In this three-part presentation, UCSF substance use experts offer prescribing strategies and tips on patient communication to ensure pain relief without enabling drug dependence. Next, UCSF hematologists discuss the advanced techniques leading to better transplant outcomes for blood cancer patients as well as how CAR T-cell therapy is creating new possibilities in multi-relapse cases.
eso tonight is gonna be really exciting. We have two different sections. One area that's really had a lot of news recently nationally is managing cancer pain during the opioid crisis. And actually at our recent breast cancer meeting, there was a lot of discussion about this as well. And it's kind of shocking data about the number of patients who were still taking narcotics after first being prescribed them for breast cancer surgery, which was pretty amazing. So we're very excited to have Mike Ray Bo here along with Brooke Carlton, who are part of our symptom management program. Mike Rainbow actually runs the program, and they've really been looking into this a lot. And I think we'll provide you with a very interesting information about this area and then in the that will be the first half hour of this session on. And then the second section is on advances in human Hologic malignancies and car T cell therapy. And we're very fortunate to have Dr Tom Martin be the moderator of that section and he will come on at about six o'clock. We have Dr Lloyd Damon, who will talk about hematopoietic cell transplants and then Dr Nina Shah, who's going to talk about chimeric antigen receptor or car T cells? A new drivers in oncology treatment to really exciting area in human logic malignancies, which Dr Shah has actually led a lot of the work on. And UCSF has been one of the leading institutions as well. So we're excited to have you here. We'll look forward to your comments. Please do get comment about the best time, and without further ado, I'll turn over the podium to Mike Rainbow and Brook Carlton. Welcome. And thank you for participating. Um, hope, thank you so much and welcome everybody who's joining this conference and definitely, I hope and expect that there'll be questions and thoughts and comments and focus on on the, uh, conference today with lots of experience to share a swell. So please do, um, use the Q and A function. Well, look forward, Toa addressing those comments, Uh, at the end of just a few prepared slides, um, to really address the question of how is it that we in the day to day basis, they're gonna be managing cancer pain during this opioid crisis, and I'm going to start off for about the first half and then Brooke is gonna step in and take it from there. We'll finish with some cases. Mhm. So we're gonna talk about the current state of the opioid epidemic in the US, are very briefly and then briefly review the risks of opioid misuse by patients with cancer. But spend most of time talking about how could develop a strategy for managing opioids in your own clinical practice. So to begin with, I wanna offer just a few definitions, um, useful, so that we can communicate well with each other. ANDI also use language that's not particularly stigmatizing for our patients and their loved ones. So first off misuse is really any use of a medication prescribed medication. It's different than what you have intended. So that might mean using medicine through a different route of administration or, more frequently than expected, uh, or planned. Um, in most cases of misuse, in many cases of misuse, the intention is not to get high. If someone's intention is to alter their consciousness or use the medicine in the way to achieve a different effect than was intended. Um, that is what's defined as abuse. Addiction is a new older term that really refers to a neuro biological disease that's defined by the foresees. So we think about patients who have, ah, significant compulsion to use the medicine. A craving for the medicine Are you using? A Despite evidence of negative consequences. And I'm having very significant difficulty with control. A number of years ago, though, we created a medical term essentially for addiction. We call it substance use disorder, patterns of symptoms resulting from the use of a substance that the individual continues to take despite experiencing problems as a result. And addiction has all sorts of stigma associated with it all sorts of meetings, all sorts of people. So we're gonna be using the medical term, uh, substance use disorder throughout our comments here, and I think useful for us to talk about that with patients as well. So, of course, the big dilemma is that pain is incredibly common, incredibly common for people with advanced cancer. Andi, even curable cancers as well. Pain could be very common during the course of treatment, historically know that pain is relatively under treated in cancer and elsewhere. And yet we also know that opioids are often necessary to Crete to treat cancer pain. And we know that opioid use disorder relatively common in patients with cancer. There's a relatively wide range of estimates. Uh, one study of 100,000 cancer survivors showed that more than 8% were still using opioids after treatment of their cancer. And hope made reference to some recent data about the frequency among breast cancer patients who underwent surgery in this study of breast cancer survivors. And I'm referencing about 3% of patients actually got diagnosed with substitutes disorder um, in a V a study slightly higher percentage 6.64% of patients with substance use disorder in a study of more than 400,000 veterans. So we know that substance use disorders common. It's common or more common among patients with cancer, and the trouble is that there are a huge number of costs to using opioids, which are we are very, very aware, necessary for much of cancer pain because they're some of our most potent and effective hey medicines. Opioid use disorder is actually the number to substance use disorder in the U. S. After alcohol use disorder, there are huge financial costs toe opioid use disorder primarily around the utilization of the emergency room on by the hospital. So more than 1180 visits per day, um are met. This was prior to covert, I guess, uh, for prescription opioid issues. And we also know that a very difficult problem and a very emotionally, um, devastating issue is the issue of diversion that is, patients who get prescribed opioids who are then giving them or selling them to other people. Ultimately, the morbidity and the mortality associated with opioid use disorder is huge. It's a leading cause of injury death United States with a 300% increase over the last 30 years in the deaths due to opioid use disorder. Majority of drug deaths today are prescription opioids. Yeah, and the challenges that we know that women had more joy when we prescribed more opioids. We have more misuse and what we're death. You see that the, uh, the line for deaths and the line for, um, opioids sold run in parallel since the turn of the millennium. Oh, we have to be very, very conscious of this direct relationship between how maney opioids are out there in the system. Knowing that about half of patients who are misusing opioids have gotten them from someone else from another person who has received them, typically from one other physician. Next left on. And here's a graphic representing what has been shown in so many ways in the late media and in the professional media as well, which is deaths due to prescription. Opioids are really skyrocketing, and notably are even greater than deaths due to heroin, which most people recognize as a major major issue. But the medicines that were prescribing are ending up being misused, and that's something for us to pay really close attention to. So here's the dilemma. Uh, for damned damned phone. Uh, no over. I'm on with eso, Really? The rest of are going to be about How do we figure out a strategy toe deal with this dilemma? So the first issue in managing opioid safely is to make sure folks who we know have a pre existing substance use disorder. I'm get treated appropriately, and this could be and probably should be done with medical assistant therapy. So methadone buprenorphine. Ultimately, we are going to have to away this risk for O. P. A phobia or under dose versus under dozing or under treating of pain with opioids against the need to treat appropriately. And the key here is treating with a really good, careful and recurrent assessment of risk. And that's really what we're going to stay focused on for the rest of the talk. So, um, he here is our relationship with the patient relationship between the oncologist and the patient and between the rest of the interviews from a team on the patient is key. There is a potential role for home health and our colleagues and hospitals as well. But this system works best if it could be based on trust and if we could do everything we can to decrease the stigma. Folks who have substance use disorder, including opioid use disorder, deal with a lot of stigma in their own hearts, uh, in their communities and especially with their close loved ones. And they don't necessarily need to have the health care system extend or promote that stigma. So we're going to be very, very careful to prove to provide a very universal approach, not identifying patients, uh, as potentially substance use disorder patients