Chapters Transcript Video CAR-T Cell Therapy for Lymphoma: Updates and Progress Back to Symposium Caron Jacobson, MD, MMSc, gives updates and shares progress with CAR-T cell therapy for lymphoma. Hi my name is Karen Jacobson and I'm going to be talking with you today about car T cell therapy for lymphoma, reviewing some of the recent updates and progress in the field. These are my disclosures So I will talk about the evidence for car T cell therapies in large B cell lymphoma, mantle cell lymphoma and indolent B cell. Non hodgkin lymphomas will start with a review of some patient cases and then delve into some of the clinical trial evidence and real world experience for these therapies and these diseases. Well then take a look at emerging data regarding response and toxicity and how it impacts patient selection and care. And finally we'll discuss the patient journey both in terms of best referral practices and then short and long term monitoring and successful transfer the patient back to the community. Our first case is a case of refractory transformed follicular lymphoma. This is a 56 year old man who was diagnosed with refractory transformed follicular lymphoma. In 2010 He was treated with our chopped with a complete response to therapy and did well for about 2-3 years before he relapsed at that time he received rice chemotherapy followed by an autologous stem cell transplant but only remitted for about a year when he developed recurrent disease. Again he was initially treated on a clinical trial without response and then our gem Ox followed by our diy happy both with progressive disease. This patient then received cd 19 directed car T cell therapy in february of 2016. His course was complicated by grade one crs or cytokine release syndrome lasting from day two through day six. And he received the aisle six receptor antibody tests, ELISA mob For the management of this on day six. With resolution of his symptoms. He developed grade 1 to 2 neurologic toxicity marked by disorientation, expressive aphasia and dismay tria. Starting on day seven, it lasted through day nine with spontaneous resolution and no therapy was indicated. His one month pet scan showed a complete response to therapy that persisted through his month 36 pet scan which showed an ongoing complete response to therapy shown here. So this patient was actually treated on the Zuma one clinical trial which was one of the three pivotal phase two clinical trials establishing cd 19 directed car T cell therapy for the treatment of relapsed and refractory large B cell lymphoma and the third line and beyond. Three different FDA approved products are now available for these patients Based on these pivotal clinical trials. They are actually Captain jean silhouette cell or access So technology unlock cell or tissue cell and listen Captain jean Marilou cell or listen to sell. And on each of these trials you can see that patients with highly refractory disease were treated with a single infusion of the CD-19 directed car T cell therapies And they yielded responses in anywhere between 50 and 80% of patients with complete responses and 40-50% of patients and many of these responses were durable lasting beyond six months. And approximately 40% of patients. We can see that with longer follow up on each of these clinical trials, about 40% of patients achieve a durable remission. Following these three different FDA approved car T cell products and relapse or factory large B cell lymphoma. And this greatly outpaces historical controls. When we compare the patients treated on the Zuma One study to those treated on the Scholar One study which is a meta retrospective meta analysis of other available therapies. At the time of the Zuma one trial, we can see that the meeting overall survival for Scholar One was only about six months And it's it's nearly two years or more on the Zuma one study. So this isn't a significant improvement for our patients with chemotherapy. Refractory large B cell lymphoma. Of course, once these products were FDA approved, the concern was that, would they perform as well in a non clinical trial setting where patients have other medical comorbidities or maybe have worse performance status is um and uh and maybe would not be expected to do as well thankfully, we have several real real world experiences both in the United States as well as in europe. Looking at these agents over the past several years. Um And on each of these series, about 60% of patients would not have been eligible for the corresponding pivotal clinical trial. And what you can see is, we're seeing the same excellent response rates anywhere from about 40 to 80% and complete response rates In about 35-60% of patients. We're seeing the same excellent durable remission rates about 35-50% at six months across the board. And what we'll talk about toxicity a little later in the talk. But we're not seeing is worsening toxicity. In fact, over time we're actually seeing an improvement in toxicity both in terms of cytokine release syndrome and neurologic toxicity owing to the fact that we are able to implement some of our toxicity mitigating agents earlier in the patient's toxicity course to prevent their occurrence of high grade toxicity without a negative impact on efficacy. So, given the success of these car T cells in the third line setting. Um there were three randomized clinical trials looking to move this therapy up into an earlier line of therapy for high risk, diffuse large B cell lymphoma patients in the second line. Now, these are patients that were either refractory to their first line of therapy or who relapse within 12 months of the first line of therapy. And patients were randomized in a 1 to 1 fashion to either received the corresponding car T cell therapy for each of these three clinical trials versus salvage chemotherapy. And if they had a response