 Okay, welcome everybody to the Ethics in Research and Biotechnology Consortia series. This is a monthly series that brings together leading researchers in science, biotechnology and medicine together with bioethicists to talk about not only the science but also the ethical and social issues that these technologies raise. My name is Nsiu Hian, I'm your host. I am the Director of Research Ethics for the Center for Bioethics at Harvard Medical School where I'm also a faculty member. I'm also a professor of Bioethics and Philosophy at Case Western Reserve University School of Medicine in Cleveland. For those of you who have been part of the series for quite some time now, welcome back for many of the newcomers. Welcome for the first time. Many of you may have wondered what CAR T-cell therapies are. You may have heard about these therapies and you may have had some questions about how these therapies work and what are some of the ethical issues that they raise. So we're here to answer as many of those questions as possible today. We have a terrific guest to lead you through all this. Our guest today is Dr. Karen Jacobson. She's the Medical Director of the Immune Effector Cell Therapy Program at the Dana Farber Cancer Institute in Boston. She's also Assistant Professor of Medicine at Harvard Medical School. As a clinician, Dr. Jacobson treats patients with lymphoma. It's a type of cancer that affects the lymphatic system. And as a scientific researcher, she's an experienced principal investigator on several CAR T-cell studies at the Dana Farber Institute. I'm going to go ahead and turn it now over to Dr. Jacobson to Karen. She's going to lead us through some of the science for about an hour. And here and there, I'll pepper in some questions that I think may be on your minds as you're listening to your presentation. Then the second part is the last half hour of today's session from 1.30 to 2. And that's when we'll take questions from you, the audience, and back and forth with you. As questions come up along the way, please enter them into the Q&A box. Don't put them into the chat box. Put them into the Q&A box. That way they'll be put all together in one spot and I can curate them at the end. OK, so with that, let me turn it over now to Karen. Karen, welcome and the floor is yours. Excellent. Thank you so much for that kind introduction. And I always I always love coming to talk about this topic. It has been like the distinct pleasure and honor of mine to be able to enter this field at just the right time. It's really revolutionized the way we treat cancer patients. And I think it's going to revolutionize how we treat cancer patients in the years to come. So I will talk to you today about CAR T cell therapy really from clinical trials into real world practice. These are my disclosures. So as an overview of the topics we'll cover today, I'll start looking at the early clinical trial data, looking at CD-19 CAR T cells and B cell malignancies. We'll take a look at their efficacy as well as mechanism and frequency of toxicities. We'll then talk about some of the real world data after FDA approval in the United States specifically looking into lymphoma. We'll talk about some of the prolonged effects of therapy, and then we'll spend some time talking about where the field is moving and how we're going to move CAR T cell therapies into other diseases. So I know there are a variety of people on this listening in, some of whom are very familiar with CAR T cell therapies and some of whom are not. I just thought I'd set the the stage and the playing field as evenly as possible and really go back to basics and think about what is a CAR T cell and how is it made. So CAR stands for chimeric antigen receptor and it refers to the receptor that is refers to the receptor that is the result of the genetic engineering of either a patient or a healthy donor's own T cells to generate a CAR T cell. So the receptor that gets that is uniquely expressed in these CAR T cells is depicted here on the lower left hand corner and it's called a chimera because it's really part antibody molecule, which is the part of the receptor that's outside of the T cell that actually has the specificity for the tumor cell. And it's a bind to a protein on the surface of the tumor cell. And then it's part T cell activating molecule, really what these these intracellular portions of the molecule are. And so the cars we're going to talk about today are generally the second generation cars, which include a CD3 Zeta T cell activating molecule. And then a second co-stimulatory molecule in green, which for most of the cars we're going to talk about today is either for one BB or CD28. And I'll talk about in a couple of slides the implication of the two different co-stimulatory molecules. So that's what a car is and it allows the T cell to recognize the tumor using the antibody portion of the molecule and then activate become activated using the intracellular portion of the molecule to hopefully kill the cell that it's bound to. The way these are made is that we when you have a patient who's a candidate for car T cell therapy, you collect T cells from their blood through a process called Phoresis. These T cells have been sent to a laboratory where they are transfected usually with either lentiviral or retroviral transfection to their transfect. Those are those are vectors that carry the gene for the chimeric antigen receptor. The gene is then brought to the nucleus where it's expressed and then the receptor is now on the surface of the T cell. These cells are then sent back to the cancer center where the patient undergoes lympho-depleting chemotherapy. This is generally three days of chemotherapy and it's not meant to treat the underlying cancer. It's actually meant to make the patient a better host to allow the T cells to expand better and become activated upon the reinfusion following the lympho-depleting chemotherapy. We will talk a little bit about some car T cells where we're actually deriving the T cells from a healthy donor later in the talk but for the majority of the car T cells we're talking about today, these come from the patient themselves. This process from patient identification to patient treatment can take anywhere from 16 or 17 days all the way to about 30 to 40 days depending on the different car T cells that we're talking about. All the while these are patients that have an active malignancy and so it is a challenge to maintain stability of the patient while their cancer is getting worse and many of these patients have exhausted other treatment options and so it's hard to control their cancer during that wait time. That's one of the major limitations of these car T cells when they're derived from the patient themselves. I think we have to think about what makes a cancer a good car T cell candidate to understand why this isn't sort of after you see some of the data for CD-19 why this isn't sort of taken over all of cancer care across the different cancer subtypes and it's because the cancers that are good car T cell candidates, they have to have a tumor antigen that's present on all or most of the cancer cells so that so that the T cells will kill all or most of the cancer cells and it really has to be necessary for the cancer cell to survive so that it's not easily lost as a mechanism of resistance but that tumor antigen really can't be present on normal healthy cells such that an immune attack on those normal healthy cells would lead to unacceptable toxicity and so CD-19 really emerged as a good car T cell candidate because it is present on all or most B cell malignancies and B cell malignant B cells I should say and it is necessary for those cells to survive so it's not easily lost and it's only healthy counterpart that it's on is the normal B cell and we know patients can live without B cells because there are some genetic syndromes where patients are born without B cells and the end result is that they don't make antibodies or immunoglobulins to help protect them from infection but we can give people transfusions of these immunoglobulins and keep them free of infection and alive into their natural old age so this was felt to be an acceptable form of toxicity from an off tumor but on target effect of the car T cell and so there are three now three FDA approved car T cells that target CD-19 for the most common type of lymphoma we diagnose in the United States large B cell lymphoma and that is axi-captagine solucil or axi-cell which is from a company called kite Tissage and Luclucel or Tissacelle from a company company called Novartis from Novartis and then lyso-captagine marylucil or lyso-cell which is from a started with a company called Juno it's now a BMS company and these three car T cells are actually all the same in terms of their antibody fragment they all have this FMC 63 green antibody molecule outside the cell which is what binds to CD-19 on the tumor cell they all have a CD-3 zeta T cell activating domain intracellularly and they differ with respect to their second costumulatory domain so axi-cell has a CD-28 costumulatory domain whereas Tissacelle and lyso-cell have a 4-1BB costumulatory domain and then that has some important implications in terms of the pharmacokinetics of these car T cells upon reinfusion into the patient so the CD-28 cars tend to expand very very rapidly and actually reach a very high peak car T cell level before they before the numbers start to come the number of cars start to come down over time whereas the 4-1BB cars tend to expand a little bit more slowly reach a lower peak and then persist for a little bit longer before they come down and the end result is that the the toxicities that we'll talk about later tend to happen earlier and a little bit more pronounced with the CD-28 cars compared to the 4-1BB cars these cars also differ by their mechanism of gene transfer so for axi-cell they use a retroviral vector whereas for Tissacelle and lyso-cell they use a lentiviral vector and the last distinction really is for for lyso-cell what comes back to the cancer center is not just one bag of cells but actually two vials of cells one with CD-4 positive car T cells and one with CD-8 positive car T cells and they're meant to be in a one-to-one ratio so that you're giving a defined ratio of CD-4 and CD-8 T cells back to the patient it's unclear if this is important for activity but what comes back for axi-cell and Tissacelle is a bag of cells and none of us know exactly