a complicated person, role functioning emotional functioning social functioning all of these things also were elevated beyond a certain threshold and came and persisted throughout, even though there were several months out from the initial treatment so I think that's a really big way that car T cell therapies differ from other therapies and I think this quality of life data is going to be huge. When we try to compare things one from another. So how do we evolve knowledge to limit side effects. Now, okay, there's a practical aspects of giving car T cell therapy there's what's the FDA labels right like the FDA says that you have to have at least four prior lines of car T therapy and I can't even get into all that because it's difficult to get there but and you can't have significant co morbidities What does that mean, that means that you have to be generally healthy. Now there's all these scales you can use, I have my own test it's called the target test. I always ask the patient, if I asked you to go to target and pick up a few things because you do it. And they're always like yeah totally there and their spouse like now I'll think I'll do it. And because going to target is very stressful. And so if you can do that I think you can definitely get car T therapy but I you know you have to be generally healthy, because it's actually easier to do than a melphalan transplant and I love transplant so for me to say that is a big deal. There are logistics you have to think about you probably going to have cytokine release syndrome we'll talk about that that CRS, the cell infusion is inpatient you have to go to a cell or it could be inpatient or outpatient but you really have to be at a specialty center, and then afterwards, there's this co monitoring between you. The specialty center and then your local doc and that has to be a really really tight conversation, so you know that you can go back home and still be monitored. The way you need to be okay cytokine release syndrome is like what I call it the graph versus host disease of immunotherapy because basically can affect any organ, it's, it's basically the worst flu you ever had a lot of fever it's marked by fever, but other vital signs like high blood pressure affected and we think that maybe the disease burden can be related or they're not not always. We have a drug called tosa loosen up so once somebody has this fever after car T cell therapy, I'll give Tylenol but I mean actually I'm quick to get the tosy I've noticed, I always call it hashtag no tosy shame because why because it works. This tosa loosen up as an antibody against the isle six receptor and it's very effective, it's sort of turning off the syndrome of CRS, and why because we don't want people to see you right the whole point is to do no harm we want to do good. So we get that if necessary, we have steroids and in rare circumstances, we have to give additional key note turn those cells off. Why do I like to get tosy. It's a complicated table but we just published this data last year, basically we looked at all of our car T cell therapy infusions at UCSF and for people who got early tosy, meaning within 12 hours of their first fever versus late tosy like we let them fever we let them have more time, and then gave him to see no differences doesn't change the progression free survival the efficacy any of that, it doesn't change anything. And theoretically it could shorten hospital stay which is a big deal. So I actually feel like with patients have that second fever, I give the tosa loosen them out right away. And the next day, they're like, Oh great I feel much better. And honestly who wants to get patient in the middle of the night right so that also helps me. There are other symptoms you can have you may have heard neuro toxicity we call it icons because it's because we have to make an acronym for everything immune cell effector associated or immune cell associated neuro toxicity syndrome anyway, basically, people become confused and I'd say, honestly, it's like you're drunk. And the reason for that is that it there's some sort of information being caused by the systemic information. And there's a lot of things that can manifest it if you let it go for too long people can have seizures go to the ICU, but if you don't recognize it, it's important to see and assess. Remember all these other things are going on in the hospital to write people are staying overnight a lot of patients are older they're getting through derby and they have fever, there's a lot of reasons why people may be a little off. So we want to keep a good eye on how to make sure we're tech checking people from time to time to time. And to do that we have this ice tool, which has been developed through the ASP CT that's our self therapy society and agreed upon, and we asked these kind of silly questions and they're good, and they give you a 10 point score, and they really focus on things like your ability to concentrate, recall and write, and you can see we do it twice a day it's like just a standard like other other vital sign now for our nurses to administer, and you can see how the handwriting can change during the time that person may have neuro toxicity. I'm telling you the first person to ever notice that the patient has neuro toxicity, the caregiver, right because that person's in the room with them a lot the second person to notice is the patient's side nurse, because that person knows. So as soon as these ice cores start to drop. I actually jump on it right away because I don't want the patient to get a seizure I don't want the patient to go to ICU, and we know that giving steroids in the lymphoma data really hasn't caused any bad effects as far as the efficacy goes. So how do I manage this, I put all my patients on seizure prophylaxis, so you may be getting an extra drug something called Keppra or something like that to prevent seizures, only in the time that you're going to get the car T cell therapy. I usually start a little bit before the cells get infused. And then if we need to we can give steroids, or eventually we can give chemotherapy, if necessary to turn off the T cells but really I think a dose of steroids, a couple doses can really mitigate this very nicely. Other toxicities this is what you will experience once you leave. And these are the low blood counts we call cytopenias, we can give things like new pigeon or GCF to help a lot of times people leave the center you know 30 