because of any demographics that we are presuming based on our biases and I presume, but really going to make this universal assessment of everybody on. We're gonna be careful about the language we use, uh, keeping in mind this people first, people with substance use disorder rather than drug addicts or other kinds of stigmatizing language And then think about patients were not actively using versus talking about clean vs, uh, presumably dirty or abusing, uh, substances. And then, Brooke, you you're gonna take it from here, I believe. Thanks, Mike. Eso What we wanted to do now is just to provide you with a practical approach to managing opioid safely. And suffice it to say that there is no, you know, perfectly data driven, evidence based approach for doing this, even just a cup. It was even just a couple of years ago in the symptom management Service that we realized the need to have our own protocols in place. Um, as we noticed that issues around opioid safety and, um, opioid abuse started to rise in our own practice. And so we just wanted to provide you with some helpful tips and an approach that you can hopefully apply over the coming weeks in your own practice. So these were the different steps that we're gonna talk about a little bit in more detail. So the first step And, you know, I also want to highlight that. I think it could potentially be overwhelming to thinking to think about doing all of these yourself as, um, if you're treating oncologists O r nurse practitioner who and so remembering that ideally, other members of your team can help with pieces of this it well as well. So the first step is to really take a focus history, um, regarding risk. There is no standardized approach to doing this. Certainly important to always consider high risk factors. These air listed for you here and there are some, obviously, that you can also ask about, like a history explicitly of a substance use disorder and then other things that you would be screening for in your in your mind or asking questions about to inform your history. A couple suggested screening questions that might be helpful. One is a single item screener that you can use and is, um, evidence based. How many times in the past year have you used in a legal drug or used a prescription medication for non medical reasons. I find this really helpful, this question in part because I find otherwise I might kind of stumble over my words or not know exactly how toward the question. And so I really incorporated this into my vocabulary when I am thinking about starting an opioid pain medication and want to assess for risk, the others is the tried and true cage aid questions. Mhm and these air list for you here as a reminder, because I think probably a lot of us saw this in our medical training. The things that are related to Cage are difficulty cutting down. Have others been annoyed by your drug use? Have you felt guilty, um, in the past about the consequences of using, um, particular substances? And then have you ever had an eye opener? That's the And so these questions can be helpful both in the assessment of risk, but then also for monitoring Mhm. The second step is to consider using a risk assessment tool. Formally, Thio categorize folks into their risk category and in terms of their risk of opioid misuse and abuse, this is your reference. The O. R t, the opioid risk pool. And as you can see, it's something that a patient can fill out themselves, and then you tally up the points, and it puts people into low risk, medium risk or high risk category, and that can help inform your future management plan. There is another, um, tool called the soap S O a P p. And that is in an alternative. Some people prefer that one because it doesn't ask about pre adolescent sexual abuse on bond. While that's important, E, I think that there does need to be safeguards in in a plan in place. If people were to answer that question, yes. And so some people do prefer the other one. Um, these tools have been validated in non cancer populations, but we do not have data for cancer populations, so we're essentially extrapolating. The third step, once you've assessed for risk with your history and with a patient administered tool, is to devise a management strategy based on risk thes air, just a couple ideas of things that you might consider incorporating into your practice that are safeguards. So the first it opioid agreements. We prefer to call them opioid agreements as opposed to opioid contracts. The data is variable for these, um, in the non cancer pain community population. What I find helpful about them is that it it makes you explicitly go over the potential benefits of opioids, the risks and then how you're gonna work together to prescribe them safely in your clinic. So I use it for that reason, um, you know, certainly. Then you can also use it in the future. If there's an issue that comes up and say I remember we had this agreement. But for me, the most helpful thing about it is that it serves as a way toe have a broader conversation about opioid safety. Yeah, in terms of other things that could be helpful. E think by and large, we probably don't use urine toxicology enough in part because sometimes it's hard to know what to order, but also because it can be difficult to interpret. But for the sake of time, we don't have time to go into how to interpret them, but important to think about. If this is something that you want to include in your practice, it can be used initially before starting opioids. It can also be used just part of monitoring. And again, we don't have strict guidelines on when people should be tested. But it is something that you could consider. It could be helpful in ruling in substances that you want to make sure our in someone's urine opioids that you are prescribing. And then also it could be used to see if there's other substances that people are using that you don't have knowledge of. And the way that I typically frame it is in terms of patient safety and making sure that everyone is a safe as possible, that it's important for me for my patient. Thio be safe. As you probably know, cures is California's state database, where any controlled substance should be listed by the pharmacy. It is exquisitely helpful to look at, and it's also mandatory now in the state of California within the last couple of years. So when prescribing any new controlled substance including opioids, it should be checked initially and then every four months after, um, and I have been on multiple occasions, I think enlightened in terms of what, what, you what you find when you check yours, a reminder to that it can be you. It may also be someone another team member in your clinic, that is, that is checking cures. One of the things that I have tried Thio more recently incorporate into my own practice is the idea of dozing limits. So if you think that perhaps someone's pain is going to be either variable over time or they're not on a chronic dose, and so you may either need to change them to something else or, um, change the dose quickly. Or if you have deemed your patient to be high risk, just remember that you don't need to give them a month long supply of their opioids. And in fact, we would recommend doing far less than that so that you can either make changes quickly. And they're regimen without needing to be worried that they have a huge amount of medicine rd at home. Given the risk, particularly of diversion, that might talked about Onda, also you for people that you're struggling with or that are higher risk, it could be a nice way to more closely distribute their medicines in a way that's safe. So sometimes, you know, I'll even just give folks a seven day supply of medicines on bond and then follow up with them, then quickly after that. That's also, I think, a good reason. If you are struggling with someone who has cancer, um, pain. And they have active cancer in particular to think about a referral to palliative care, we can help with those things. Finally, just a plug for frequent visits for people who you may be worried about and also the role of pill counts, which are potentially even easier. Right now. People always forget to bring their medicines into clinic. But given how much of um, medicine is being done by telling medicine right now, people have their medicines, they're at home. Or at least they should. I wanted to present you with a potential flow chart of a way of something that you could think about. Incorporating into your practice is a way to manage risk for the sake of time. I'm not going to go through it in great detail, but it's available on the Internet. If you want Thio, look at it more closely. It's in the ASCO educational book, published in 2019 by one of the greats in the field of palliative care and pain medicine. And, um, it talks about a lot of the same things that we've highlighted in terms of the role of universal screening for everyone and then stratify ing people into low risk patients and higher risk patients and determining what management steps are needed. After that, I want to talk just briefly about some key prescribing principles and for the sake of time, will probably try toe talk about these relatively quickly. So one thing that I think is really critical that we often forget to do is to really be clear when you're starting and opioid about what the goals of treatment are. So