what's inside except that they are car T cells at the dose that is FDA approved. So I had mentioned that there were those three FDA approved products for large B cell lymphoma but actually the first FDA approval for car T cells came in pediatric and young adult B cell acute lymphoblastic leukemia based on this trial on the left the Eliana study so this was a study that included 75 patients who were under the age of 25 with the ALL these are patients who had exhausted other treatment options even so many of whom had relapsed after an allogeneic stem cell transplant and their survival would have been on the order of weeks to months and with a single infusion of Tissage and Luclusal they entered a what we call a minimal residual disease negative complete response 81% of the time so 81% of patients had a complete response to therapy and more importantly than that at 12 months 50% of patients had not had their disease come back so probably were cured of their leukemia which is really remarkable considering that this was a group of patients who were really out of treatment options and who survival would have been quite limited and so that led to FDA approval at the FDA hearing this little girl Emily Whitehead came and gave her testimonial at the time of FDA approval I think she was about eight or nine years old and she was one or two years cancer-free she's now eight years cancer-free or she must have been three or four years cancer-free at the time she's now eight years cancer-free and still doing terrifically well and so this is really why it matters we have looked at using CD-19 CAR-T cells in adults with ALL as well this one study in the middle the rocket study actually was quite effective but the toxicity was unacceptable and so that product's no longer in clinical development but we just learned a week two weeks ago on Friday that Brexacaptid gene auto-lucid which is closely related to axi-cell was FDA approved for adult patients with B-cell acute lymphoblastic leukemia based on the results of the Zuma 3 study which are shown here so this included 71 patients and the complete response rate was 71 percent and after about a little over under a year and a half follow-up you can see that 50 percent of patients are still in response at around 13 months and about 50 percent of patients are alive without disease relapse at 12 months similar to what we saw with Tissa-cell and so that was the most recent FDA approval and now we can give CAR-T cells to our adult patients with B-ALL as well and these are the three clinical trials that led to the approval in large B-cell lymphoma Zuma 1 for axi-cell Juliette for Tissa-gen-lucleusal and Transcend for Lysocaptid gene Marilusal and I think what's really just notable here is that typically with these patients with large B-cell lymphoma who have failed to respond to multiple rounds of chemotherapy the response rates to available therapies had been around 20 to 30 percent and the complete response rates have been about under 10 percent and the median overall survival was only about six months and on these three trials across the board you can see sorry I didn't mean to do that yet you can see that the response rates are in the 50 to 80 percent range the complete responses are in the 40 to 50 percent range and at six months which is a really good marker for long-term durable responses we're seeing about 40 percent of patients still in response and that really probably means that these patients are cured with this therapy and so again these were patients who you know their options are really hospice or go on these trials and 50 of them ended up with a cure which is really remarkable and so that led to FDA approval for these three products. Karen I have a question for you are there reasons to pick one of these products over another you know what goes into choosing some of these above others how do you compare them? Yeah so that's a great question and so I think the obviously we're balancing efficacy safety and then logistics here which is a new factor when we're thinking about picking between therapeutic options for a patient because most of the time our therapies are available in the pharmacy we just order them and they come to the patient but here we have to we have to think about sort of the logistics of collecting the cells shipping them to a third party the time it takes for manufacturing and the reliability of that manufacturing process and how those cells come back to the cancer center and so you know I think we can think about safety and efficacy all we want but the bottom line is if you have a patient in front of you you have one chance to order one of these products most of the time because their cancer is progressing and so you know it doesn't matter if a product is a little bit more toxic if it's not going to if it's the one that's going to come back to you more reliably than a product that is maybe a little bit less toxic but less reliable. So the truth is that on the Zuma one trial and I think I'm going to get rid of this bullet here I want to look at this complete response rate by intent to treat so these responses here are based on the number of patients who were actually treated not the number of patients who were had their T cells collected and I just want to call your attention to these you know 111 patients on the Zuma one trial had cells collected and 101 were treated so there were 10 patient drop-offs some of that was most of that was because of patient issues the patient got too sick to get their cells only one product was not successfully manufactured whereas on the Juliet they were over 50 patients who dropped out and on the Transcend study it was even more and that speaks to sort of reliability of manufacturing one and then it also speaks to the fact that the turnaround time for axi-cell is 17 days the average turnaround we sometimes get them back in 14 days you know it's the fastest turnaround time for tissue cell it's sort of reliably 22 days but on the clinical trial it was actually much longer and for lysoscelia it can be anywhere from 24 to 30 days and that makes a difference a week is a different is an important amount of time for these patients and you know you the folks at kite can make axi-cell from almost no lymphocytes whereas we do end up in situations where we get a product that's not fit for re-infusion when we order tissue cell and lysosceles so when when I have a really sick patient in front of me I'm picking axes you know what I don't think can wait I'm picking axi-cell when I have a I had mentioned before that the 401 bb cars tend to be a little bit safer they and that's that's tissue cell and lysoscel and so if I have an older patient who has a less progressive lymphoma maybe they have a little bit of kidney failure maybe they have a little bit of heart failure I'll be more inclined to pick one of these two products so you know it's a little bit of a balance but what it means is that as we start to treat patients in the real world and we're getting data about how these products perform in the real world we're not comparing apples to apples you can't say that axi-cell is better or less good than tissue cell or lysosceles because we're not treating the same patients with these products that's a great question maybe a long answer that's fantastic I mean that clinical perspective is so important thank you for that yeah of course all right um so this is just uh these are just Kaplan-Meier curves to really show you know both duration of response and progression free survival after these CD19 CAR T cells in large cell lymphoma which really across the board shows that patients who of all patients about 40 to 50 percent of them have these durable remissions most of the relapses happen in the first six months and then it really plateaus out and patients who have a complete response have a very high chance of maintaining that complete response throughout follow-up and this is really why it matters I had mentioned before sort of historical controls the complete response rate was about 10 percent overall response rate was about 30 percent on the CAR T cell trials we're seeing response rates up to 80 percent and complete response is up to 50 percent and then the curve here is really overall survival so you can see about half of patients were unfortunately would pass away within six months if CAR T cells didn't exist now you can see that it takes about half the patients are still alive at 27 months following CAR T cells so it's a big big improvement and this is just an example for what a patient experiences this was the patients lymphoma burden going into CAR T cells with AXI cell and this is what their disease looked like at one month and I know this patient actually is still alive and in remission now about 18 months after his CAR T cell infusion so large B cell lymphoma is not the only type of lymphoma that CAR T cells work in so it also works in a less common type of lymphoma called mantle cell lymphoma which is one of our incurable types of mantle cell lymphoma of lymphoma rather median survival is about 10 years and when they when patients with mantle cell lymphoma fail you know stop responding to us really their second line therapy which is a group of drugs called BTK inhibitors their median survival is about six months and they usually relapse very very quickly and and sort of explosively at that point so these patients were treated on the Zuma-2 study of brexit-captagene and otolucel which is the same CAR T cell therapy that was just approved for adult patients with ALL and like I said it's very closely related to AXI cell it's actually just different because there's one step in manufacturing that is to purge the T cell collection product of CD19 positive B cells so that you don't have any lymphoma or leukemia cells in your product but otherwise it's exactly the same as AXI cell which means it's a CD28 car as well and with one with a single infusion of brexit cell 93% of patients had a response and 67% had a complete response and on this study we have about an average of 18 month follow-up and it looks like about nearly 60% of people are still in response at 18 months so this is really promising and even begs the question are we going to be able to cure patients with mantle cell lymphoma now with CAR T cells I can't say that yet we need longer follow-up but it's certainly provocative so here just to also bring this back home to a patient this was a patient that we treated on that Zuma 3 trial