Chapters Transcript Video Advances in Targeted Therapy and Immunotherapy of Lymphomas Good afternoon. Uh so it's going to be my pleasure to talk to you about the advances in target and the military official informa. And to me there has been a journey that started around 1995. So I want to go quote you through the journey in which I have witnessed a significant advances in the management of peace. Our informers. And this is just to add my disclosures. Uh so when we talk about no hospital informer, so it's not just one diseases, many subtypes of uh informers with different natural history, different prognosis as well as different treatment. And when I started my career in the field of lymphoma. So this was the strategy that we have I would say in the early 90s, you know, chemotherapy with chopped with a combination of different agency BP or through therapy Cytoxan we have radiation therapy and therefore those patients that had aggressive disease and failed from line therapy. So we have hydro chemotherapy followed by extension trends. And that's what was all that we had at that time. But then in the I would say early 90s, because of the advances in understanding what's wrong with the cancer cells in this case the malignant b cells. So we start to develop novel therapists that were directed against a specific molecules. And that's what we call target therapy. And this is just to show you. So this is a concert sale that has a receptor on the surface. And as you can see that receptor is going to transmit signals to the cancer center are important for certain survival and proliferation. Uh and then you can see in blue. So these are proteins that scientists discovered was important in the transmission of the signal and that's become a target. What scientists did is they start to study this protein this molecule and they found that three dimensional trade dimension structure but also they found that this protein can have an enzymatic activity. Uh that is America activity was important for the function of this protein. And then the other group of scientists found a specific inhibitor that will block the cinematic side of this protein. And therefore basically by doing this with this specific inhibitor, we were blocking a target protein that is important for social barber and proliferation of tumor cells and by blocking this pathway now, so that would die. So that's what we call target term. Mhm. And that's in the 90s. So then In 1997, so we have the approval for the first time of um monoclonal antibody for the treatment of cancer. And this is an anti cd 20 monoclonal antibodies uh called the toxin map that target City 20 expressed in malignant B cells, but also in normal B cells. And actually this is quite relevant because when we use the toxin map by killing the normal B cells, I mean they recovered but take six months to for those normal B cells to come back but by kidney does normal B cells. So that patient that you're receiving three and for informal is going to respond less to vaccination with the flu shot. And also, you know, this day we talk a lot of covid vaccinations pages. The right reason reduction of as part of treatment for their lymphoma are less likely to respond to vaccinations to uh call the vaccination because as I said, so this manipulative recall kill malignant cells that's our goal but also killed norman says with the advent of these anti cd 20 minutes category. But we did it we start to combine or adding re talking after chemotherapy and then we came with the name R chop or chop are uh F C R C B pr What it means is we are talking of conventional. I'll keep that. So I would say in the last 20 years now where we have a significant number of target therapy and as as well as similar therapy and they are rapidly changing the landscape in the treatment of patients with bees. And unfortunately for me and you can have a better idea and this is like this a busy slide. But just to highlight that there are different type of monoclonal antibodies in red reduction of two maps that are going to target antigens that are expressing the surface of the malignant B cells. But also they're going to be uh several drugs like uh the P eight recognition inhibitors that are going to target specific intracellular pathways inside the Molina Visa. That's also the case of the vehicle inhibitors. it's routine for calum routine is busier two inhibitors but also in the bottom of this life we have that what we can use immune cells to attack uh visual informers and that's what we know now as a primary anti receptor. Uh So sick if this I would say is an explosion of both target therapy in the military for patients with the same question. And just to further highlight what I say. So this is all the FDA approvals of different target therapy or immunotherapy for the treatment of physical size. And you can see that this is from 2013 to 2021. So you can see different type of monoclonal antibodies, different type of pediatric and execute er different type of B. T. K. Inhibitors. Uh Several types of car car T cells antibodies conjugated epigenetic therapies like uh uh does it mean to start? So it is good to have all these target therapy. Uh but at the same time it's a challenge and I'm going to review later on during my talk. So the question is okay we have great agency like having a great team. So you have tom brady, you have ground costs, you have all of the interpersonal, how are you going to put it together and they improve the efficacy of our treatments uh patient will present opportunity uh malignancies with the hope that provide cures for these diseases. Yeah. Mhm. And the cycle continues. So you know, it's a lot of excitement about carty sales but it's kind of old news car t cells at least in my view I have been on the field for so many years. I was involved in bringing partisans to several institutions where it was before. But now I think as we move forward by specific categories are quite promising for the three of these diseases. And we have several several favors or several types of these by specific categories. Some of them that can be given I. V. And there is one that you can even given sub q two patients with aggressive the ceremony. So in terms of target therapy so let's focus target therapy. So there are many successes but also limitation. So normal target agents either alone or in combination are clearly improving clinical outcomes of patients with piece of informants. So mainly in the relapse refractory setting. 