for some people, that might be a number for some people that might be function. And I would certainly advocate for function being a really good goal of pain management s so you have something to shoot for so that if it's not working like you hope, it's easier to have that conversation into change course also, especially if you expect someone's cancer to get better, really important toe. Have that conversation early on when your starting the opioid about you know I hope you're improve and that you are gonna have less pain. And when those things happened, I'm gonna work with you to get your opioids down. So you're setting someone up for success, letting them know that this is not something that they're going to be on forever. Hopefully, And you're gonna work with, um, as a team, obviously managed maximizing non opioid strategies, including non pharmacologic strategies, is really important. That's really, you know, multiple talks in and of itself, the role of going of starting low and going slow. So unless someone is in really, really severe acute pain pain, it's always a good idea, particularly in older patients. But really for everyone, just to know that you can start low and go slow and and ramp up from there, I think this really highlights the important role, Um, that the Inter professional team can play in providing some close follow up, maybe making a phone call in a couple days to see how someone's pain is on ben. Tight trading from there, by and large, always starting with short acting agents, is the safest thing to do and someone who's opioid naive, making sure that medicines are out of reach and locked in someone's house. Thio prevent or reduce the temptation of diversion, and particularly if there are any young Children in the home. This is important, and the research shows that this is something that we prop Hey, patient. It's about as a general principle, avoiding methadone. Unless you're formally trained in how to use it, it is a tricky medicine could be exquisitely helpful. But if you have not been trained how to use it definitely asked for our help or the help of other pain management colleagues and then thinking about the individual risks and benefits of opioid therapy if you're getting above 50 or a morphine equivalents, and I'll show you a quick graph in a moment about why that's important, remembering that Narcan, which reverses the effects of opioids temporarily, is a really important drug for safety and that it's now required in the state of California if someone is concurrently using a benzodiazepine with opioid therapy or their opioid more their oral morphine equivalents or above 90 mg per day. So I just wanted to show you as an example, because probably not everyone thinks an aural morphine equivalent. But these are, um, doses of different opioid pain medicines that are equivalent to 50. So you'll have this for your reference in the future. And this is why that that threshold of 50 and thinking about recent benefits, particularly if you're getting to that level is important, is important. You can see here that the that the risk of fatal overdose and patients who have prescribed opioid really skyrockets both for cancer pain and the far right and per chronic non cancer pain. Once you get above 50 Orel Morphine equivalents per day. Finally, Step five is to monitor for effect. And, um, not forgetting that once you start in opioid, it doesn't need to be forever, and someone may not be struggling with trouble with it at the beginning, but that could potentially change it any time. So the things that you're gonna monitor for our benefit of the opioid toxicity what what side effects are somewhat happened is potentially having and then monitoring for risk of misuse and abuse. Using some of the questions that and tools that we talked about earlier in the talk and you'll have this here for your reference to I like this little pneumonic in terms of the forays thinking about opioid therapy's effectiveness in terms of an al Jesu ability to do activities of daily living potential adverse effects from opioids and then aberrant behaviors. And this is a list for you in terms of assessing aberrant drug behaviors, things that are more predictive, drug seeking behaviors like selling prescription drugs or stealing or borrowing and other patients drugs versus things that are less predictive like drug hoarding. Onda request for increased doses, which sometimes can be, is not always but sometimes can be just because someone's pain is out of control and needs to be better managed. So just a couple of more points for us to make, um, two cases for us to consider. We're not gonna run through these cases in any detail, but just to throw them up so that we can all recognize how common the complications are that we're talking about here in kind of balance the benefits and the harms of opioids for our patients with cancer. Um, I presume a number of folks on the call have someone like this 65 year old woman with cervical cancer whose status post resection she was given oxycodone 5 mg tablets to be used as needed post operatively. But two months later, she's in your office requesting refills because the oxycodone is helpful for her total body pain. And here's a situation where we might not be expecting that the patient is having post operative pain. Still, at two months if she is, it's definitely something to evaluate and really wanting to look into the complexity of what her pain is and what it means in this particular situation. It turns out, um, this woman was, uh, dealing with alcohol use disorder on when her opioids were stopped. Um, she started drinking heavily, and through that mechanism end up back in a andan treatment for her alcohol use disorder. Um, not needing the opioids. Actually, another interesting case. 37 year old man with a history of I V drug use and, uh, methadone maintenance 30 mg per day distributed by the methadone maintenance clinic with pain from a new head neck cancer status. Most recent section who is now in the midst of chemo therapy in radiation treatment. And so then the question of how it is humanity, someone who's committed to his own recovery and continuing, uh, to use medical assistant therapy to deal with his substance use disorder but still also has pain. What do you do? And some of the things you might think about would be the idea of breaking up the methadone into, uh, more frequent dozing because the analgesic effects of methadone are actually relatively short lived. And certainly certainly coordinating with the methadone maintenance clinic as to whether or not you're gonna be increasing or adjusting the methadone dozing, um, or using the methadone for methadone maintenance and then using a different opioid, uh, for the pain. So next. So we wanted Thio also really highlight situations where, um, there are really important other kinds of interventions that really made the benefit people in terms of the pain that they're dealing with that takes them outside of the use of aural medications, including opioids. So think about, uh, the patients who are complex thinks about those patients who aren't achieving the goals that you set out right at the very beginning of working with patients. Those who are using complicated medications, including just very high doses of medications, um, or who are using methadone complicated situations, those with preexisting substance abuse, substance use disorders and then complex psycho social situations and then when a specific intervention of a particular type is needed so you can think about is surgery actually a solution to this person's pain? Trouble Is radiation oncology a solution? Or does a patient likely to benefit from interventional pain management strategies? All these things that would really preempt the need for super high doses of systemic opioids and then, um, to really invite one last thing broke one slide back just to invite folks, too. Think about referral for specialty palliative care. I know everybody on this call is doing what we would call primary palliative care and managing pain and other symptoms with your patients. But if you feel like things have gotten past what you have time for or even expertise for, please do think about making a referral to the value of care program at U. C s effort of their medical centers are problem is called the Symptom Management Service SMS. And if you're on the FX E M r, you can find us through that as a referral, and you're certainly welcome to call us that our remain number four and 5857671 and then the last slide book. Thank you. So there's just the list for the resource is including the Lalonde Brera paper caps. C center for Advancement of Palliative Care has wonderful resource is on and then important resource of substance Use warm line, which allows you to talk with a pharmacist, physician or nurse about these opioid substance use issues with someone, uh, confidentially who has a real expertise. This is great. Uh, you know, we'll have to We're gonna have to move. I mean, there's so much way Have toe move on to our next section. But Aziz Thomas clapping for you. This is really a great, great discussion between you and Brooke, and I think a lot of incredibly helpful information with the case presentations as well. I think that rather than because you did the cases and so Maney really helpful bits of information resource is we're gonna