it's a 55 year old man he had relapsed high-risk mantle cell lymphoma he had all of the high-risk features he had a mutation in TP53 he had the blastoid variant he had a high key 67 and he was refractory to first line chemo second line chemo and then the BTK inhibitor like I mentioned so he received brexit cell on trial in November 2018 he had a really uncomplicated course we'll talk about the Texas cities in a minute and actually went home at the earliest day he could possibly go home on day eight and these are his pet this was his pet scan going into treatment and now he's he actually just had his three-year pet scan as well he continues to be in a complete response this is someone who didn't go into didn't respond to anything so this was really phenomenal another incurable lymphoma more common than mantle cell lymphoma is follicular lymphoma and so the Zuma 5 study looked at using axicell for patients with both follicular and marginal cell lymphoma when these patients are in the you know in their third or fourth line of therapy their median overall survival is about five years so this you know many patients with follicular lymphoma can do well over their lifetime but when they're multiply relapsed their longevity starts to become threatened and available agents for this group of patients usually lead to responses about 30 percent of the time and complete responses about 10 percent of the time and the response duration is usually only about one year here you can see that with axicell patient 80 percent of patients had a complete response with follicular lymphoma and at 18 months of follow-up about 78 percent of patients are still in response and so this trial also led to approval of axicell and expanded approval for axicell and follicular lymphoma and this is just to drive home that point that this is much better than what we would see with other available agents so when we look at response rate it was 94 percent on Zuma 5 versus 50 percent in historical controls complete response was 80 percent on Zuma 5 versus 30 percent in historical controls and both progression free survival time to next treatment and overall survival were all statistically superior after CAR T cells in this in this setting and so this is just again to show you what CAR T cells can do this is a woman who had follicular lymphoma and she went through nine different lines of therapy you can just see them all listed here over the course of about 10 years you know she actually did quite well for the first five or so years of or eight years of her disease and then from between 2019 and 2021 she went through about eight additional lines of therapy and you can see sort of her PET scan and at the end of those eight lines of therapy right there so she was treated with axicell soon after it was FDA approved based on that trial it just showed you had also a pretty uncomplicated course and went home pretty early and this is what her PET scan looked like at one month and and she continues to do well so this is again just to show what the power of this therapy and what it can do for patients who really have exhausted other therapies. Testogenal flusos also being looked at in follicular lymphoma on the allara study and we're seeing excellent the same excellent responses I won't I won't go into all these details because I think we should get to some of the other some of the other aspects of these therapies. Do you have another question? I was just about that I mean that's terrific news but what's the bad news? You know what are the results? Yeah so yeah we are going to talk about that right now so there is always a yin to the yang with these therapies and CAR T cells have a really unique toxicity profile compared to other cancer therapies just based on the nature of how they work so the first thing we worry about when we give patients CAR T cells is a syndrome called cytokine release syndrome and this we really do understand the pathophysiology of cytokine release syndrome so these T cells are re-infused back into the patient they encounter antigen and they are activated and part of that activation process is to start secreting cytokines into the bloodstream those cytokines then serve to activate other immune effector cells which then further elaborate these inflammatory cytokines and so you get this this cytokine cascade and so at a minimum you can get flu-like symptoms it's sort of the same concept of what our immune system does when we're when we're combating the flu with fever, malaise, body aches, head aches but we we can't modulate sort of the level of activation and so if it gets too if it comes on too strong patients can get capillary leak where fluid leaks out of the blood vessels and can cause the blood pressure to go down or to cause fluid to accumulate in the lungs and that can lead to low blood pressure and difficulty breathing that can progress to you know frank shock where patients need you know medicines to support their blood pressure or you know respiratory failure and that's where patients would need to go to go to an ICU that's sort of what we call grade three or high grade three or four high grade cytokine release syndrome cytokine release syndrome usually happens early after CAR T cell infusion lasts for several days it kind of mirrors the peak CAR T cell expansion and then we'll get better on its own as long as the patient can survive that and what follows is a unique toxicity call that we call immune effector cell related or associated neurologic syndrome or ICANS or we also call it neurotoxicity and we don't totally understand what causes this except that we know that it involves some degree of inflammation of the brain it can be very scary for patients and their family members this inflammation of the brain can increase their risk of seizures and most of our patients are maintained on anti seizure medicines because of that risk it can cause a variety of you know a variety of neurologic symptoms from mild confusion to difficulty both speaking and understanding language and then really an inability to take care of themselves and some patients can become you know frankly comatose and it can last for a couple of days or in some some patients that last for a couple of weeks so it's very variable and when patients do recover they recover fully we don't you know that we don't think they this causes permanent neurologic damage but there have been cases where the inflammation of the brain causes brain swelling and when the brain swells and doesn't have enough room to expand it can lead to herniation of the brain which can be a fatal event so these are really serious toxicities that we that you know we're constantly being vigilant about and why many of our patients receive these cells in the hospital so they can be monitored very very closely um I won't go into all of this we've been trying to learn more about sort of what can predict for and what causes neurologic toxicity so we can come up with better therapeutics for it both preventative as well as to treat it right now our mainstay for treating neurologic toxicity after CAR T cells are steroids to decrease that inflammation in the brain but this is sort of the crux of you know of what we've learned from these therapies so um I just only call your attention to grade three cytokine release syndrome and grade three neurologic toxicity because those are the ones where patients may need to go to the ICU and as you can see across these studies there are a couple of themes so one is that this the grade three toxicities are higher in the CD 28 CARs compared to the four one BB CARs so for instance compare Zuma one to transcend right 13% grade three CRS versus two 28% grade three neurologic toxicity versus 10 you can't really interpret grade three CRS on the Juliet study because they use a different scale but the neurologic toxicity was graded similarly um the other the other theme from this is that um for whatever reason uh CAR T cells in the uh in follicular lymphoma which is a slow growing lymphoma leads to significantly less high grade toxicity than it does in diffuse large B cell lymphoma and mantle cell lymphoma so CD 28 for CD 28 CAR um the toxicity is about half in follicular lymphoma than it is in uh diffuse large B cell lymphoma and mantle cell lymphoma and the highest toxicity we see with CD 19 CARs is actually in acute lymphoblastic leukemia um so I mentioned that um you know because since these have been FDA approved since 2017 um we've had ample opportunity to see how these CARs perform in the real world where patients would not be sort of perfect clinical trial candidates are eligible for these clinical trials they may have met other medical comorbidities or um needed to have other treatments uh while the cells were being manufactured and so and uh you know many people thought they would not do as well when we treated a broader population of patients and so on many of these series that I'm showing you here about 60% of patients would not have been eligible for the clinical trials uh for either axi-cell or tis-a-cell um and what you're what you can see across the board is it's still about a you know a 60 to 80 80 percent uh response rate it's still about a you know 40 to 60 percent complete response rate and and also importantly at six months uh about 40 to 50 percent of patients are maintaining their response which is sort of a good predictor of long-term response and so it looks like they're just as effective even though these are sicker patients um and we're not seeing an increase in toxicity we're seeing the same rates of grade three and higher CRS and neurologic toxicity uh in fact we may be even seeing an improvement in toxicities over time and owing to the fact that we've gotten better at sort of uh treating patients earlier with some of our toxicity mitigating agents um to prevent it from escalating to higher grade toxicity um from all of these studies both uh clinical trials and some of these real-world experiences we've learned about some predictors of response and toxicity so on the side of improved response we know that patients who have a low tumor burden and low pretreatment LDH which is a marker of tumor burden and low pretreatment inflammatory markers are more likely to have durable responses patients who even though patients who have medical comorbidities didn't necessarily affect um outcomes on those real world experiences when you look particularly at those patients they do seem to do a little bit less well