to that therapy, an autologous stem cell transplant. So these results were reported at Ash and then subsequently published last year uh and two of the studies, the Zuma seven study of Amoxicillin. The transformed study of license sell were positive for meeting their primary endpoint, which was an improvement in the median event free survival. Um And so you can see here that on Zuma seven axis salad to an improvement in median PFS from 8.3 months over two months with standard of care. And on the transformed study license sell it to a median overall event free survival of 10.1 months compared to 2.3 months for standard of care. The Belinda study of decision like Lucille, lortel sl was was a negative study with a nearly identical median event free survival of three months in each arm. We also saw results from ash uh some some interim results of the Zuma 12 clinical study, which was really looking at actually Captain jean solu cell in the front line for high risk large B cell lymphoma, which was defined as double hit lymphomas or high I. P. I. Lymphomas that had not achieved a complete response after two cycles of chemo immunotherapy. And in this study we saw a really impressive 78% complete response rate. And with a median follow up of about 16 months, we're seeing that about 80% of patients are maintaining their response. And what was interesting on this study is that they actually took a look at the composition of the car T cell product that was made from these patients. Uh and I'll call your attention to the CCR seven positive CD 45 positive are are a positive T cells. The higher proportion we're comprised of these naive undifferentiated t cells. Come on the Zuma 12 study compared to the Zuma One study and these naive T cells are associated with better response. And so one of the hypotheses is is that by collecting these t cells earlier in the patient's treatment course, you actually enriched for a population of fitter t cells that could do a better job for patients. And so we await longer follow up from this study and also maybe confirmatory randomized trials in this setting. So we'll go to our second case now and now we have a 55 year old man with relapsed TP 53 mutated blast oid mantle cell lymphoma with a high ki 67 of 80%. This patient was initially diagnosed towards the end of 2000 and 17 with some B symptoms and cat scans showed linkedin apathy and spline omega li and the biopsy showed blast avoid mantle cell lymphoma with a TP TP 53 mutation. So all bad risk characteristics. He went on to receive three cycles have been a mustang and riTUXimab and his pet showed essentially stable disease. He then went on to have three cycles of re Taksim inside caribbean. Again. His pet scan showed essentially stable disease. He then was started on the B. T. K inhibitor a calibrated nib and his pet scan, unfortunately, after three months showed progressive disease, He received car T cells on a clinical trial towards the end of 2018. His course was complicated by grade one cRS but no Icann's or neurologic toxicity. He was not given to socialism a vortex and methadone um for his treatment of these toxicities and he was discharged home on the earliest possible day, eight days after his car T cell infusion. And here you can see his post treatment pet scans over the ensuing two years showing an ongoing complete response. So he was treated on the Zuma to clinical trial of Brexit. Captain jean oughta loosen which is also a cD 19 directed car T cell therapy that looks identical to actually sell. Except that there's an extra step in manufacturing where the car T cell for is this product is actually purged of any circulating cd 19 positive B cells. Um and this trial was an open label Phase two study that treated relapse refractory mantle cell lymphoma after chemo immunotherapy as well as a B. T. K. inhibitor. So we know that these patients are bound to do very, very poorly Generally with a median overall survival on the order of months. And here you can see that 67% of patients had a complete response to therapy just like our patient and with a 93% overall response rate. Um and here you can see in on this Kaplan meier curve of duration of response that with a median follow up of about 18 months, about 60% of these patients or maintaining this response. And so obviously longer follow up is needed. But there's this is these are encouraging results um that definitely outpace historical controls but that also lead people to be optimistic that maybe a proportion of these patients could be cured of their otherwise incurable mantle cell lymphoma, just like for a large space a lymphoma. There is the Scholar to study that looks at historical controls for mantle cell lymphoma relapsing after a B. T. K. Inhibitor. Uh And uh when you compare overall survival and Scholar to two overall survival on the Zuma to clinical trial shown here in black versus Scholar to shown here in the two blue curves, you can see a clear improvement in survival with the addition of Brexit sell for these patients again, because this is now FDA approved in the United States for mantle cell lymphoma. Um that's relapse after any prior line of therapy. We now have some data from the real world looking at a number of patients who would not have been considered eligible for the Zuma to clinical trial. And just like with large B cell lymphoma, we're seeing the same excellent response rates with a cr rate of 63%. Uh We're seeing these responses uh match high risk patients with tP 53 mutations also for patients who would have been ineligible for the Zuma to clinical trial. And we're also seeing that these responses are irrespective of prior exposure to a B. T. K inhibitors. Because some of these patients were not able to receive or it did not receive a B. T. K inhibitor before their car t cell infusion As they waited for approval of this therapy