jump onto the section on hematopoietic malignancies and really appreciate your participation for the attendees. There will be a recording. There's a recording going on of this, and Kristin Del Rosario has the has the ability to send you the link. So she sent out a chat which has her email Kristin del Rosario at UCSF dot e d u c. You can see it in the chat section. You can email her after this. If you want to get a link to the recording also, please do remember to register for our additional sessions next year. You'll get a notification of that. Um, if you want to see any credit, you pay a little bit. If you don't, you can register anyway. And it's a great pleasure to turn over the podium. Dr Tom Martin from our institution to start our next session. Thanks again, Mike and Mike to as you're listed. Brush. Thank you very much for having us. Yeah, that was really awesome. And we're gonna send you a lot of concerts from our side of the street, that's for sure. After that, Um, well, thank you. All the attendees. Thank you. Hope, um, for turning it over to the blood cancer portion of this tonight. I have the great pleasure of introducing a couple of our speakers. Um, just like all cancers, thes days. It's quite exciting being actually, uh, novel therapies and immuno therapies. I tell people, um, that the reason back in fellowship that I went into, um, transplant in blood cancers was because after an AL a genetic transplant for CML, you could give somebody lymphocytes from the donor, and those lymphocytes can put him right back into remission. And I said, Oh, my God, that's immunotherapy. That's the best immunotherapy there is. But nowadays, what keeps us young is what Doctor Daimon and what Nina Shar gonna talk to us about. So, Dr Shaw, Doctor Daimon, who's gonna go first? Okay, that's Doctor Daimon. Damon's gonna talk to us about, you know, advances and, um, Hamad aquatic transplantation. And, um, you know, we can't do it all in in the next 25 to 30 minutes, but he could do a good job at it. And, um, you know, if you guys have any questions, please just put him in the Q and A and we'll do the questions, right? Right at the end. Doctor, do you have the floor? Are you on shared Tom? Can people see this? Yes, we can see it. Okay, good. Hi. I'm Lloyd. Damon. I'm gonna talk to you about him out of putting cell transplantation. And of course, this started out as B m t bone marrow transplant, and then it moved to mean blood and marrow transplant. And now today we have him out of what Extell transplantation Stem cells been left out because it's not always stem cells that we're transplanting. And Nina Shaw will give you an example that car T cells. This is what I'm gonna talk today about UCSF volumes in matter poetic. So transplant, including those pre and post co vid types of transplants. We do give you a snapshot of our outcomes. And then with what time left? Talk about major advances, as I perceive it in HTT over the last two decades. So, looking backwards over 10 years, this is our volume of activity. For the first five years, it was roughly around 190 from 2010 to 2014. Since 2015, we've been closer to 220 we sit there and I don't really perceive that this volume is going to increase a great deal in the near future. Just to put this in context for you. A large program like the Fred Hutch, City Hope or MD Anderson. They're doing 600 transplants a year. So we're about a third of that pre and post cova data. So this is the transplants that we did from eight months before Cove. It got started July 2, February and then eight months since then, ending at the end of October. And if you go to the second row, you can see that are allergen eight. Transplants did not change in that time period. 44 pre Covad 45 posts. But the autos dropped. They went from 106 Preto 88 post and that was a deliberate move in March. We were really uncertain how this was going to play out eso we cut back on certain auto transplant. It's especially myeloma where, actually, as the patient continued treatment, they could wait a bit. Um, I'm happy to report that we've only had one death that I'm aware of in a transplant patient, and that occurred from Cove in 19 that occurred 18 months after his transplant. So it wasn't during the actual transplant hospitalization, so overall our activity dropped 11% and then the autos that dropped 17%. This is our activity based on the donor source. So in blue are the autologous transplants, and in the orange are the allergenic transplants, and it hasn't changed much over the last decade. And it's rough roughly a 2 to 1 ratio eso overall. In this time period, 31% of our transplants for Allah genetic and 69% were autologous. If we look back from our first transplant in 1986 um, we've, uh, three factors. Transplants that 70% related and unrelated allergenic are nearly 1100. That's 28% apple identical transplant We've been doing now for four years roughly, and it's at 57 but rapidly growing. Andi, this is something I'm going to talk about in a few more minutes. Umbilical court. We have not done many, and we don't consider ourselves Accord Center. And three identical twin transplants are 4005 100th. Patient was transplanted this summer. What this looks at is allergenic transplantation by the indication for transplant and is common and typical in North America. Que Molly Leukemia is our number one indication at nearly 500. What's different is a l. L is number two here, and that's because we are a nail l referral center, both for new diagnosis and relapse disease. So that's the second, as opposed to what's typical in North America, where the number two indication would be MDs. CML has been quiet. We do about 3 to 4 per year. They're usually entire sing kindness, intolerant or terracing kindness. Inhibitor failures. So not very common anymore. And then we rounded out with lymphoma, a plastic anemia and myeloma. In terms of autologous transplant, you could predict this myeloma amyloid was number one, nearly 1400 patients transplanted since 1986. Number two is typical non Hodgkin's lymphoma over 500. What's unusual in our data is AML is number. Third is number three on this is because in the 19 nineties we had a strong research interest in auto transplant for AML, so this typically would be way to the right in your typical North American center. Breast is at 3 28. Our last breast transplant was in the year 2000. Don't expect that that will ever change at this point. And then we have the usual Hodgkins germ cell and l l. Here's a snapshot at some of our outcomes, mainly in calendar year 2019, The last column here, which is one year overall survival. I have to take the 2018 data on. Basically, if you look at the left column, we have autologous transplants. We have M R D, which is match related donors. So sibling M A C means my little blade of conditioning. M R D Rick means reduced intensity for a sibling. Mud is matched. Unrelated donor, both my low blade of and reduced intensity and then, happily identical In the second column, we see the numbers that were done in 2019 are 100 100 day mortality, zero for autologous, zero for sibling for an unrelated and zero and happily identical, very good one. Your non relapse mortality. We had one in the autologous group, so that's under 1%. Typically in the country, it's about 2 to 3% for siblings. We had zero for the unrelated. We had three deaths, Um, which remains low and none in the chapel. Identical then, lastly, if we look at the last column, which is the one your overall survival using calendar year 2018, 95% auto, 70 to 80% if you will, and most of the allergenic were a little low in unrelated reduce intensity, but the denominators small and that likely is due to patient selection. And then lastly, Happel identical 60% which is quite good. So these air what we believe to be very good competitive outcomes compared to the rest of North America. And is there more proof of this in terms of how we're doing? Well, the answer is yes. We have to report our data to the C i B M T R, which stands for the Center for the International Blood and Marrow Transplant Research Registry. And basically we were an over performer compared to our competitors group 2010, 11 and 12. What does this actually mean? So in 2010 there, looking at one year overall survival for allergenic transplants only from years 2000 and 7, 2008 in 2009. So we're in over performer. Here are more than two standard deviations above the mean to our competitive group. We then started to doom or transplants, and when we started to do more transplants, we changed our competitors group colleagues, if you will on based on that, we have been since then an average performer since 2014, but our survival has been gradually coming up. And this data came to me on Monday 75% 1 year survival. So we're doing extremely well to statistical comparisons with reasonable, um, other centers in the country. A few quick look at some diseases and how we've done this is allergenic transplant for you, Ali. Leukemia. The Blue Line is a sibling donor and the oranges unrelated. As you can see, there's no difference on I'll tell you why in a few minutes. Uh, that's due to H. L. A. Gino typing these air good data. This represents people in first remission, second remission, third remission or not in remissions. They're all lumped together. So if it was first remission data the curve would sit up over 