than the patients who otherwise were medically fit and then patients who didn't need bridging therapy between the time that their cells were collected and their time that their cells were given back to them also seemed to do better remember these T cells are mostly coming from the patient themselves and these are cancer patients who have had received a lot of anti-cancer therapy so their T cells their immune cells may not be similar across the board and in fact when when patients have more early memory differentiated T cells collected or in their T cell product they tend to do better so that the sort of the fitness of the T cell matters and then patients who are able to to reach a higher peak car T cell level compared to their tumor burden can actually overcome the negative impact of a high tumor burden so that it's that ratio that seems to be more important than the tumor burden itself and now we're starting to look at the tumor and try to understand you know what are some of the factors within the tumor that can lead to resistance and what the group at Stanford was able to show that mutations in CD58 actually lead to down regulation of CD58 which is a binder which is a ligand for CD2 on the T cells and so loss of CD58 may lead to insufficient T cell activation and those patients do less well we're also learning that the car T cells may not do all the killing of the tumor cells when they get to that tumor they actually probably serve to to do some of the initiation of the killing but then they activate a bunch of tumor infiltrating lymphocytes that are already sitting there to do the rest of the killing and so tumors that are have high tumor infiltrating lymphocytes and low suppressor cells these myeloid derived suppressor cells actually tend to have longer more durable outcomes and then tumors that don't overexpress the oncogene mick also tend to have longer remissions on the side of increased toxicity we know that patients going into car with a high tumor burden high pretreatment inflammatory markers and high pretreatment LDH are more likely to have higher grade toxicities and then once patients get their CAR T cells if their CAR T cells peak at higher levels if their cytokine levels peak at higher levels they're at increased risk for these toxicities if they develop markers of a condition called disseminated intravascular coagulopathy they may develop high-grade toxicity and patients who have early cytokine release syndrome are at a greater risk of having high-grade CRS as well as high-grade neurologic toxicity and so I don't have time to go through each of these these these really are just some of the slides to like to elucidate some of those points but I'll go through them very very quickly the bottom panel is the one that I want to call your attention to here these are in black are the patients who would have been eligible for the Zuma one clinical trial whereas in red are the patients who are ineligible because of medical comorbidities and I just want to call your attention to the fact that even though these patients in red do better than what we would expect with other available therapies they do less well than patients without medical comorbidities and so it does raise the question that these are a group of patients we still need better options for and this is just a look at the Zuma one study showing that tumor burden is a negative predictor of long-term outcomes however if patients are able to achieve a high peak carticell level compared to their tumor burden ratio that that that can overcome that negative influence of high tumor burden and this is another way to look at tumor burden it's actually looking at circulating tumor DNA and so if before treatment patients have very high levels of circulating tumor DNA they they tend to do less well versus those who have low levels they tend to respond more favorably and then following treatment you can use that same test for circulating tumor DNA to test the depth of remission we call this minimal residual disease and if patients are MRD negative which are shown here in the blue they have excellent outcomes where patients who are MRD positive one month after treatment tend to relapse and do less well. I had mentioned that the T cell product is important and so the group of Penn noticed that only 25% of patients with CLL had durable outcomes which is chronic lymphocytic leukemia had durable outcomes after CD19 cars and so they took the carticells from their responders and gave them to mouse models of CLL and those mice did well and then when you gave carticells from patients who didn't respond to the same mouse models those mice did not do well so it told them that it was something about the T cell itself and not the patient or the disease that was important for a response in this case and so they then did gene expression profiling which showed that the responders had more early memory differentiated T cells they also had greater stat three signalings so these were more activatable that by flow they also showed that responders had T cells that were more early memory differentiated and that non-responders had higher levels of exhaustion markers on the surface of the T cell and so one thing that you can do to try to make the T cells a little bit fitter before you collect them is actually treat patients with therapies that can do this and BTK inhibitors can do this and so this group of Penn actually then went on to give patients with CLL BTK inhibitors for at least six months before they collected their T cells and they were able to show better than better than standard responses to car T cells in that setting. This is just that data for CD58 so the mutant CD58 patients were all bound to relapse versus the patients that were CD58 wild type and so what this group is proposing is a novel CAR T cell where not only does it have a CD3 zeta activating domain and a 4-1BB co-simulatory domain but it has a constitutionally active CD2 domain so that it can overcome the loss of CD58 in some of these lymphomas. Here's some data just to show that concept that it's not the cars that do all the work within the tumor but it's other tumor infiltrating lymphocytes so the top is work done by Scott Rodig at Dana-Farber where the green cells are actually the CAR T cells and the white cells are non-CAR T cells so you can see how many of the activated T cells within the tumor after CAR T cell infusion are actually normal T cells compared to the one green CAR T cell and the bottom panel the CAR T cells in red so same concept and then the group at Novartis looked at that patients treated on the Juliet study and showed that patients whose pretreatment tumor biopsies had a higher proportion of CD3 positive T cells had more durable responses than patients who had fewer tumor infiltrating lymphocytes those are shown in orange here. I'm going to skip this just for the sake of time but the bottom line here is that the tumor itself can influence the tumor microenvironment and tumors that have certain gene expression profiles that are enriched for interfering gamma gene signature tend to have less durable responses and this may be because of two things one is that there are more myeloid derived suppressor cells and the other is that it actually inhibits CAR T cell expansion and so that's what's shown here so there's a lot of things we've learned over over the years to think about how to move this CAR T cell therapy into the future and how to improve you know a 40 to 50 percent cure rate to something higher and how to move this into other types of tumors so one is we want to make safer cars these are cars that either have increased signaling complexity at the immunologic synapse so either require two signals to become activated or if there's a second signal it actually inhibits the CAR T cell or cars that actually have more physiologic signaling through the T cell receptor itself and then we obviously want to overcome mechanisms of resistance so a major mechanism is exhaustion of the T cells and so people are looking at combining cars with checkpoint inhibitors and other immunomodulatory agents or even further gene editing of the CAR T cell to knock out some of those genes that lead to T cell exhaustion and people are also looking at alternative conditioning regimens that maybe can lead to more favorable tumor micro environment so the CAR T cells don't get quite as exhausted before they get there I mentioned before that what makes a good CAR T cell is that the antigen is necessary for the tumor to survive and can't be easily lost but we do see loss of CD-19 it's not actual total loss of CD-19 it's CD-19 that's alternatively spliced so that the epitope for the CAR binds to is no longer expressed so they still get signaling through CD-19 and it keeps the B cell alive but there's no way for the CAR to find it and so people are looking at dual antigen targeting cars that combine that target more than one tumor antigen to lose the uh oh I have a copy of her slides you want me to control the deck from my screen my screen is just black I'm so I'm trying to join by my phone and then I will have you um all right all right okay can okay you're getting a uh an echo I'm back I'm so sorry about this I have no idea what you're having would you like me to step in with the slides I have yes yes that would be great that's fine so this was the one that you were on before yeah right and so I was I was getting to the concept of antigen loss and the fact that the um that uh by combined by by having CAR T cells that can target more than one antigen you lose the selective pressure for antigen loss um and then we there's a lot of focus on on the the composition of the T cell product itself um and uh like I mentioned before that group at Penn looked at pre-treating patients with BTK inhibitors which can shift CAR T cell the T cells in the patient to a more early memory differentiated phenotype and so people are looking at that versus actually using some of these drugs X vivo during manufacturing and tissue culture to try to shift the phenotype of the T cells before you get them back to the patient and then finally um I had mentioned one of the biggest limitations of this is the fact that um of this therapy is the fact that it takes so long uh to make the CAR T cells for patients who are sick the other limitation of course is cost these are very expensive to make and so increasing accessibility is obviously a major concern and so people are starting to look at doing