2nd line. 3rd line. That's great. So we are now moving some of these agents uh and being evaluated clinical trials from like therapy alone or in combination with chemotherapy with other targeted agents. And they these early clinical trials early results are showing that these combinations improve clinical outcomes in some piece of Molina's in the frontline setting. It particularly are in CLL SLM. So however not all the pieces are going to respond to target therapy. There are patients that do not respond at all. So that's because there is a mechanism of innate resistance. But then there are another group of patients that will respond beautifully to target therapy. But then at some point the disease with progress and that's what we call mechanism of acquired resistant that involved both the tumor cells as well as the tumor migrant violence. So in terms of immunotherapy so we have failure without successes and there are lessons that we have learned. So list of our checkpoint blockade. So checkpoint blockade categories pain Boniva have transform the way that we treat cancer significant activity in solid tumors. Great activity in hospital informal. However, very disappointed resources in the management of patients with peas and a fortune in form. And the big question is I mean we have great expectations. We said, okay, checkpoint is going to work beautifully in no ha jin informa because the malignant visas are surrounded by an army of teasers. So therefore by giving checkpoint we're going to kill that you follow. Well, it didn't happen. And that's because there is uh the immunosuppressive tumor, the former immunosuppressive environment plays an important role in preventing a checkpoint blockade to have increased efficacy. The city for peace and informers. So but then we learned the C. 19. So I talk to you about 20,000 target for city for detoxing. So C 19 so become an appealing target for nobody military political approaches. Invisible informal. So we're going to talk about the 19 car T cells or Cartesian targeting cd 19. So there are monoclonal antibody like Uh Rosita map that targets and 18 there are antibodies that are conjugated is an antibiotic to which to whom we are attached chemotherapy. That is called antibodies conjugated one longer uh that has shown efficacy in the management of patients progressive reformers. And also we have a bi specific antibody that will create a bridge between the cells Expression c. 19 and T Surgery Press CD three A significant activity in patient with Ellen and also in some patients with the same question. So see we're going to talk about seeing I think artie Sayles significant activity but also they are associated with some with significant toxicities. Aside you can really syndrome never toxicity. At the end of my talk I'm going to talk about by specific categories targeted C 20 B cells. Uh they are off the shell uh and seems to have less toxicity. That car deserves an efficacy. I think time is going to tell whether they are going to be as good as carty said or perhaps better time will come. So now let's focus on target therapy B. T. K. So this is just to highlight I mean there is this pathway, the B cell receptor is present, the surface on the on the piece of meat in the measles and then there is signaling pathway. And then in orange we have this molecule that is called PdK, a brutal tyrant kind. So there are inhibitors of PDK. So the first one to be uh the Pelham was included. But now we have others such as a kind of routine, so routine and what they are going to do it by blocking B. T. K. They are going to deprive the minimum the cells of a survival proliferation signals. So three of them they have been approved for several B cell malignancies. Cll multi cell informa all this from Martinez on informa. Uh So they are. So if routine if it's once a day a collaborative is twice a day and can be given once or the idea and it's important to remember because you know some patients are preferred. It's better for some places just to have I want one tablet a day right at B. I. D. Overall I'm going to show you data the efficacy with this vehicle inhibitors is is quite similar at least in Madison informa. And the toxicities are different and it's important to remember whatever the toxicities associated with critical inhibitor among them. And more than bleeding hemorrhage, bleeding is bruising uh some eight defibrillation, headaches and others that we're going to review during the. Okay, so now let me talk to you about Madison in front so much as an informer is a subtype of not fortunate for me that I have been excited for the past 20 years and before he brutally the way that we treat relapse refractory. Mhm mandatory farmer was with some more chemotherapy a the more chemotherapy to the point in which the patient will just die. So and therefore when someone mentioned that here we have appeared that is going to provide some responses to relapse refractory Madison informal. There was, let me say a lot of skepticism among the the physicians start training official matters very informal but you know, we were all greatly unpleasantly surprised in a good way when Michael one presented initially the resource of using a brutal live uh 