60%. Same type of story with acute lymphoblastic leukemia, where there's no real difference between using a sibling or a related donor. This is autologous transplant for myeloma shown here in blue a steady curve that drops. Uh, if one accepts the concept that we're not curing the disease, but we're improving survival and improving quality of life. Uh, note. Here it five years, 70% overall survival in myeloma patients. So really outstanding Every time I see this curve, I have to pinch myself. Non Hodgkin's lymphoma The curve is sitting at about 75% of five years overall. Survival for autologous transplant This is really very, very good data, and I think really speaks to our group that is very dedicated. To be sure, patients are truly chemo sensitive before they go toe. Auto transplant. Hodgkin's lymphoma Also very, very good over 80% survival. Having a little trouble with my arrow? Here we are. Okay, Now I wanna end by talking a little bit about what I consider the major advances in al. A genetic transplant in the last two decades that includes actually genotyping ganciclovir, preemptive monitoring, a CNB alternative donors, post transplant cyclophosphamide, Rex litany and something called fact. Basically, historically, we've done a chilly typing for allergenic transplant Syria. Logically, that is, using monoclonal antibodies to identify the H l A antigens to determine a match or not a match. But we've come to learn now with Gene sequencing or Gino typing that serological matches are not at all the same as Gina type. Matches and genotype matches air better. And as a result of that, I showed you some proof of that. Outcomes are improving when we use an unrelated donor now relative to a sibling and becoming very similar and particularly substantially less graft versus host disease. So, Justus An example. If I were to do Gino typing today and let's say we had an a low side that I would locus that I was interested in, we'd get a result like this. So 4, 43 32 the old four refers to the old Syria typing a 04 which really refers to identifying the antigen or protein. We call that an Asian level matching. The next are polymorphisms within the A 04 Let's call it 43 which is a polymorphism that is important for graft versus host disease and also graft rejection on. We refer to this as a Lalique level matching or Gina type level matching 32 or additional polymorphic changes in or near the gene of uncertain functional significance. But, um, for compulsive sakes, the H l A lab reports it. So we're looking for four numbers to match at each low sigh in order to declare a match donor what has happened in unrelated transplant acute graft versus host disease, which is severe grade 3 to 4 has gone from 15 to 20% was urologic, matching down to a roughly 10%. An extensive chronic graft versus host disease has gone from 50 to 60% down to around 30 to 40%. And, as I said, resembling that of sibling matches, another advance was discovery and promotion of D H P G or against clever and anti viral against CND. And this is important because historically, uh, 30 years ago, uh, C N v. Newman itis, which used to be called the idiopathic pneumonia of allergenic transplant, had a death rate of 10% of allergenic transplant recipients. So it was horrible. I knew if I patient was intubated in the unit early during Gallo transplant, they were going to die. Can cycle beer made it influence not so much at reducing death to to see and be Newman itis, although it did. But major issue was using it correctly to prevent CMB Newman itis in the first place. So one advances getting the drug. The second is using it appropriately. And so when again second beer came out, they prospective randomized trials were performed using it prophylactically. So half of the patients at risk, but get it after transplant and half would not. Andi. It's substantially reduced CMB Disease and Newman itis. However, the side effect is marrow suppression and neutropenia, and it picked up more deaths due to neutral peanut confection. When ganciclovir was given. So it became a wash. There was no improvement in survival. So then it was switched to taking people at risk for CMB disease and preemptively following. They're seeing the PCR and blood for the 1st 100 days, and if it's negative, you don't do anything. But if you start to get very mia and you see the CMB rising, then at that point you start ganciclovir. So this has led now to very little death through the CMB Newman itis or colitis and no increased deaths substantially to neutral Penick sepsis. So there's a survival advantage using preemptive ganciclovir. What about alternative stem cell donors? I'm not talking about unrelated. Now I'm talking beyond that the use of cord blood or the use of now happily identical donors for transplantation, a breakthrough what which I'll mention in a moment in happily identical transplantation has permitted the routine of half close, which we now prefer over cords. Um, and I just want to mention that the overall impression that we're getting, which is not proven yet is that five year outcomes from all donors air becoming the same. So whether it's a sibling, an unrelated accord or ahap low, you may have differences about who dies in the first year or you're 1 to 4. But at five years, everything looks similar, and for the sake of time, I'm not gonna show you the graphs on the right. I do want to mention the breakthrough, unhappy, identical transplantation, which is post transplant cyclophosphamide. So what happens here when you have a happy, identical donor eyes? The graft is given on day zero and then on day plus three plus four after the transplant. Very large doses the cyclophosphamide are given because the donor T cells air at that point raging, and they are identifying the discrepancies in the H. L. A androgens and attacking you. Eliminate that repertoire of T cells and then allow the tomato poetic stem cell to create a new T cell repertoire, which is tolerant of the recipient or host. This has made happily identical transplant tolerable. And actually there's actually less graft versus host disease, both acute and chronic, with a half blood transplant done this way than a fully match donor in the usual T V H prophylaxis mode and the curve on the right, we participated in this study. The red curve is post transplant cyclophosphamide and someone receiving I matched sibling or unrelated transplant compared to other forms of graft versus host disease prophylaxis, the standard being tackled. Lima's mental tricks eight etcetera in the point being post transplant cyclophosphamide look better. A phase three prospective randomized trial is now underway. Post transplant cyclophosphamide versus using tackler. Lima's method checks A has the standard approach and a matched, fully matched transplant. I think this is gonna be really a substantial breakthrough in our business. Graft versus host disease has been, ah, big problem for us, Andi. The usual approach with corticosteroids and anti time aside globulin haven't been great rock solid nib, which, you know I was after they approved for Milo Fibrosis, another mile perimeter of neo plasm. Jack wanted Jack to inhibitor. Actually, through these pathways inhibits inflammatory side of kinds and as a result, has activity in corticosteroid, refractory acute graft versus host disease and is the second drug in the U. S FDA approved for graft versus host disease. Uh, this paper was just published and it showed in critical steroid acute graft versus host disease rocks. A litany provided a 70% response rate, 22% complete ableto taper corticosteroids into thirds as three quarters and in chronic GBH, 50% percent response for Rusa and complete over half its a well tolerated drug. It's really become a remarkable assist for us in patients with graft versus host disease and other approaches similar to this are underway. Phase three study actually was just shown that the ash meeting rock solid nib 10 mg twice a day versus best alternative therapy for moderate to severe corticosteroid factory, chronic GBH D. And you can see the failure free survival curves shown here, much favoring look Rosalinda. In fact, what is fact fact stands for the foundation for the Accreditation of Cellular therapy. So about 15 years ago, the FDA became concerned about the cord blood industry and the fact that was unregulated. Um, the writing was on the wall and the FDA was going to now start to regulate hematopoietic cell transplantation. So the American Society of Blood and Marrow Transplant took it upon itself to create facts to do self policing and self regulating. Hoping to minimize the amount of FDA involvement. As a result of that, transplant programs have to have site visits that air quite extensive every three years. Um, and and although this is a lot of work and the standard, uh, fax standards for the current year are over 500 pages long, it's made it worth it. I think it's made a CT better, and I think it's made it safer. So thank you. Be sure you get your flu shot. This, of course, comes from the swine flu era. And now we have the cove in 19 vaccines. So thank you very much. Happy to take any questions. Thanks. Thanks, Doctor Daimon. That was awesome. Way Have a question for you. Um todo um do you predict less GBH in muds with post transplant sigh? Uh, the answer is yes. And so that phase two randomized studies suggests