in Europe, there was a compassionate use program for Brexit sell. Um and the Europeans reported at Ash last year 19 of their patients treated on the compassionate use program. And again, we're seeing the same sort of results corroborated with a 68% cr rate and very good um six Month progression free and overall survival rates. And so the last disease we'll talk about today are the diseases we'll talk about today or the indolent B cell, non hodgkin lymphomas namely follicular lymphoma and marginal zone lymphoma. And we'll start with a case of refractory follicular lymphoma. This is a 58 year old woman with multiple t relapsed Refractory follicular lymphoma that was initially diagnosed quite a while ago in 2011. She was initially observed for about three years before she developed um a perennial plastic rash that required therapy. And she was treated with venomous neurotoxin and had a complete response. Uh She did well for about about five years when her rash rickard prompting cT scans that showed a low volume relapse when she was treated with single agent riTUXimab at the time because the rash was bothersome but unfortunately had progressive disease. She then went on to receive open atoosa mob with CVP with progressive disease. A re biopsy confirmed follicular lymphoma. Now CD 20 negative. She then went on to receive five additional lines of therapy including liability, meid and copan elusive as well as off label products. And uh it was treated in a clinical trial all with progressive disease and you can see her pet scan um here so she was she received cD 19 directed car T cells on april 21st 2021. Her course was complicated by grade 1 to 2 cytokine release syndrome with fevers and mild trans am in Itis that was treated with socialism ab she had no neurologic toxicity and was discharged home on day 10. Again this was her pet scan going into her car T cell therapy and this was her pet scan at one month. At which point she you could see, she clearly had extensive bone marrow involvement and by this point she had had a complete hematology IQ recovery. So she was treated she was one of our first patients at Dana Farber treated with actually captain jean Luc Lucille following FDA approval based on the results of the Zuma five clinical trial. Um So accessible has been approved for relapsing refractory follicular lymphoma and the third line and beyond. Based on this trial which enrolled both follicular lymphoma patients as well as a small cohort of marginal zone lymphoma patients. And you can see here that the complete response rate was nearly 80% in follicular lymphoma and 63% in multiple relapse marginal zone lymphoma. And when we look at duration of response in time to next treatment we can see that um that for follicular lymphoma the median duration of response is about was almost 40 months And the median time to next treatment was similarly almost 40 months. And just like for um mantle cell lymphoma with Azuma to clinical trial and large B cell lymphoma with Azuma seller one clinical trial uh Scholar Five as a retrospective meta analysis looking at historical controls that were available to patients at the time of the Zuma five clinical trial for relapse refractory follicular lymphoma. And by every measure Zuma five statistically superior to Scholar Five in terms of overall response rate. Complete response rate progression free survival time to next treatment and even overall survival. Um After just three short years of follow up now, access cell is not the only cd 19 car T cell that's been explored in follicular lymphoma. We've seen the results of the LR a clinical trial of precision the colossal in follicular lymphoma. Again, these are patients in the third line and beyond. See the same. Really excellent response rates and cr rates at about 70% for two SSL and follicular lymphoma. And when we look at the Kaplan meier curve of progression free survival. You can see the median, overall the median progression free survival is nearly 30 months. So similarly excellent responses uh to to sell sell and follicular lymphoma. And these responses hold up for even some of the higher risk disease including high tumor burden patients with extensive pre treatment history and in patients with P. O. D. 24. So there's been great success in terms of efficacy of car T cells in these lymphomas. But what about their toxicity? So of course the things that were most worried about are cytokine release syndrome and neurologic toxicity. We've touched upon these already in this talk. Um of course cytokine release syndrome is the inflammatory response to car T cell activation upon re infusion which then activate further inflammatory cells that that reiterate cytokine production. And patients can get a cascade of inflammation ranging from low grade toxicities such as fever and malaise all the way to shock, requiring multiple vase oppressors and respiratory failure. Um This usually occurs anywhere between one and four days after car T cell infusion and lasts about 3 to 5 days mirroring peak car T cell expansion. Um And again as we've gotten much better at treating patients at earlier grades of toxicity, we've been able to prevent or decrease the incidence of high grade toxicity. Following car T cell therapy. Uh neurologic toxicity on the other hand, doesn't have really well understood path of biology. But it definitely involves some degree of inflammation of the brain usually happens after cytokine release syndrome or towards the tail end of cytokine release syndrome. So usually more like around day six or seven and it's a duration can be much more variable. It can last for a couple of days to even sometimes a couple of weeks in some cases, but as long as patients don't get critical brain swelling which can lead to herniation into death, which thankfully happens very very rarely. This is a this is a fully