560 million people in the larger factory Madison informal. So here we have to me this was a transformational event in the management of Madison informal. So here we have appealed that is taken once a day that impatiently relapse refractory is providing an overall response rate of 62%. A complete response of 21 Media. The rational response of around 18 months. So just just having this build, controlling seven was a big event for us. And that's the reason why awesome. Uh New England massive this paper for publication and then we long follow up. So the data even gets better. So this is a patient that were enrolled in the initial study that showed to uh And then with a million follow up of 46/7 months over the response rate is 88%. Complete response is 58 dr Sotomayor we have a question I think it was from a couple slides ago. But can you elaborate on the best way to combine or use the targeted and immuno therapies. What is that? What that yes. What is the best way to combine or use those two therapies? Well it is it is a very important and we are the enemy for I'm going to give you one example in matters sell informa. So we had a critical inhibitors to have three political inhibitors approved and also we have a car T cell uh which is immunotherapy approved. Uh So now there are ongoing clinical pricing which we are treating patients with PDK inhibitor followed bike artisans. And I think that that's uh it's an important clinical trials because there is uh didn't mention that. But one additional benefit of the political inhibitors is that they can improve the function of sensors of the immune system in particular deriding cells. So it makes sense to combine them. Uh But but the results of the clinical trials are going to tell us whether uh so this combination is the most improper combination for patients with matter selling form. Uh So there are other examples in uh other diseases in which so we are combining uh some patients that receive so target therapy like alan a little my is a target therapy in combination with anti cd 19 monoclonal antibody to it's called Tafel in combination that has shown significant activity patients relapse refractory uh large selling farm. So we are getting there but as I mentioned is a good problem to have. We have so many good agents and it is up to as all the academic centers to develop clinical tries to give us answers to that question. Very good question. Thank you. Okay, so so just to mention here, this is a routine if as a single agent relapse refractory Madison informa. And these data from DR rule who put uh combining a full analysis of all the clinical studies done uh using a routine is basically Madison informa. And as you can see here uh so so this is the progression free survival delays. The overall survival is quite good. But now if you look at the patient with complete responses are so you can see that those patients do very in terms of progression free survival and overall survival in comparison with patients achieve pr or stable disease. So, I think, I mean again, these are patients that are failed initial treatment. The relapse. You are trained with an oral agent and they're achieve a CR and the cRCs to be sustained. But also and this is why I just want to show you. And I think this is sort of becoming the new, I mean quote unquote a standard of care for patients with relapsed refractory Monticello informer. So the patient first realize that patients should receive treatment with uh medical inhibitor. What you see here regret is that one prior treatment. So the patients that received one prior line of treatment and 33 recruiting too much better than patients in which you just wait until the second or photos relax and you start to use your reporting live and I just want to focus on the overall survival on the right curve. And I am always an optimist. Uh and I would say that perhaps if we patient with Madison informal relaxed and we start to use a routine, if not only we're going to have a good response rate, complete response rate, but in some patients this response seems to be sustained, which raised the question whether we are curing some patients with relapsed refractory medicine informal. Again time will tell but it's important data for you to see how to present. Mhm. Okay, so these are the three different uh vehicle inhibitors approved of relapse refractory Madison Informa, broadening avocados and routine or that I have to say is in terms of efficacy, there seems to be the same, there is longer follow up with routine which was approved in 2013 or 2014. There is a less follow up with Akala and sort of routine. But having said that my prediction is that efficacy is going to be the same. So the difference is in the safety profile. So if routine it is associated with uh easy bruising bleeding, a tribulation uh infections. So Akala and stand up routine also be a media, they belong to the same class of agents and the side effects are going to be similar. But there are studies especially in C. L. A. That shows that with a kana and sort of routine if you are going to be seen less complications in terms of easy growth bleeding as well as a tribulation. But with a collar you have increased incidents of of headaches and he's twice a day. So which led me uh to make some recommendations. So the treatment with PDK inhibitors is going to be driven by your own experience and also for what the patients uh comorbidities. Uh So it's a patient with uh is taking anticoagulant or anti platter agent. Perhaps your decision will be based where I want to use the PDK inhibitor that clinical trials have shown so far to be associated with less bleeding episodes. So it's going to be a personalized a treatment for patients with relapsed refractory matters and inform. So the other target agent that is a one just to briefly mention to you is a busier, busier two