that that will be true, But the phase three prospective randomized trial is underway. So it's We're not going to know the true answer to that for another four years in Dr Damon. I have one for you. And that is so if you're gonna be the donor for somebody, um, what should the donor be expected to give? Spur for blood stem cells or bone? Well, that's been tested. And there are certain advantages to bone marrow. Still, you certainly have less. Both acute and chronic gbh d with bone marrow compared to purple blood stem cells, the concern has been you have a less scrappers is malignancy effect. Um, and a prospective randomized trial that was performed using unrelated purple blood versus bone Merrill showed, uh, an unrelated show that there was a slight survival advantage to using bone marrow. The problem is, we don't have enough young people willing to go and harvest bone marrow in the operating room on DSO. For many reasons, the convenience has won out as opposed to the evidence. Okay, great. Thank you so much. Dr Damon, on DNA now to top off our night. We have Dr Nina Shaw. I'm so excited to have her give this talk in to talk about car T cells. Kind of the new era of therapy and maybe a therapy that will take away from some of the algae in a transplant business down the road. Um, Dr Shaw, uh, has more energy than all of us in the practice, which is awesome. And she has been, you know, one of the in developing our t cell therapy therapeutics in multiple myeloma, which is great. She was also, um, considered by many the most effective tweeter from Ash of 2020. And with that, I will introduce Dr Chicago. Thank you so much, Dr Shaw. Okay, thanks, everybody, for having me. I have more slides, the Lloyd, but I definitely see quicker. So this is really meant to be an overview of car T cell therapy, talking about the development and their biology and summarize a little bit of clinical data and ongoing research and future directions for the field. A Z Many of you know, adopted cellular therapy has been something that we've been looking to develop for a long time. But actually, it's just it's a young young field. Um, and it wasn't until the nineties that first started getting to solve actually, our own, uh, Steve Sherwin and Kristen Peggy were very involved in this from the beginning. But only in the late in the early two thousands and into 2012. Did we first really have a product that could have clinical efficacy? Is we learned more about the T cell? So what is a car? T cell, as I always say, combines the best of both worlds. It has the specificity of the antibody, combined with the sido toxicity of a T cell and a crime. Eric androgen receptor is a genetic manmade sequence that has both of these. So it has the sequence that has the antibody specificity against your selected tumor antigens and then internally, has the t cell receptor like or some part of it interest cellular code s O. That there could be affect your cell mechanism. Eso How's the car team made? This is a very simple slide to really sum up years and decades of work. But you first have to construct a car gene which includes, as I mentioned, the an antibody or the specific sequences that would that would translate to an antibody. So a single chain variable region, for example, which would bind to an an agent And then that has to be connected to the parts of the T cell receptor that make it work or something that would signal in the T cell. So a trans membrane domain and then intracellular signaling motif. We now know that you need not just the Zeta chamber, the city three zeta change, but also a co stimulatory sequence. Sometimes CD 28 sometimes for one BB. But all of that has to be sequenced here into this vector. And then that then is put into sorry. This has to be a sequence, and then that's sub clone into a vector. So that could be a retrovirus Orel anti virus. And once that virus is made, thes viruses can easily come into these cells. Is you know, viruses love to go with the cells, so these t cells air transducer. And now the viruses take hold of the T cell and we tricked city so into making things that we want, which is this car and expresses this car on the surface. And now this T cell is poised to kill the tumor cell which bears this particular indigent in this case, uh, CD 19. So it sounds simple it was actually taken many years of work to do. I think one of the most important things that you have to have if you're going to have a successful car T cell, is a good and a gin candidate, right? You wanna have something that the Kartik can go on target? And what is that? It's something that Z that's present on all or almost all of the cancer cells that are in question, and it's not present on other cells. You need a very Pacific protein that will allow the T cells specifically bind and kill the tumor cell without causing too much damage to the rest of the cells. So one of the things that we always have to talk about both for our planning internally and also with our community colleagues, is how is this whole process gonna happen? And there's two parts of this. There's the patient in the hospital or cancer center part of it. And then there's the manufacturing facility, so the patient is deemed eligible, and then they undergo Go Luca for Resa, which tends to be a one day peripheral blood, often with Justin ivy, not even a central venous catheter process and these cells air collected, and it's just a one day thing, and then they're sent off. And then there's a whole bunch of stuff that happens at the manufacturing facility, exactly the steps I just told you about transaction expansion and some QC steps. And then, finally, the self product is made. Often it's frozen and sent across, and it comes back to us now. We received this product, and in between this time, this whole transition. It takes about 10 to 14 days to make themselves. But what really takes a long time is the quality control. Because, of course, this is a living drug, and you don't want to have any infection or any contamination, so it takes a long time for that to be resulted out. And during that time, it's possible that the patient who may be very sick might need bridging therapy, as we call it, or therapy in between the Theresa's and the actual car T cell therapy. But no matter what the felt come back and the patients definitely gets what we called preconditioning or limp, oh, dip, tweeting chemotherapy. And then afterwards risk is the car T cells, and then it's monitored, and this could actually be an impatient or an outpatient setting, depending on the product that you're using. Um, we do have to monitor for CRS. I'll talk about that a little bit later, but I think a lot of you have heard about CRS, which eyes one of the side effects of party cells. And that's why I said, sometimes it's impatient. Sometimes it's outpatient, and we also have to look for neurotoxic City, which is a sort of confusion that can happen. But can progress toe actually seizures and another neurological manifestations, and I'll get into that a little bit later. This if there ever was a poster child. It is Emily Whitehead, as she is a young woman here on the right, but was a little girl before on she was the reason that the FDA approved the first car T cell therapy for L. L s. I just wanted to briefly talked about survival on a L L statistics, so I don't do LLC and borrowing from my colleagues. But the survival for newly diagnosed pediatric for a Y a l l. It's not bad unless you have multiple relapses. And so it's a horrible occurred that you could be here for patients who have had multiple relapses. And for this, the Eliana study was constructed in order to look at the possible efficacy in this Phase two study of the CD 19 directed car T cells. And so, as I mentioned, all of these patients got through therapy in inside toxin. That's sort of the standard window depleting chemotherapy. We give this chemotherapy to make room basically for the T cells, so the patient's own T cells won't reject these new ones coming in and to create a little bit of ah, a million. For these, he still toe be exciting and expand in the patient's body On Then, each of these patients got a single dose of these cells, also known as essential Lucas to such a local self. I'm getting look good at that. So the primary endpoint here was an overall response rate, and as you can see here, the 81% overall response rate is way beyond what they were exp affecting. But even more than that, you remember that curb I should do, which was basically dropping down here. They they had a median overall survival of 19.1 month and you can see here both on the duration of permission and event free survival, that there was the first instance of a plateau which really hadn't been seen in this very difficult to treat population. Um, there was some cytokine release syndrome, or CRS and neuro toxicity, mainly low grade, but something that things that needed to be addressed, including a little bit of Grade three, some grade three events. And I think we've gotten better at managing thes. But it's something that we have to keep a nigh on with every trial. Because of that decision ruthless seller to sell was that they approved in this a low population, patients less in 25 years old in second or later relapse. There is a boxed warning, of course, for the CRS and neuro toxicity, and therefore there is a REMS program, and