days out, and they do need some spot dosing here and there of new Pugin or GCF and so their local provider can provide this so that's why it's so important for us to communicate with you and for you to communicate with us and us for the local provider it has to be a matrix to make sure you have a smooth transition, similar to transplant. There's this idea, this called thing called mass or macrophage activation like syndrome that I don't want to get into the biology of it but basically it's like a really big systemic inflammatory syndrome. In order to treat that we actually have this I will one antagonist called Anakin rest so you may be hearing about that. Really, pretty rare doesn't happen too much but when it does we now know how to manage it a little better and immunosuppression, this is huge. A lot of patients will say oh my goodness my IgG level is so low. That's actually a good thing that means we did a good job killing all those plasma cells but it's a bad thing because you're now susceptible to other infections. So we often will give IV IgG as a supplemental supportive care, especially if the immunoglobulin drops below 400 that's our practice based on the clinical trials but that's not a hard and fast rule. We do give everybody their a cyclopyr we check the CD for accounts you may be getting back to him receptor those drugs to prevent different kinds of pneumonia. These are all part of the way to sort of support you as we give a very effective therapy that might be also suppressing your immune system. Okay, so CAR T cells right now we're going to do that so I equate this to like bringing home a new baby, and you're like, now what, because you know you have this big thing, all this excitement now you and your spouse and this newborn. So what, okay so now the label, the label now says four lines of therapy. When you know I was actually involved in all the FDA stuff to get this through and they really want to make sure that you're going to get this because you need it. And so I thought okay four lines no problem but now I have patients I'm like man, how am I going to get them through four lines because they get this therapy and they get transplant and they're they get carspills and then what happens then. And I, anybody knows I'm a millennial means like I don't use old drugs. So all the millennials we all use new things we might use all his favorite care D or Derek Rd or Dara VRD because the Griffin trial, and then what are you going to do for lines two, three and four. So we have these statistical challenges like vein to vein time this is always a problem, trying to make sure that when the cells go out for shipping, and when they come back in that time that it's too not too long so that your disease doesn't blow up. And then we want to pick the right patients to optimize outcome and talk about that real quickly. And also how do we compare this to other immunotherapies that are coming down. So when's the right time for car T. So we try to look at this. So we just looked at this and presented this past year at our conference what what predicts for who's going to get that complete response. I'm not going to go into all the statistics but the short of it is look at the red arrow, that if you have IgG heavy chain disease, or a lot of serum BCMA or an elevated coagulation factor that you're less likely to get a complete response. What does this mean in normal speak. You're less likely to respond. Well of course, we all know that right, but this means that we have to pick patients who aren't at the end that aren't having their disease uncontrolled and blowing up and unable to be salvaged we have to pick people who are just seeing the disease start to perk up. Those are the people that we should be taking, I think, to car T therapy. At the bottom this vector copy number, the higher it is the better you're able to do that means to me T cell fitness so we shouldn't be taking these patients with so many lines of therapy, we want to make sure that their T cells are healthy enough in order to actually produce healthy T cells very similar data has been seen with the cell to cell product as well. Okay, so what does this mean. I think this is this side, this is just for IDA cell but this is something that I think we're looking at for a cell to cell as well these are just the trials that are going on, we have them in the late phase, we should pull them earlier when patients are less aggressively have less aggressive disease have more time to plan, and their T cells are better that's that's my story I'm sticking to it I think it's going to become second line, but 2023 we have this ongoing BMT CTN trial, looking at patients who may not have gotten to VGPR or CR after maintenance after transplant consolidating them with car T this is open at a center near you. And then finally thinking how we're going to think about car T versus by specifics and antibody drug country it's, they're all good they there's enough my little bit to go around, but you have to decide what's right for you and what the logistics will afford one time therapy is great but you can't always get it, and if not, I think the approval of by specific therapies is going to be very very important as an available off the shelf option. So we have T cells coming down the line, not just BCMA but also GPR C5 D at the bottom there, and we're looking forward to new data from our conferences and really really because all of you guys participated in clinical trials so so important what couldn't be standing here without that. So in conclusion, car T cell therapy for myeloma yields impressive overall response rate. And then finally, we have a one time treatment I think that's the best thing about it. No cures yet my boss always says we have plateau envy meaning the curve isn't plateaued. And we have to figure out how to optimize this boat, where the patient is as far as their diseases and where they have been as far as their previous treatments and consider cost quality of life accessibility early referral is key clinical trials are a must for I don't know who's seen Ted lasso, but it's true, Danny would say the same thing. And with that I want to say thank you this is our team at UCSF. That's very compliant, and we finally resurrected our single to myeloma party that we have every year finally back in circle on the bottom left they're so excited people were able to actually have it. And I think that's the end of the talk. Thank you.