inhibitors. Uh Vonetta Clark but basically what is going to do is going to trigger apoptosis in the um Alina details. And Panetta clocks is being used in patients with uh C. L. L. S. L. S. Patient with acute myeloid leukemia and also is being used in patients with multi cell informer. So one of the good problems to have with this drug. Either it use rapid killing of tumor cells and that can lead to to more license syndrome a good problem to have. Uh but you need to know that this could happen quite rapidly and you need to be prepared to deal with the crisis center. That's the reason why when we use the network that there is a ramp up period in which we started with lower those monitor the patient and then you start to increase the those uh in order to prevent this tumor licensing but also this inhibitory associated with lowering the hematology parameters in patients with this account, regular separate trees uh also raised for infections. And this is the use of the net a class in relapse refractory Madison informa over the response rate 75%. Well, so I mentioned we have a medical inhibitor that works in relapse refractory medicine informa. We had a busy two inhibitor Panetta clocks. So what about if we combine them? And there was a clinical trial, also publishing the new England, a small number of patients in which pacing a study with protein. And then Vonetta Clark was added. And the results using this combination, we're better that single agent. Again, it's more trial. Now there is a big trial called the Simpatico trial assessing this combination in a larger number of patients with refractory matter setting for so good agents. So now with clinical trials we are we are defining what is the best way to combine them. So, pediatrician is a k a K T enter path very important pathway for Melinda visas for survival, proliferation, growth metabolism. Uh So in the top in purple is that patrik magnets, there are different subtypes and there are several inhibitors approved now by the FDA, there are four P eight recognition inhibitor approved Idella copa divisive and umbrellas for the management of patients with with four liberal inform marginal song informer. And this is just to show you the different FDA approved indications uh they can be used with in combination with anti cd 20 monoclonal to where he talks about some of them are peers. The other one is I. B. But I think what is important is when you are trying to use a pediatric annex inhibitor that the choice of therapy should be individualized. Similar. But I explained to you with a B TK inhibitors. So therefore uh toxicity profile may factor in the choice of the pediatric annex inhibitor, particularly patients with comorbidities. Forrest Idella do belacevac policies are associated with toxicity immune related colleague collides copa is associated with hyperglycemia hypertension. Uh copa is ivy. The other ones are oral. So so therefore you have several agents that is in which the patient capabilities as well as your experience managing the side effects associated with these agents will play an important role when you are making treatment decisions. Yeah. Okay, so love selling farmer and I would say uh for many years we have we didn't make, I would say significant improvements in the management of basically different represent informal for many years was chopped and then our job So and so three toxic was added to job in the year 2000 and then uh for the tree in the front line dream of the future like recently. So then we try to improve and then we said okay what happened? We are rooting into our child. Well we are uh we are uh Panama city or we I mean you name it several target agents chemotherapy and there was no improvement. So art show become the standard of care for many, many years for some subtypes like HIV associated informal primary medicine. A lot of research in form of the world were killed than live E N A. S. Led us to uh they provide data that for this subtype of large cell informers uh those adjusted epoch is the best treatment for this subtype of what he said. Not much an informal uh checkpoint blockade. You know, we said okay pam bro and evil. They are going to provide great responses to different climates and you know it didn't happen. But now I think since since 2015 uh so now we have cart is we have Paula we have top to top we have long so suddenly now we have a plethora of nutrients for patients with diffuse light resulting from. But that's what I'm going to refer in at the next uh few slides. So we have several three platforms of car deserves approved for the treatment of the fuel of recent informa. But also that we have and I already referred to this we have uh antibiotic I. C. C. 19 naked antibody like Tafa or a disease antibody drug conjugate Lanka. Uh Also we have uh other body by specific other boys. So let's talk about Primera Ardian recenter, Soak, artisans and in order to understand what we call camera. So let's let's let's focus on this uh the world kind where uh in greek biology A camera is a five reading female monster with a lion's head, a ghost body and a serpent serpent's tail. Uh So so so in other words is an animal with parts taken from different animals. So if we talk about primeras climatic cell is going to be any sale with powers or molecules taking from another cell. So what is cosmetic antigen receptor T cells is a T. Cell with power or molecules taken from a dollar sale. And that part of molecules is going to be a receptor a receptor that is only expressed in B cells. So in other words he says that have been genetically engineered to express an antibody receptor that recognized as a specific antigens into Marcel's or in cells that have been infected by viruses. So the receptor is not naturally present of the cells we are making the T cells to express our center. And you can see here in this