many of you have participated with us to get our whole staff here trained on. You have to put a little questionnaire and a little test and make sure that you know how to manage these side effects. Um, there are a lot of studies looking at l. L, and they're not just impedes their in adults as well. Uh, this is just a table to show you that we've had some really nice response rates. And Dr Logan here is running one of the trials for a low a car T cell. So, uh, he's somebody you want to talk to. Give a patient who is eligible for that moving on to non Hodgkin lymphoma. I think Carty cells have made the biggest splash in this particular, uh, disease because they've just been so remarkable in what they could dio eso. Here, you can see a patient who has relaxed non Hodgkin lymphoma, initially treated with our chops, got our response, but then have progression or relapse after two years, had right therapy, then in a tall transplant. But unfortunately, relapse within a year. Hey was treated with actually sell or actually, Captain Jean Luc the cell. And at one month he had the CR, which was ongoing, um, at nine months, and even though there were some complications of CRS etcetera, he made it through. Andi actually was doing great. So we have to I should say, three products kind of for non Hodgkin lymphoma that that are available well I should say to on the left here? Yes, Carta and camera. Or actually, Captain Jean and essential Isabel Thes are both on the left hand side, FDA approved and lifestyle on the right hand side eyes hopefully going to get approved. All of these are against CD 19, but they have some differences. Uh, the actually sell. Use this city 28 as a co stimulatory molecule, whereas camera or two fissile uses for one BB on life to sell uses also for one BB. So these air all, uh, different sort of ways to get to the same thing, but and there's different reasons why we choose one or the other, but they are, uh, definitely effective, and I'll show you some data. As you can see here, these different trials illustrate the three car T cells that I was just talking about and all the trials you could see that they had a lot of relapse refractory patients. Many of them had had transplant. Um, many of them had really good manufacturing success, that they actually had over 90% manufacturing success, which I think it's pretty important because if you're going to tell your patients that they're going to get a cart is so you want to make sure that the company you order it from is going to be able to make it. So let's talk about some more one. So this is a non Hodgkin lymphoma relapse. Refractory patients on this was presented first in Ash 2017 overall response rate with 82%. Uh, this is a really difficult patient population, as many of you know, patients who relapse, especially after transplant, their complete response rate with 50 4%. And you can see here the initial data shows that the median duration of response of those who did respond was 11.1 months. And overall, the median progression free survival first reported with 5.9 months. Uh, the curse here. I think the most significant thing about the curve second see, is that there's a plateau. And that's sort of the drive home point that there are some people who are having long term success with Carty cells and non Hodgkin lymphoma. This is really something that's revolutionized the therapy of this disease. Most recently, Mantle cell lymphoma became the next lymphoma to have in a car. T cell approved for it. This was based on the Zuma to study where a sell products similar to actually tell same companies sort of same idea of a few tweaks were given cartoon cell therapy, relapse, refractory, multiple multi mantle felt with, um, excuse me 1 to 5 prior lines and you can see here again the patients got loose I and then the car T cells. And here, astounding 93% overall response rate. And again, the median PFS so far, or median duration of response has not been reached. This was initially presented a year ago a dash and then published in the New England Journal. So this'll led to the at the approval of this product. Um and so you could just see here. I mean, the best overall response rate across these, whether for non Hodgkin lymphoma or for mantle cell. Really impressive responses. And I think the other thing that's very interesting is how some of these responses air very durable. Now we're still waiting for some of the PFS data. But if if the Zuma curves or anything Thio look at you can see that there is a plateau and there are some people that have really not good, long term follow up. One of the things I really like is this'll riel world analysis of actually seller actually capture cheese. So we sell um, City 19 Carty sell for relapse refractory large cell anthem as a riel world experience on this was done by my good friend Loretta Nashville, who was interested in understanding how people were using this once it got ce approved eso they looked at people who had were with the Fareast on day ended up getting Carty cells and they had actually a very nice almost 300 patient population toe look at. And so what I just want to point out is that first if you look at the safety that CRS for the standard of care act itself So this is what people got standard of care versus on the clinical trial was basically the same as well as the intensity was essentially the same. So no major differences, CRS or neuro toxicity, whether they got on clinical trial or not. And I think this is interesting because we always talk about cherry picking our patients. But it turns out that the physicians who picks the patients for actually felt did a pretty good job. And if you look here, the overall response rate was 80%. This is at one month Onda Day 90 was 81%. And actually, if you look here, the overall response rate for actually sell and Zuma won almost identical, which I think is also very interesting because this what if you're not on protocol? There are not all these mandates about how you have to manage the patients you started. Go with what you know on. But this is actually very reassuring data. Also, what I wanted to point out is the progression free survival here. Remember I told you, was around six months in the Zuma study. And here is the medium PFS with six months and the median overall survival that six month estimate with 72%. The media has not reached yet. What this means is that I think that in the real world were actually able to adopt this very, um, exciting and novel T cell therapy that used to be a boutique thing on Leon clinical trial were actually able to do it as a real world therapy. And I think similar to the evolution of transplant. We've gotten better at knowing how to do it and also picking the right patients and hopefully being able to manage the toxicities well. And so you can see here this very similar to the Duma one. All right. Want to take a few minutes to talk about my favorite disease? Carty sells for multiple myeloma. Everybody knows I love myeloma. This is a patient. I won't bore you through all the details because we're kind of running low on time. But just to say that this is a patient with multiple myeloma who had had three lines of therapy, and now we have the possibility of trying to be like lymphoma, which we always love to bait. That's Obama's tells us on. We have a cartoons cell therapy program that will possibly have some efficacy what we think it does, But it's a different Anna Jennette's B cell maturation. An agency, CMA is the target on class myself, and we choose that because this BCM, a molecule, is involved with plasma cell proliferation and maintenance, but most importantly is expressed uniformly on almost all plasma cells, and it's not expressed on any other cells which means that it's able to be a very specific target for multiple myeloma directed car T cells. The first study that I think really put this on the map was the B B two and two and study the CRB. For one thing, it was a Phase one study looking at car T cells against myeloma page myeloma cells for myeloma patients relapse refractory, it looked at it, had both this escalation just expansion and to make a very long story short there overall response rate with 85% which is also unheard of in this patient population who had had seven prior lines of treatment. Many of you know we've had new drugs approved in myeloma and the bar for single Asian activity, 30%. So this definitely cleared that and in addition, had a median progression free survival, um, in their higher doses in their effective doses that they call them off 11 point. So basically a year, and this was higher in the MRT negative patients, as you can see on the right, but we don't have the plateau. We don't have a plateau yet, and I think that's something that we really wish we could have, uh, it's relatively safe. I'd say that even though three quarters of the patients have CRS and some have neuro toxicity, they're very well manageable. Theme updated Karma trial, which is essentially this trial, but phase two versions. So 126 patients enrolled. We participated in this trial here at UCSF had at their highest overall response rate of 82% and a progression free survival in the blue curve here that starts blue here of 11.3 months. So recapitulated the data I just showed you. And this is the data that they're going to fourth to the F d. A. To try to get approval for