reversible toxicity from car T cell therapy as well and are only antidote for neurologic toxicity to date is really corticosteroids. So what we've learned across the different clinical trials and with the different products, there are a couple of themes I think the most important ones are that the cd 28 cars like Axis L. And Brexit cell, which tend to expand very very rapidly upon re infusion. Both have earlier cytokine release syndrome as well as uh more high grade cytokine release syndrome as well as neurologic toxicity compared to their 41 BB counterparts like SsL and listen sell. Um And then the other thing that's interesting is that all of these agents in follicular lymphoma tend to be safer than they are. And the more aggressive lymphomas like large B cell lymphoma and mantle cell lymphoma. So when you look at XXL and follicular lymphoma, you see about half the rates of grade three cRS and neurologic toxicity. The same is true for ssl in follicular lymphoma compared to the ssl in large B cell lymphoma. So from all of these studies we've learned quite a bit about predictors of response and toxicity and I don't have enough time to go through each one of these uh for um for the purpose of this talk. But what I really want to call your attention to is that patients do better if they have low tumor burden, a low pre treatment LDH and low pre treatment inflammatory markers and even have less of a need for bridging therapy. Um That's true for for having improved response as well as well as for having lower rates of toxicity. And so what that means is that um you know referring patients as early as you possibly can in their treatment course. And what I usually recommend is referring patients one line of therapy before the FDA indication will optimize outcome both in terms of efficacy as well as toxicity. Because if we can if we can treat patients when they're fitter and they have a lower tumor burden with fitter T cells. Um They are bound to to do better. It's also important from all of the real world series as I mentioned to recognize that patients with borderline organ function and co morbid conditions can still do quite well with car T cell therapy and non autologous transplant patients may still be good candidates for car T cells. And so I always recommend refer any patient who's eligible or who's eligible by the label and let the car T. Cell treatment center evaluate eligibility based on organ function and co morbid status. Uh to ensure optimal outcomes. It's important to realize that the short term monitoring the days to weeks from carty cell infusion will happen at the car T cell treatment center. Now these these therapies can be done as an inpatient or outpatient depending on the patient's the therapy being used and the disease being treated. Um If the patient's outpatient, they're generally housed near the treating center for four weeks and they're educated on how to take their vital signs and monitor for toxicities and given tools and uh to do so. And then also to record their data. Um They need to come to the training center for at least seven consecutive days for monitoring. And they generally are admitted at the first onset of fever or confusion through the resolution of those toxicities. And if they're in patient that patients admitted for up to seven days until or until resolution of those toxicities. And after discharge patients have to stay within two hours of the trading center for up to four weeks and abstained from driving for up to eight weeks following car T cell infusion, during which time they are monitored for ongoing side of kenya's hydration status and at four weeks for response with their first pet scan. Again I don't have time to go through the grading for cRS. Um But I just wanted to include these slides for your reference in the future. Um As well as for the grading for Icann's or the neurologic toxicity. I did want to talk about some of the long term car t cell toxicity because these are what are going these are the types of toxicities that are going to affect um patients when they go back into the communities to their community oncologists. Um So of course with the cd 19 cars we worry about BSL APL asIA and hipAA gamma globulin anemia from an on target off tumor effect. And so I generally follow immunoglobulin levels for my patients and replete when they're less than 400. We know that about a third of patients will have prolonged side up India's which means had opinions lasting for more than 30 days following their therapy. The exact mechanism is poorly understood. Generally patients will recover their accounts between six and 12 months but it will require for these group this group of patients close blood count monitoring and transfusions as needed and G CSF is needed generally if they don't start to recover by six months. I consider looking for alternative ideologies including a bone marrow biopsy and then finally about 40 to 60% of patients will develop infections and their postcard course. Um And so patients need we need to be vigilant for that. I generally keep patients on P. J. P. And HSV prophylaxis for at least six months after car T cell Infusion. Um and then I start to monitor check their CD four count and I only discontinue those agents when their CD four count is over 200. So I wanted to just go back to two of our cases or at least go back to go back to one case and then introduce the second case to just outline some of these late toxicities. So if we go back to the gentleman who was three years after his car, his car T cells on the Zuma one clinical trial still in remission with transformed follicular lymphoma. I did want to point out that um 4.5 years after his car T cell infusion um he had no signs or symptoms of relapsed disease but at this point he had developed evidence of five q minus mds. And so he recognized that this patient had been