slide so on blue you have the T. Say that they recognize, baptizes pressing the context of anti present themselves on the right. You have a bill emphasize and recognize antigens through a B cell receptor. So that's the way that mother nature created our T cells and B cells. But now we are going to to the T cells to express a receptor that only is his present Visa. And that's what we call. Okay uh That is the way it works. So c. 19 Express in malignant B cells but also in normal. So that's our target. So now we can produce a cell that we call a car T cells that is going to impress a receptor that's called anti saying I think uh huh. Or receptor. So it's going to recognize the scene I think is present. How do we get there? So that's the final product. So the way that we do is we make a construct of DNA that you can see on the top and there is going to be a D. N. A. That is going to in called for uh a segment that is going to recognize as C. 19. So there is going to be co stimulatory domain and the T cell activation domain. So this is a construct you put this concert inside a retrovirus or anti virus. And then you are going to infect your T cells with a retrovirus or anti virus. And then you're going to have uh expression of these car T cells in the surface of the T cells. To very beauty. So this is this is our concept that the D. N. A. That was sort of uh incorporated into the T cells because you know retro virus and the antivirus they can infect the cells. So they are going to put the DNA there. So there's going to be transcription, translation and then you have your receptor being is present the T cells. So then with the teachers encounter that people in the BCS present present C. 19. They're going to say okay I see you got you. I will kill you. And the beauty about this he says if they can go from they can kill 1 to 1 Molina is a move to the second the 3rd 1 Kill 100 cells. But in doing that they're going to produce cider kind. They're going to do a lot of things, a lot of good things but also a lot of potential bad things and that's the way it works. So patient with aggression informers. So you're going to collect uh peripheral blood cells and then you're going to send the cells to uh special labs in which that that teachers are going to be isolated, expanded. And then you in fact that he said with your retroviral antivirus that has this car T. Cell D. N. A. And then you're going to have an army or highly trained soldiers. Meanwhile the patient works in some sort of chemotherapy. Then two or three weeks later the car he says are going to be sent back to you and you re infuse the patient the car T cells into into patients with the B cell malignancies. Cd 19 expressing tumors. So now there are cat is has been produced against other antigens. Cd 20 cd three antes expressing my love assails, antes expressing uh leukemia cells and so on. Uh huh. Three different uh car T cell therapy is approved by the FDA Axis cells. So it's difficult for me with my access to pronounce the full name. So it's easy I think for everyone is access L ties to sell or license sell all of them approved of patient with the laugh factory if you're likely sell informa after two or more lines of therapy. Uh Ssl has also been approved for patients with L. L. And there's another one that has been approached called Brexit sell approved for patients with amoxicillin for so plenty of parties. So do you have to show you large clinical trials with three different type of cart is so in terms of efficacy I will say I mean the course looks quite similar. I would say uh efficacy is about the same. The next question is because of these successes in inducing carty says can we move in real after factory. Can we try to move carty says to the front line uh setting and there are several trials addressing that questions whether carty cells he's going to be as good or perhaps better than alcohol assistance transplant. Therefore we don't need your assistance is transferred in the future. But I think those clinical trials are going to tell us what will be the best way to treat patients with her labs. Uh But the patients with our larger factory different like the former but also I mean there is now studies ongoing to identify patients with a high risk uh the future reasoning former that can benefit with some sort of induction therapy and then taking those patients to sort of consolidation carty's. Yeah. And actually I am dealing with one of those places in in my right now, patients with a very aggressive and larger in form uh triple hit. I gave him intense chemotherapy. His progressing. So now we're going to do is try to uh control the disease and then send the space and for car T cell therapy or normal clinical trials using by specific Mhm. So these these car T cells also work for patients with relapsed refractory for legal informa in green is to see the overall survival progression free survival unless in basically marinas on informants at the bottom of the court from which there is a rapid drop in terms of progression prison. So because of this data, the FDA approved uh oxygen for patients with refractory for economic form uh reasons. So this is the platform breaks itself for patient with Madison informal relapse refractory over a response rate. As you can see very high complete response rate also quite high. Uh Some of the patients that respond does that response are sustained? However you you look on the on the bottom right? So this training is associated with grade three cytokine release syndrome and also with Great Three. No toxicity around 31% of patients. So you need to be aware although these days we are very equipped to early identify this complication and then treat these complications are properly. Because of this data Brexit sale was approved for the treatment of adult patients relapsed or refractory Madison