this with allogeneic CAR T cells from derived from healthy donors or alternative cell products like NK cars um and so those are those are some of the the directions that we're that we are moving um so I think you can go uh so there are endless engineering possibilities I'm not going to go through each one of these in particular but ways that what we could both increase activity recruit other cells within the tumor micro environment avoid inappropriate activation of the CAR T cells and these these are all uh shown here um and so these are all concepts that are sort of starting to enter preclinical development although not quite into clinical trials yet next slide I had mentioned I already mentioned this uh I think in in a lot of detail about the fact that it's not so much that CD19 is lost as a mechanism of resistance but that it's alternatively spliced and so the binding epitope for the CAR T cell is lost and so if you can't bind to it you can't kill the cell that has the truncated CD19 on the surface so this is this is a major mechanism of resistance in ALL um it's less so and lymphoma to date next slide but one of the ways to try to decrease this risk is to start treating patients with CARs that target more than one tumor antigen so these CARs that are shown on the left on the right here rather target CD20 and CD19 or CD19 and CD22 and so there's a little bit less selective pressure to lose CD19 some of the early data that we're seeing so far on these clinical trials though is that they seem to be about the same in terms of efficacy as the CD19 CARs by themselves next slide this was that study out of the out of the University of Pennsylvania looking at improving T cell health by giving patients a brutinib one of those BTK inhibitors pretreatment so they were actually able to show that the T cells were better after treatment with a brutinib by all measures and that the outcome of patients treated with CAR T cells from T cells that were collected after a brutinib were much better than what they had been seeing beforehand next slide okay i have a quick question for you so you said that you know for some patients who are getting sicker and sicker while they're waiting for their CAR T cells to get created um you know they may not remain well enough to benefit from the treatment are are people trying to use off-the-shelf T cells or even donor cells to kind of reduce that cost and that wait time yeah so so yeah so that was so it was my last point on two slides before this so so people are starting to look at donor derived CAR T cells they're looking at NK cells too which can be derived from um umbilical cord or healthy donors and so the advantage of this is that the the cells can be frozen and available you know in your freezer available for patients on demand um you can also make about a hundred products from one foresis and so that also potentially can bring down the cost of these CAR T cells because you can treat many more patients from the same you know from from the same collection um the the concern of course was that these are from donors and they could cause graft versus host disease right they could these T cells could interact with healthy tissues and lead to immune attack on healthy tissues because those healthy tissues would be felt to be different the from you know and foreign the way they combat that is they actually get rid of the T cell receptor in these donor T cells and that's where they actually they put the car gene in the T cell receptor position so that these these cells don't cause graft versus host disease the bigger problem actually is the host versus T cell response so these T cells still have antigens on their surface that the host will respond to and say oh you don't belong here i'm going to get rid of you before you can have an anti lymphoma effect and so the end result is that most of these companies have had to enhance that lymphodepletion so that we decrease the host immune um the ability to for the host to launch an immune response um and what comes with that is you know potentially increased infectious risk um and so you know we're starting to see proof of concept that we can get the same response rates from these cells but but it is potentially at the cost of increased increased infection and we don't know yet if these cells are going to be as durable as cells collected from the patient themselves because we just don't have long enough follow-up data but some of that data is shown here on the slide that you're showing right now um then we can go to the next slide and this is just the end to show some of the early work for nk cells as an alternative cell source next slide and this is a really interesting um uh a concept which is to actually generate the car T cells in vivo so you actually use nanoparticles that have a cd3 antibody on their surface to deliver the car gene directly you inject the patient with the nanoparticles because of the cd3 antibody they bind to T cells deliver the gene directly to the T cells and and then the car is the car gene starts to be expressed on the surface of T cells um and so it's not this is not out of preclinical development yet but we may be moving into a field where you don't have to create these car T cells X vivo but you can actually just inject these nanoparticles directly into the patient and let the let the T cell uh engineering happen within the body next slide um and so I had showed you this slide before just to show that it you know we're starting to understand some of the biomarkers as well as mechanisms of neurologic toxicity and you can hit next slide and so what this is leading to is now trials of a variety of different drugs and therapies to see if we can both treat and prevent neurologic toxicity more effectively next slide I mentioned before that we want to expand car T cells into other diseases and the next disease that's been or the next target that has been successful is B cell maturation antigen which is a marker for multiple myeloma it's a marker of plasma cells which are the cancer cells in a in a blood cancer called multiple myeloma next slide and so there is an FDA approved product targeting BCMA and multiple my myeloma it's called idicaptogen viclusal and it was FDA approved based on this study the karma study which showed that these are multiply relapsed myeloma patients and you can see that the their response rate is about 73 percent and the complete response rate is about 30 percent and patients who achieve a complete response have about 20 months median progression free survival means meaning that they're alive and without disease relapsed during that time so this is a great advancement for patients with multiple relapsed multiple myeloma next slide we are awaiting the FDA approval of a second product in myeloma silticaptogen autoleusil or siltacel and that's based on the results of this study the cartitude one study so this is being reviewed by the FDA as as we speak but this is even more effective where 97 percent of patients responded and 67 percent of them have a complete response many of whom had really deep complete responses with mrd negativity next slide and here you can see because the depth of response is so great the actual overall progression free survival is over 20 months in this study so you know really offering a substantial benefit to these multiply relapsed myeloma patients next slide toxicity in multiple myeloma with the bcmc cars is different than in with the cd19 cars so cytokine release syndrome happens pretty commonly but grade three or higher happens in you know five percent or less of the time so it's less frequent than with cd19 cars you almost see almost no neurologic toxicity although you do see some except with siltacel where there is an unusual neurologic toxicity that looks a little bit more like parkinson's disease and the reason for that is that we they've actually found that cells in the substantia nigra in the brain express bcm a to a low level and these so it does look like you're getting some you know logic activity in the substantia nigra which are the is the area of the brain that's affected in parkinson's disease next slide we are starting to see cars being developed for hodgkin lymphoma where the target is actually cd30 which is a unique marker on the surface of the hodgkin lymphoma cancer cell that reads sternberg cell and so we've seen some early phase data and now the phase two sort of multi-center large clinical trials are ongoing next slide and i don't mean to go through all the data on this slide in detail but it really i just want to call your attention to what's in blue which is you know no responses complete responses in a small percentage of patients responses in a small percentage of patients this is what car t cells look like in other diseases and other solid tumors next slide so a lot of work to go so why is it that they may not work as well so one is that they may not have the tumor antigens next next so a couple of strategies to overcome that are these cars that target more than one tumor antigen especially if the tumor antigen isn't isn't universally expressed or a concept called armored cars where the cars are actually engineered to secrete immunostimulatory cytokines within the tumor microenvironment to enhance the recruitment of tumor infiltrating lymphocytes that are already there the other problem is these cells may not be getting to the tumor right so it's hard to try that these lymphocytes may not be trafficking into these hostile tumor microenvironments next slide and so people are starting to engineer cars that actually express either chemokine receptors or receptors for the tumor microvascular to help facilitate this t-cell trafficking and then lastly when they do get to the tumor the microenvironment may be so inhibitory that it can decrease t-cell activation and proliferation and cytotoxicity both because of some of these myeloid drive suppressors cells that we've talked about or some tumor-associated macrophages next slide and so some of the solutions for that include combining cars with some of those checkpoint inhibitors like I've talked about earlier those armored cars that I had just mentioned or even alternative conditioning to sort of target the tumor associated macrophages and myeloids that drive suppressor cells so that they are less inhibitory and and again the cars have less they're they're up against less when they get to the tumor next slide so 2010 was when the first CD-19 cars were being