this therapy. Now, I know many of you may be thinking, Oh, my goodness, you know all this for 11.3 months, but it actually is so much more. We know that patients with this type of multiple realized myeloma live three months, four months at best on. But the biggest progression free survival we've seen from the new agents has been around four months for the patient population. So this is an extension, and it's just one time treatment, so we're very excited about this. We think it could be made better, but it's definitely something that's important. And I just want to point out that another thing that's really been important for Car T cell therapy is the quality of life. And so we looked at this both primary and secondary domains, that quality of life. And basically, if you look at this before and after, you can see that this blue versus this blue at month nine almost across all of these domains, the patients felt better on this may be a reflection of the fact that patients are responding and possibly that they didn't have to have chemotherapy during that time. Because once you get the Carty, it's it's over. It's a one and done definitely on the tales of this is the Jansen product. This is the cartoon study. This is also a American androgen receptor product against the CMA originally developed in China. I am very proud to say our own Tom Martin was leading one of the leader leading efforts leading people in this effort, and was a senior author on the abstract from the past ash. This actually binds to two different domains of BCM, a so it has a little bit different kinetics Onder. What can we say? The overall response rate? A whopping 97%. I've never seen this before. Uh, just from just multiple realized patients five or six prior lines of therapy, just incredible data and be GPR rate or better of 93%. Really, really impressive data. We don't have the long term follow up. We don't know what the progression free survival is yet, but I think this is probably going to beat the B B to 1 to 1 product or idea. Fellas, it's now called, but that's great, because we're gonna have hopefully more than one products available for our patients. He's have different kinetics, similar to how actually sell and pieces. L have different kinetics, so we'll have some different choices to make for patients when we can consider. And if you want to talk about choice, I stole this from Tom. Don't read everything. I just want to point out this column. It's unbelievable. You have 60 to 95% response rate across all of these car T cell options, and this is something that we've never seen before. Um, certainly not even in the past couple of years for FDA approval for this late line therapy. So we're really excited to see what else we can bring to the car t cell therapy. Because if you look when there's really rural analyses done, this is what Carty does. This is what happens in the real world. It just drops. So there are benefits. This is time that people have with their families. This is time people have to goto weddings on This is time that we think is increased quality of life with parties. So we're really hoping to develop this Ah, little bit more and get even better outcomes. Why don't we use cellular therapy, your party self in solid tumors, yet multiple reasons I borrowed these from Bridget Canaan. Basically, the entire solid tumor matrix is one big immuno suppressive area. It's hard to get there, and there's many cells in their, uh, their thoughts about tumor targeting and adding things like PD one, um, binding or inhibitor? Um, adding side of kinds or engineering Carty's to have sided kinds in there that actually are produced in a peregrine or auto Quinn fashion eso. We look forward to that, but it's not quite ready for prime time in solid tumors yet, although there have been some thoughts of using medicine method feel and targeted car T cells, I think this was presented in a CR last year. Um, this is one option that that people are looking into for car T cells, and Daito is leading a similar project here for prostate cancer. So we're really excited to see what comes on that wanted to briefly talk about what cartoons Ozcan dio and not good way, which is the toxicity. Although I think we're getting better at that c. A. R s and neuro toxicity. CRS is basically an inflammatory syndrome that can affect any part of the body, sort of like the GBH of of inflammatory syndrome that can affect any part. And it's driven by a sided kind storm that is, from the T cells that are very excited to kill their tumor cells. And finally, after many rounds of different people being on different fire hydrants, we now have a consensus score with our cellular therapy society to show what grade people are with CRS and to make a long story short. If you have a fever it's grade one, and if you have additional hypotension or hypoxia, it's great to, and then it goes on from there. Thankfully, for most of our Carty's sell experiences, PRS Day that great one or two on we can treat it usually with total is, um um um, if needed or steroids it really needed. Although we try to avoid that, it's possible. Just Elizabeth, as you can see, is an Aisle six receptor antibody and works very well when done early, I will say Also our fellow Raul Energy, just public or just presented it. Ash. Ah, poster on using kind of using Tesla's map early. So we call it Time to Tosi. And we found that in myeloma Carty, there was no difference using it early. It's sort of the 1st 12 hours after fever versus late. So, uh, Sandy and I always say no toasty shame. It's fine to use. What about neuro toxicity? We now have a term for this. I can, but basically there's it goes from confusion. We're finding difficulty. As I always say, the patients seem a little bit drunk. It's very subtle, uh, and this could be exacerbated by the factors on the right as well. Um, we don't know why this happens, but there might be some disruption in the blood brain barrier that makes it possible to have neurotoxic to the and it may be sort of a subsequent to quell a of of this, uh, inflammatory reaction going on with the car t cells. Thankfully, there are some assessment tools that we can use on their very similar. They take about a minute to do now. Our nursing staff knows how to do it. Thank God they've been very, very helpful to help us understand that the patient is starting to have a little bit of neuro toxicity. And there is a society consensus grading on neurologic toxicity. Finally, and it uses the ice core to help you define that. So that's been very helpful for us to assess patients. How do we manage these patients we put or we I and someone calling always put our patients on seizure profile access as they start their car T cells. But if they start acting a little confused or or something separate from, just try to kind release syndrome. We will start steroids pretty quickly. Um, and and those can be increased. But in more severe cases, you may need to do something more drastic. Like Cytoxan, it's generally reversible, but definitely something you don't want to get to grade for a lot of others. Toxicities related to Carty, but they're manageable. Mainly side opinions were used to go. There is this mass like syndrome on our fellows. Vanessa Kennedy just had an abstracted ash about that on Ben. There's immuno suppression. We often do have to give five G, particularly for lymphoma and myeloma patients, where we're targeting the B cells and, of course, antimicrobial prophylaxis. So we know that car T cells are affected, and we know that they're pretty safe in the toxicities. They're manageable. We don't have that plateau just yet. Uh, there's a bunch of ways we can do this looking at different targets, how we culture the cells, different engineering techniques, maybe allergenic car t cells. Um, and what we call thinking inside the box, which I'm so thankful to. All the team here at UCSF, led by Tom and John L and Show, and all these wonderful people looking at the Prodigy system, which allows us to make our T cells in a box on our own. And then so, um, proud to say that under the direction of all of us, we actually have, uh, started this trial for City 19 Directed Karki Self therapy. We're working with UC Davis. UCSF has a prodigy machine that's there and being used to produce home grown Carty cells 1st, 1st CD 19 and we're planning next for myeloma. When we produce them, we own them and were able to get them to our patients. How we see fit. So it's sort of like if we ordered Carty's less libido grubhub. But this is the way for us to make it on our own. And we're really excited to be able to use the science here easy ffs to do better. So Carty is poised to become the part of our treatment algorithm. For he embolism sees, uh, the toxicities. They're manageable, but they have to be anticipated. I think everybody knows that the Carty's can be more successful by the way the iPhone 12. Now I have to get a new iPhone picture here on. We can make them more successful by novel, even profiling culturing engineering on. We're excited to design better trials with that. I think I have 12 seconds. I just want to say thanks to everybody. That's our Christmas picture. So awesome that we used to go with a selfie stick or what? It was a healthy, you know, a selfie stick. And, uh, I wish everyone a happy holiday and hope that you send us patients for Kartik. Thanks.