informal. So this one platform but also uh last december. The second platform like to sell also shows similar results for the treatment of patients with relapsed Refractory practicing medicine informer on the on the text. And it's highlighted uh is it seems to be I mean the only way to know whether one platform has less side effect that the other one is to do a clinical trial comparing head to head. But I mean list of cells in those patients. This place with Russian factory Madison informer seems to be associated with less CRS on this Great three uh crs and seems to be associated with less toxicity as compared with the other plants. Okay, toxicity cytokine release syndrome. Uh neural toxicities. Uh So these are well described. Uh now there are very good treatment to manage cytokine release syndrome. I think. I mean we need better uh better strategies to deal with toxicity fortunately in a large majority of patients these are reversible top cities associated with heart disease. I mean I would say that so we are getting better in knowing the side effect. And now some highly specialized centers are moving car T cell for the impatience to the outpatient setting. So we are we are going to be soon starting our own car T cell product here at the th council institute. But we're going to start just with a patient. But at some point we're also people into outpatient uh city. So the next generation anti C. 19 antibodies antibody drug conjugate 40 few recent informa. So I'm just going to highlight quickly. So this is a combination of stuff up our little little mind again this a combination of immunotherapy with target therapy. Uh Just someone asked a question, improve response rates of relapse, refractory, diffuse recent informal overall response rate. 60%. Complete response 50% in heavily pre treated faced with the recent informa this is just to show you the curves. So there's another agent, this antibody drug conjugate. So remember this anti cd 19 that is going to be the specificity but then attached to the fc portion of the antibody. There is this chemotherapy agent uh that that is going to be released after the antibody binds to the target cell. So that's the reason it's called antibodies conjugated. I mean it's a long name. We just call this treatment lock Uh long to give us a over a response rate around 40% because of this uh both uh tough Elena along that were approved by the FDA for the treatment of patients relapse refractory mayor. We have another question. Yeah. Great. Regarding the T cells, where do you see they fit in with aggressive lymphomas? So I think so Curtis says I say we know now that if feed in the future larvae selling forms uh there's there's all of them so they feel informed, regularly informed that transform too aggressive. So or or there is a group of or regularly forward that we call is a need for legal informant usually is an indolent disease. Uh So we do watchful waiting or and then when we treat the patient they're going to have a very good period of time information. But there are a subgroup of patients with follicular lymphoma that you treat them and then when they relax within two years. So they are aggressive and car T cell has shown that it works quite well in that patient population. It was also an aggressive Monticello informa to the point that now we're trying to move carty cells to the front line of Monticello informal for patients with high risk p 50 tribulation dilation, high expression and so on. So I think for uh for the large majority of aggressive B. Cell inform us. So I think our t cells have a half aeration significant activity in relapsed refractory setting. That way is how to move this straight into the front line setting. And also uh trying to design sort of the next generation of car T cells with less side effects. Great thank you. Okay so so we are so what are the challenges as at least as as we're moving forward And I have a few minutes just to talk about this. So we are victims of our own successes but these are good challenge to have. Uh So the question how to combine these novel therapist, I gave you just some examples but then is to place versus triplets. Uh So what is the role of assessing minimal residual disease to say? Okay right and continue with this therapy. You had a great response. Let's stop. They give you a holiday until the disease come back. So have to use in the frontline setting with came out of three combinations. But also it's important we have these agents right now we are using these agents forever until the patient has toxicity of the patient progress. But this associated also with financial what we call financial toxicity. There is a co payment every month and therefore now the next generation of political trials are incorporating M. R. D. To give a sort of a limited time of treatment and then if the patient has achieved a deep molecular response then we're going to leave the patient along. We can monitor the patient with serial blood samples, looking for molecular relapse and then at that point use our therapist. So it's a good problem to have. Don't get me wrong so resistance. Uh so we talk about political inhibitors. Well there is a resistant to be TK inhibitors but also I think it's important to mention that checkpoint blockade and tight but it didn't work in the relapse refractory selling and I'm going to present data that perhaps we use checkpoint blockade in the frontline setting. We're going to have better outcomes. And finally there are already mentioned to do this. There are these difficult to 3% of watching informal and magnate, 53 matters and informal. Doubletree, persecuted informa relax for legal, informal, within 24 months and primary cns lymphoma is still a challenge. So let's have our system. Uh So let's start with a resistant to political inhibitors. So just to show patients that progress on