tested in single institution centers just to see if they had activity and then in you know 10 short years we've seen an explosion of car trials across the globe so these are just the different the different the number of clinical trials across the globe and you can see that you know China and the US are certainly leading this effort but but there are just this has been an explosion in medicine and in cancer care and so I'm really really optimistic that you know we are going to see big you know we already have seen leaps and bounds of improvement from from this last decade but in the next decade I think we're going to see cars for the more common types of cancers like lung cancer and breast cancer and colon cancer and we're going to start to see the benefit of this therapy to a broader population of patients next slide so just in summary the future of cars and oncology we really need to focus on some of that toxicity management we need to develop safer cars more prophylactic strategies to decrease the risks of these toxicities and newer treatments for these toxicities we have to overcome mechanisms of resistance and we're starting to do that in a variety of ways including dual antigen targeting cars combination with checkpoint inhibitors looking at the t-cell product and then also looking at the tumor microenvironment and then overcoming issues of cost and manufacturing and efficiencies we talked about a bit about the universal off-the-shelf allogeneic car t-cells as well as nk cars and then again the biggest thing is to expand the indications identifying new targets and new cell sources new ways of manufacturing all to be able to treat some of the more common cancers with this really revolutionary therapy next slide and with that I will I think I'm perfectly on time to take questions I really wish I could see everybody I'm sorry about this all right well thank you so much for that presentation I'm glad that we were able to use the backup slides well you know I certainly have questions that have come in let me sort of prime the pump a little bit I want to ask you one of my initial leading questions I'm really curious to get your point of view of what it's like in your experience both as a physician and as an investigator did you ever run to situations where you think the two roles might be at a little bit of attention you know would you as a physician think that it would be optimal to provide or offer this therapy at a different time course in the patient's disease progress as maybe you might want to recommend as an investigator I'm really kind of curious about is there a possible tension there between how you interact with the patient as their caregiver and how you might kind of think of them as a research subject yeah so yeah so that's a great question so you know early on the diseases that we were treating as I mentioned were diseases that really had no other options people were lining up for these for these spots on these clinical trials and in fact people would talk about you know the every center would have a wait list for for these slots and patients were referring it on online forums as the death list right if you if you weren't at the top you know you were if you were 30 on the list you were only hoping that the other the 29 patients didn't make it for whatever reason and it was just it was this really kind of horrible situation and because they were just way fewer slots than we had patients now we have FDA approved products but we obviously as a field need to improve those products but how do you and how do you think about enrolling a patient on a clinical trial with an unknown safety and unknown efficacy profile when you know that you can give them a commercially available product off of a clinical trial you know so the push and pull there is you know you want to give someone you want to it's really hard to tell a patient well take a risk and take a product that may not be as effective or maybe more toxic but but it could be the reverse and that's what we're trying to test you know that's hard to do as a patient's clinician but on the flip side as a researcher you know that the only way we're going to make this better for patients is if we continue to test these products in clinical trials we are in a unique situation now where we want to make these products better there's there a lot of room to make it better but it's hard to really ethically you know try to convince you try to you know to talk to a patient about recommending a clinical trial over sort of a known entity and then I think in that when we start to expand cars into some of the sub types of lymphomas where there are lots of other options that's a touch that's a really challenging discussion as well right because you know you you want to see if these are going to change the natural history of these incurable diseases with long natural histories but those patients may may die with their disease not of it and they they may do very well with something less toxic and and less sort of less invasive so those are those are also challenges and you know I think the bottom line is it's it's it's often comes down to a really a really in-depth conversation with the patient in terms of what's important to them and and what how you think you can best meet those sort of priorities of the patient thank you so I'm going to start turning it over to some of the questions that have come in I want to stay on this vein of thought just a little bit longer but maybe shift the focus a little bit more to the patient so this question comes from bob true he's the director of the center for bioethics he says uh given the yin yang relationship between efficacy and toxicity do you ever take the individualized preferences of the patient into account in terms of dosage for example bigger dose more effective and more toxic or whether and when to give the steroids etc do you give patient preferences and give give them take them into account if not why not yeah so that's so the doses for the doses for these products are fixed we don't get to sort of modulate those doses actually we have we are we're sort of it's it's all the honor system the bag comes back to us and we're told it's this dose and and we don't have any way of verifying that and so you know the dose is fixed we are you know we have a lot of patients who who were very worried early on about you know giving patient giving them steroids or some of the other drugs that we use to combat some of these toxicities that they would make their cars not work and it often was a could have been a long discussion at the bedside explaining why it was so important to give steroids at that point or to give tosylismab which is a drug we use for cytokine release syndrome that's become less less of a discussion because because so many of the studies have shown that those giving the drugs to treat these toxicities has not led to a decrement in efficacy and so that hasn't fit so that's that's really kind of going by way of the wayside you know going that's going we're no longer experiencing that that issue the I think the sort of patient preference comes in almost exactly leading from the the last comment I made before we went to this question which is you know when you have when you have a patient who has other treatment options how but those treatment options may be indefinite dosing of a drug could be chronic low-grade toxicities as opposed to a single infusion with you know a defined period of high-grade toxicities you know that's where the patient preference really comes in where you have to have a discussion with the patient about you know again what's important to them you know what they'd rather live with what what kind of risk they would want to take how important is it for them to be off of therapy as you know for the one and done therapy versus you know sort of chronic and definite therapy so those are the those it's when the patient has multiple options that those are the kind of discussions that come into play. Great so Dr. Terry Ross Bard has a question are there any studies that have tried CAR-T8 therapies as a first line treatment? Yeah so that's a great question so one thing we didn't discuss you know obviously right now as with all cancer therapies we start in the multiply relapse setting where patients are without many options we always think that these therapies will work better in patients as an earlier line of therapy and and so there there have been three randomized studies looking at CAR-T cells in the second line so right now CAR-T cells for large B cell lymphoma are actually only approved in the third line and beyond and so there are three randomized trials looking at these the three approved CAR-T cells in large B cell lymphoma in the second line and they have completed two of them were positive favoring CAR-T cells over other second line therapies where the third was actually not positive. There was another trial looking at AXIE cell for very high risk large cell lymphoma patients where they started patients on standard chemotherapy for two treatments and if they had if they didn't have a sufficient response by radiographic imaging they then got CAR-T cells instead of going on to receive more chemotherapy and that was a single arm study but the results look quite good. The problem with the diseases that we've treated so far is that front line therapy actually works quite well so you know 65 to 70 percent of patients with large cell lymphoma will be cured with their front line chemotherapy and so and we don't have a really good tool to identify the 30 to 35 percent of patients that aren't going to be cured so the best tool we have is that they relapse and so I think until we can identify who those patients are before we start them on at diagnosis before we start them on treatment we're not going to be able to move CAR-T cell therapy up because CAR-T cell therapy has a higher mortality and a higher risk than standard chemotherapy for front line large B cell lymphoma now that may be very different for diseases like metastatic colon cancer and lung cancer where our front line therapies are not as effective if we can get CAR-T cells to work in that setting that may be prime to move them up to front line treatment. So interesting so I have a question from one of our graduate students in bioethics Rigo he wants to know what's the quality of life for the patients during this therapy and I want to add to this too another question from Dr. Bard what are the