treated with our chopped rice, a transplant, our gem Ox aR D. Hop and then got the flu paraben and cyclophosphamide before his car T cells. Um And so he was a perfect setup for treatment related MGs. And so um you know this is definitely something we have to be on the lookout for hopefully less. So when we start using these therapies earlier in patients course and then I have a second case of refractory transformed follicular lymphoma who was treated with car T cell therapy um and did great for the first approximately three years. She had a complete response to therapy by one month and it persisted for about three years when she had a pet scan that had caught um some fdd avid masses in her right lower extremity. Um And the pet scan was then extended and she had multiple masses in the bilateral lower extremities. They looked like they were within the muscles. She had an aspiration and culture um that showed no lymphoma but also revealed no organisms. And then our astute infectious disease colleagues actually sent cell free DNA and identified a species of mycoplasma Haman ins that was evident in the blood and she was treated with antibiotics with good clinical response and resolution of these masses. Um She is now in an ongoing remission through five years ever since this infection she's been getting I. V. I. G. Infusions every month to prevent recurrent infection. And at about 5.5 years after being vaccinated and boosted, she did develop severe covid Covid was intubated in the ICU for 30 days and eventually made a full recovery. So I just wanted to point out just this infectious risk that these patients can have for quite some time after car T. Cell therapy. Um And it's it is really important that we monitor their immune status and keep them on appropriate prophylactic medications and I pay attention to whether they would be good candidates for I. V. I. G. Infusions as well. So there is a lot of work needs to be done for car T. Cell therapies. Of course we want to make safer cars. Uh These could be cars that increase the signaling complexity at the immunological synapse or utilize a more physiologic t cell signaling through the T. Cell receptor. And so some of these are entering clinical trials right now. We also need to overcome some mechanisms of resistance including T cell exhaustion by combining these therapies with other checkpoint inhibitors and other immuno modulator torrey agents or even consider alternative conditioning regimens. Um uh Energy loss is not a huge mechanism of escape for lymphoma but we do know that some patients will lose cd 19. And so to decrease that selective pressure people are looking at dual androgen targeting cars targeting more than one tumor androgen. And then we know that the T. Cell product itself is a really important determinant of response that patients who have less differentiated and more naive T cells in their product tend to do better. And so you can think about treating the patient differently before you collect their T cells or even potentially manipulating the T cells ex vivo during manufacturing to increase the number of naive T cells within the product. And then finally you know we want to increase accessibility. This is an expensive therapy that takes a long time to manufacture which can be prohibitive for some patients. And so looking at donor derived T cells as an alternative source for the cars or even in K cells as an alternative source for the cars are being investigated. I do want to call your attention to a couple of clinical trials that are ongoing at Dana Farber. So we do have a clinical trial looking at a dual androgen targeting car targeting both Cd 19 and CD 20 for car naive patients that are relapsed or refractory in the third line and beyond. We also have an off the shelf donor derived car T cell directed against CD 19. That's open for patients who have seen prior autologous car and have subsequently relapsed. We have an upcoming roar, one directed car T cell therapy for patients who had a prior car 19 relapse. And then finally we will be looking, we will be participating in the randomized confirmatory study of ACSI Captain jean. Still elusive versus standard of care for either early relapsing follicular lymphoma in the second line or any follicular lymphoma. Relapsing in the third line and beyond. So in summary cD 19 directed car T cell therapies lead to durable remissions and 40 to 50% of patients with aggressive B cell lymphomas leading to their FDA approval and third line and beyond. Uh they also lead to high rates of complete and durable response in mantle cell lymphoma and follicular lymphoma leading to their approvals and these diseases but longer follow up is needed to see if some of these patients are indeed cured. The use of Cd 19 cars in the commercial and real world setting has really corroborated these excellent clinical trial results uh and the expansion of these therapies for broader patient populations. Um, and it's, you know, to optimize outcomes. It's really important to refer any patient who's eligible as early as you possibly can allow the treating center to decide if the patient is fit to go forward with car T cell therapy. This will optimize outcomes because it will optimize patient fitness, T cell fitness and disease burden before a patient is treated earlier. And more aggressive toxicity mitigating strategies have decreased high grade toxicity rates and have allowed for treatment of a broader patient population. So even individual centers have liberalized their eligibility criteria over time and lastly, relationships between the referring and referral centers and oncologists in both the short and long term are vital. Um, and we look forward to these partnerships going forward. Thank you Published May 26, 2022 Created by Related Presenters Caron Jacobson, MD, MMSc Medical Oncology View full profile