vertical inhibitors the prognosis was really bad. But now we have car T cells and we can record some of those patients with cardiac cells. We have other target therapies. But in this is the approach. So beating an inhibitor, the pressure progress so we can do other target agents. We can do chemotherapy. But the goal is to take those places to car T cells if available. Mhm. But so there's this sort of new generation BDK inhibitor and then what percent last year as And then I mean before the presentation said oh my God, another one. Number four B T K. But these are different ones. Mechanism of action is different. And the reason why I'm highlighting this today is because this BDK inhibitor works in those patients that have resisted to the first generation 1st 1st generation BT can inhibit. So so you can see here in blue there is a group of patients that so each bar is what patients, so there are patients the blue the progress on the BDK inhibitor and still you're getting a response. So there's a lot of enthusiasm about uh this new PdK here. We don't have we're going to see seeing more data in the next meeting in a couple of months in december of this year. So in other ways, so we decide target therapy that to myself become a smart, they develop mechanism the system. But then I think we become a little bit smarter and we decide novel therapies that are going to overcome mechanism social system created in this case by by Melinda by medicine inform ourselves. So checkpoint blockade and and let me just go quickly here. So checkpoint blockade didn't work in relapse refractory present Mahajan informal, so the question was a perhaps if we moved this treatment in the frontline setting, we're going to get a better resource. And there's already some I was a background because checkpoint blockade antibodies is now moving to the neo adjuvant setting in the solid tumor space in pace with lung cancer. Colorectal uh is showing very good response activation of the immune system. It makes sense because from nine therapy the patient hasn't been exposed to chemotherapy. So the reform the immune system is in a better shape, right? That the patient will relapse refractory savings, chemotherapy radiation and so on. Then immune system is not going to be in a good shape. So the bill of map is an anti PD one antibody. Uh in vitro studies show that has synergistic activity with the toxin about. So the question is so what would happen if we use checkpoint blockade we? Re talking about for two cycles. And then the patient will go to see a conventional treatment which is R chop for six cycles. Uh This is just to show re toxin up in green plus available anti pd L. One and the pet scan after two cycles. This just to show you after two cycles again. Each bar is one patient and as you can see the body's going down means a response. Uh And using just I mean this is non chemotherapy. This is not a job, it's just anti pd L. One probably talks about the response rate was I would say quite interesting. Uh This is the response on the left after checkpoint blockade, flattery toxic maps uh complete response. Uh And the overall response rates. So now after two cycles of our chopped the response rate increase. And then when you finish your prime in with a checkpoint we talked about followed by six cycles are chopped. The response are even higher and this is just to highlight Or two patients. This one patient credit card that shows generally defined nobody on the left. And then again uh additional so the patient hasn't seen chemotherapy yet is just check point. Harry talks about is completely disappearance on the left. Is a patient with diffuse large B cell lymphoma on the right is a patient with primary media sign that be selling form a large media steiner math. As you can see after checkpoint probably talking about two treatment, fantastic response. Of course this patient needs to go to receive a standard treatment which is six cycles of art. But all that I want to highlight is how a therapy checkpoint that didn't work in the reliable factory setting is showing activity in the frontline setting. And so over the response rate 60% with CR. 21% to eat a checkpoint located plus our prime. And uh just to three. So very exciting news. So finally I think the last few minutes I just want to go through the by specific categories uh targeted. See 20% of hajj informa. So this is one of them more soon. A twosome app. And basically what this entire body is going to do is a bridge is going to attach to that city twenties present visas and also is going to attach to the C. D. Three if President that normal T. Says. And by doing that basically you're bringing these two cells together but also you want to activate T cells and that he says will do is the job of killing the Molina pizza. Right so in carty said you need to get a sense out of the body, manipulate the cells and then infuse themselves back to the patient here. What we're trying to do is manipulate that the cells inside the patient's body. So it's that reason why it's called off the shelf by specific and there are several of them. So you unlike carty says is one treatment. So when you use by specific you have to give several treatments and actually because some of the side effects are similar in terms of uh I mean you can see cytokine release syndrome. You can see neuro toxicity. Uh So we start with a lower dose. I think we step up the dosage of this bi specific antibodies on second number one and therefore second number 28 is a fix those of the market. And then just to show you the data presented at Ash two years ago. I mean these are patients that have failed uh prior treatment. Several treatment and you are able to uh induce uh complete responses in patients with relapsed refractory percent of ocean informa and more importantly, patient that failed car T cells from a patient