frequencies of the toxicity as you mentioned? Yeah so you know the so it's a big it's a big spectrum and and we also don't have a great way of guessing how it's how patients are going to fare so there are some patients who get their CAR-T cells they may have a day or two of fever they may have nothing and they just kind of sit in the hospital bored and want to go home and there are others that are in the hospital for four weeks and so obviously quality of life is very different on those two spectrums we have some people who say like I don't know I went home on day eight I went back to work at six weeks I like I was back in my life you know it was it was wonderful and there are other patients that say well I was in the hospital for four weeks I was you know totally confused couldn't speak and by the end of it I had to go to rehab and it took six months for me to recover from this so it's a big spectrum which is why you know working on some of the safer cars and also working on some of the toxicity mitigating strategies so that we can prevent the sort of outliers in the negative direction are so important but but it is important but for the vast majority of people you know it's about two weeks in the hospital it's about another two to four maybe six week recovery and then patients really do feel back to normal and you compare that to you know some standard treatment regimens that take six months to go through or even some other drugs that you you stay on until you progress which could be years where you experience low level toxicities the whole time and you know or you know have to constantly be exposed to these therapies that is you know there's there is important that's an important distinction between these two types of therapies and the studies are now only starting to look at quality of life endpoints so people can really address whether this is you know superior to what we've been doing and treating our cancer patients with that beforehand. Yeah I'd like to start moving the discussion now toward cost issues and access issues about how much does the therapy on average cost this is not including like for complications hospitalization but just the actual CAR T cell therapy generally what's the price range? Yeah so it's hundreds of thousands of dollars the CAR T cell therapies that are approved at range and cost from about $363,000 to $475,000 per product. Is that at all covered by insurance and this like for example Medicare take care of any of that? Yeah so it's almost universally covered by insurance of course you know so from private insurance it's you know it's covered almost in full but for Medicare reimbursement is not one-to-one so they're yeah so it's I am not you know a hospital finance person so I wouldn't be able to speak to kind of what the losses are in terms of treating Medicare patients but there it was a it's a real issue for some centers where you know it certainly raises some ethical issues about you know can hospitals survive if they're you know treating a majority of Medicare patients and losing a lot of money with each patient that they treat and there were some centers that had said they would had a quota for how many patients with Medicare they would treat and some patients who said they would not treat anybody with Medicare you know we're lucky to live in Boston and work where we do and you know Dana Farber and Brigham and women said that that is not they would not get into that business where they would have quotas for Medicare patients or just allow treatment of Medicare patients. Is it possible for some hospitals to make a decision about what version of the therapy to offer to the patient based on costs and not what may be optimal for the patient or are these therapies close enough that it wouldn't really be that kind of trade-off? Right now they're close enough that it's hard to imagine that kind of trade-off but it is certainly you know you do have to every time one of these therapies is approved you know talk to your hospital's formulary board and justify why you need the third product or the second product and there there there have been you know in the land of transplant in the world of transplant there there have been payers that have made you know unique financial relationships with certain centers and said if you have our insurance you can only get your transplant at X, Y, and Z center you can't go to A, B, and C and there are some insurance carriers that may be starting to think along those lines for CAR T cell therapy as well and you know I think and and they may be forming specific relationships with specific products as well. Here's a question from Andrew Hantel. Given the intensity and specialized care needed what access and equity issues have been seen in getting these treatments to patients how will these be expanded to broader populations beyond places like Dana-Farber or to get these populations treated at places like Dana-Farber? Yeah so I think so one thing we didn't talk about is the fact that yeah obviously these therapies are only administered and specialized and certified centers we actually have to be federally accredited to be able to deliver these therapies as well you need you know ICU care that that can be an expert in this therapy we need neurologic care that can be an expert in this therapy and so this can't be safely given at every community center or even some academic centers across the country. So I think actually geographic localization is the biggest problem I think obviously in a city like Boston where we have four different hospitals that give CAR T cells within you know a 10 square mile radius you know we're very lucky but there are parts of the country where the closest CAR T cell treatment center is you know 10 hours away driving and patients are mandated by the federal government to stay within two hours of the treating center for the first four weeks. So this is a big problem for people right they have to relocate they have to you know find housing they have to have family come with them and stay with them for 24 hours a day for that four week period and so the biggest limitation I think so far has been been geographic access but even within Boston you know I've been shocked by how we get referrals from lots of places but Boston Medical Center which serves our most underserved populations we see very few referrals for CAR T cells from Boston Medical Center so there's still a socioeconomic access issue even within Boston where we have you know four different CAR T cell treatment centers. I'm wondering in your experience this is cost a major issue for patients and their own decision-making of course this will vary on kind of how much you're expected to take up of the expense but you just mentioned travel all these other big expenses that families could be hit with you know is that a major factor and does that come up in the decision-making do you see that kind of big role in people's decision-making about this? Yeah so I think I think it's a fact I think the biggest so it's a so right now CAR T cells are given to about a quarter of patients who who would qualify in the United States we are not treating as many patients as we should with CAR T cells and some of it is referral bias you know I think it's the physicians in the community that have who believe these believe some myths about cost about how hard it is to get insurance approval and things like that and I would say so it's not the patients themselves by the time the patient comes to us they understand they feel confident that you know will work to make sure insurance will pay for it and they won't get a big bill but but there's a there's sort of a there's some there's some there's still some mythology mythology in the community about this from the provider standpoint and so some that that hinders referrals and the other factor I think when a patient gets to us is just sort of you know saying I can't possibly live in but you know we all have to work we all if we don't work we don't we can't keep our house I can't me my wife and I can't move to Boston for four weeks both of us be out of work stay in a paper hotel even though we have you know we can do this in a subsidized way and you know give up our livelihoods you know I think it's it's it's uh it's the way that that disruption impacts uh that our financial bottom lines that can and the ability to have a caregiver 24 hours a day seven days a week for those four weeks that has been the most rate limiting thing I think for some of our patients you know Karen right before we went on air live we were just chatting a little bit about how COVID may have affected you know hospitals in the in the area in Boston and in your experience and you said during the actual major part of the crisis in your line of work you didn't see a big difference but maybe nowadays you know as as the pandemic continues to linger on if people are are removing themselves from some of their jobs and roles in the healthcare profession you may be taking on an issue so my question for you is this um this is a very complicated therapy now on the hospital or on the the medical professional side of things who all is involved in this therapy clearly people like you but like can you kind of walk us through all the different role players that are that have to be involved in this kind of therapy yeah absolutely so obviously there are the the clinicians the nurses the nurse practitioners and physician assistants and the and the physicians um who who meet the patient who um you know who identified the patient and who get the patient you know lined up for their therapy um but uh you know the behind the scenes work um so obviously obviously it's getting geared up to even start a CAR T cell program um you know the all hospital administrators both at Brigham and women's and at Dana Farber um you know we're all hands on deck to make sure that we had the infrastructure in place that we could do this uh in a safe way I think that was the biggest concern as we were starting um starting this program and so that meant that we were um liaising with um you know quality groups who were liaising with the ICU we were liaising with the emergency room um with our pharmacists because we have to be able to get some of these toxicity mitigating drugs to patients really really quickly um with um both inpatient and outpatient nursing uh with uh the the our blood donation center which is where the cells are collected with our cell processing lab which is