that failed car T cells do not respond car T cells. Uh The prognosis is not as good but now so we have bi specific antibodies and this is the data that shows that even in patients that have failed car T cells so you can still at least a good response joseph is preceded uh so relaxing factory again, can we move this treatment to the front line uh sitting and you know, so that standard Treatment for patients if you love is an informal are chop time 4-6 cycles. But then there's a group in Australia that they say, hey wait a second. Can we use this by specific in the frontline setting? In early patients that are You know elderly than 80 years old cannot receive our job because products are job might kill them. So can we use this by specific. And the answer is yes. And the overall response rate 63% complete response, 45% durable responses. So what we do normally this patient that early area is what we call mini our job. But perhaps I mean a small study but the point I want to try to make it with immunotherapy that works in the relation factory setting is perhaps it's possible to move them into the front line say so there are different by specific categories. One of them is obscure and they have as you see they have activity in aggressive informa in India and informa a lot of exciting about the by specific category. But again they are also associated with aside country syndrome. Never toxicity. Although the frequency of this side effect is less as compared to car T cells. So by specific antibodies in B cell, non hodgkin lymphoma to me represents uh the future half appearing fortress and heavily P. Three Visa mahajan informa. So they develop can develop CRS and no toxicity but these side effects are manageable. They are available uh of the shell you just write a prescription. It's unlike Mccarty said that there is a self processing and there is a potential for combination of this virus specific antibodies with. Again the question with target therapy with chemotherapy with other uh perhaps other military piece that would be developing the future. And this is the last slide just to highlight the different advice specifics uh Car T cells by specific of the shell card is required Manufacturing process that takes 3-4 uh weeks advantage of car T cell is one treatment by specific is several treatments and the CRS incidents and no toxicity is created with cardi says that with by specific patterns. So it's a lot of information today. I want to thank you for your attention but I am excited. I was part of this uh I would say that the 1st 35 years of treatment of peace and hodgins from uh with target therapy uh uh immunotherapy. I think that I I did my part and now it's up to the new generation of Himalayan sea doctors that we are recording here but also everybody uh to move the field forward. Thank you very much. Hey everyone, thank you for joining us. Uh We have one more question in the Q and a couple of other minutes left. So if y'all have any other questions or comments, please use this time to type them into the chat box. Uh Doctor this I think was more towards the middle of your presentation. But um with all the therapies being used in relapse, are they being moved to front line therapy? Yes. I mean I think this is a very important question I think with I mean there is more and more evidence that is feasible to move uh immuno therapies to the frontline city. I gave you a few examples uh the use of by specific and devoting elderly population that cannot tolerate or receive a standard of care. And we are seeing activity. I mean the question is is this responses are they going to be durable and we don't know that yet. But also open a new window of opportunities because we can say, okay let's combine by specific with toxins or we let a little mine and therefore we are going to be able to treat in this case elderly populations with treatment that are associated with less side effect. And this patient not only going to benefit with the treatment but it's going to be able to maintain his of her quality of life. So another example is so imprudent. So in Bruton if uh started in religion, I was a PDK inhibitors in january, starting the relapse refractory and now they are being used in front line uh patient with CLL uh there was one interesting important study though that's called the window is studied MD Anderson by Michael juan in which he asked the question, can I use the protein is as a frontline therapy involved is an informer and what he did, he said again, going to give two cycles of the protein primary talks about from line Madison informa and just see what type of response am I going to get? And the response rate was close to 99% over a response complete response rate, 85%. So quite impressive response rate. But of course the in the patient needs to go to receive chemotherapy but I think that now we are having hints that yes it is feasible and more importantly it is safe to move target therapy along or immunotherapy along to the frontline setting but also what we are going to be seeing in the future this combination of target therapy immunotherapy in the frontline setting with the goal of perhaps provide more cures uh to this patient B cell malignancies. Excellent. It doesn't look like there's any more questions. So we'll give you all a few minutes back to your day and I just want to remind everyone that I will send you with excuse me I'll send you directions on how to claim your C. M. E. And C. EU. Credits within the next couple of days. But um for now thank you to everyone for joining us and thank you daughter Dr Sotomayor for your time this afternoon. My pleasure. Thank you. Thank you everyone and have a great day. Published October 26, 2021 Created by Presenters Dr. Eduardo Sotomayor Director, TGH Cancer InstituteProfessor, Department of Medical Engineering, College of Engineering, USF