where the cells come back and are thawed before the patient gets them um with uh we have a whole group that is only involved their only job is for financial clearance acquisition before a patient can proceed with the therapy um we have a because this is a federal this is a federal we we are able to deliver this therapy because we are federal federally accredited we have to re-up that accreditation and show that we are uh that we are auditing our program and maintaining quality assurance within the program and so that that's a whole other group um we are mandated to report our outcomes through a international registry um and so we have to have data and we have to have you know data personnel who can enter all of that data into these databases um I'm sure I'm forgetting uh forgetting people um along the way and then of course this that's that's all to support our commercial program but we are a big research institution and we want to continue to grow this across the institute and so we have clinical research coordinators research nurses um regulatory coordinators and uh research managers all working with us to try to keep our research program alive and thriving so um it's it's it's a village it takes you know if I put a if I put a an org chart up if I could if I had a computer and I could put an org chart up you would see that as you know we probably touched like a you know 100 to 200 uh staff numbers just to be able to deliver these therapies you know I've seen in some of the literature people arguing that you could try to drive down the cost of the therapy by offering it as an outpatient um kind of context but what you just said seems to indicate that's probably not realistic what are your thoughts on that? Yeah so I think the the the the cost issue um so I think the the issue with whether doing this outpatient is cost effective has to do with your hospital's reimbursement mechanisms um and whether uh so so so for some centers uh because of their their cost structure and um you know once a patient is hospitalized there's one lump sum that's delivered to the hospital for that hospitalization and it's you know everything that happens to the patient during that time is encapsulated in that and so you don't add on a $400,000 um uh cell product charge it's it's whatever they get reimbursed and so in that case if you could if you could actually give the cells to the patient as an outpatient you could bill for the cells themselves um and if they stay as an outpatient for technically 72 hours and then get get admitted that admission is separate from that out charge and so many centers that operate under that cost structure and that cost that reimbursement structure um for them an outpatient administration where patients can stay out of the hospital long enough uh that they uh that the outpatient care any inpatient care will be considered separate events um would be cost effective that's not how Dana Farber uh is reimbursed and so it's never been um it's never been like the priority for doing this as an outpatient we are starting to do this as an outpatient um because we because patients want it um some you know some patients want it i should say some patients say i don't want to have anything to do with taking care of myself when i'm at home put me in the hospital let someone else do it but some patients want it um and because as products get safer and safer this is going to become a reality that these are going to be able to be outpatient and we we just want to continue to be at the cutting edge but it's not it's not a cost issue um for us um i think the um the one thing that i think could really drive down cost is um on-site manufacturing so most of these centers that give CAR T cells actually have cell processing labs that have the capability of making you know me too CD-19 cars um and if we could make them in house they would be significantly less expensive um the there are two problems with it one is that there's no regulatory path right so you these trials to to get the FDA to these trials to generate data for the FDA to review are incredibly expensive um and so and if i have to do that at Dana Farber and someone else has to do that at Mass General and then we're just spending an enormous amount of money to do the same work um so i think this is definitely something that CMS and the FDA are looking at in terms of trying to figure out a path to regulatory approval for homegrown cars but if if you know if you turn to the three big companies that have CD-19 cars right now and say well we're just you know you did all the work but we're just going to start making them at Dana Farber instead and we're not going to buy them from you that loses their both incentive as well as their bottom that reduces their bottom line to be able to invest in future R&D and we can't we can't move this field forward without them so it's it's you know there's a push and pull us with everything and medicine um but we uh you know I think that we have to sort of meet some place in the middle and maybe it starts with drug pricing but um making it you know taking the pressure off to do them at home and just by charging less um but you know it's a complicated it's a complicated world so my neighbor decided that now will be a good time to mow his loss it's getting a little noisy here on my end because I hope you can hear me but welcome to the world of live webinars um another question's come in this is from Kristin Van Vleet she said MIT hi Kristen um I'll paraphrase her question do you think that there are opportunities to reduce the total cost by improvements to the car to sell product manufacturing that end of things what do you think yeah I mean um you know I I'm not a pharmaceutical I'm not a biotech company and I don't actually know sort of I don't know the my my impression has always been that um the cost of these products is not actually the it's not driven by profit it really does take a lot of money to to make these products also you have to realize that these companies are getting you know you know cells from institutions probably you know 30 to 50 cells you know sell products a week and they have to make sure that they um uh are giving back that the same patient cells right so there's a lot that goes into you know sort of the quality assurance aspect of of this um that is expensive um I think I but the bottom line is all you know that that can all be streamlined if we could do the cell processing in-house so I think it's you know yes obviously these companies if they could come up with sort of more streamlined ways for manufacturing but I think there are some built-in costs there that are just for patient safety but but if we did it within the halls of our own institution where we you know we literally take the cells from the patient's bed to you know three three floors up and deliver them to the lab and they go right into manufacturing um that that's going to be a lot cheaper but it goes with the downsides that I or it's it both right now is not feasible from a regulatory perspective and then also uh does sort of cut cut the incentive for research and development within the field I think okay I've got one last question for you this is also from Rigo um curious you know the the past prospect of using off-the-shelf or donor car T cell donor T cells for car T cell therapy um number one do you think that would help reduce the cost my guess is not from what you just said but also just in general you know what are the prospects of this is looking very promising to use donor cells donor cells a little bit yeah so um so there is one way that it can reduce the cost which is that they can make you can make like a hundred products from one for ESA so so you know um I do think it can and and of course in in these instances you're not worried about sort of uh chain of custody like you know making sure that the same the patient got their own cells back so there are that you do lose a sort of like you lose some of the the the requirements that are expensive for autologous car T cells so I do think it could drive it down um the my biggest concern about these lgna cars is its persistence of the car T cells themselves that you know I think the patient the patient's own immune system even though you have tried to lympho you know lympho to pleat them or condition them so that their immune system is less robust um you know it does seem to come back and get rid of these car these donor car T cells and if they do it too soon if it doesn't too soon before the tumors are eradicated then then there's going to be a risk of relapse so we don't have long-term data yet to see that these are are going to be as durable in terms of response because there's extra gene editing involved in these donor T cells you know there's theoretically a concern that there could be you know more long-term issues down the road because of you know issues we've seen with gene editing and I don't know if there has there was a one of the most furthest along trials of allocard T cells was actually just halted by the FDA because of an outcome where a patient had a complication that was probably not related to the gene editing but when they went and did the bone marrow biopsy they found that the CAR T cells themselves had had a genetic translocation of one of the that was not present in the healthy donor so that it raised the question of whether these these you know the complexity of the gene editing that's happening in these allogeneic CAR T cells may have downstream repercussions you know for the patient down the line so I know I didn't really answer the question I think I'm you know I think they they serve a role I don't think they're going to replace autologous CAR T cells well with that thank you so much for your presentation I learned a ton I'm sure our audience did as well so I really thank you for joining us today Karen I also want to thank Ashley Troutman and Helen as the fanitis for their logistical support for this series so that concludes today's session session I invite you to come back on November 19th to hear about what we can learn from the ACE2 cellular receptor by Joseph Penninger apparently we can learn a lot so I'm looking forward to that session next month and with that I'm going to conclude today's talk have a great weekend we'll see you next time thank you and my computer is back up so I will join your other zoom through my computer and you can see me okay thank you all right I'm sorry about this I'll be I'll be back