 Good afternoon everyone. My name is Ana Vallejo. I'm the communications manager of myeloma patient Europe And I will moderate this webinar today I would like to welcome you all to this online session on CAR-T cell treatment in myeloma And I would like also to thank you for joining us today to learn a little bit more about this treatment Well, the main goal of this webinar is to provide an overview of CAR-T cell treatment in myeloma And also an introduction to some of the advantages and challenges that patients need to face in bringing this treatment to the market Just for your information this webinar will be fully recorded and uploaded to the myeloma patient Europe website Which is www.mpurove.org and also to the MP youtube channel and Before I start I would like to make a small summary of the webinar dynamics As you know the webinar is scheduled from 6 to 7 so the presentation will last around 40 minutes And then I will open the session for questions There are two ways in which you can make questions to a doctor one of them is using the microphone in your computer Which is something that I am strongly recommend You just have to press the right hand bottom that you will see in your screen And then I will unmute you so you can make your question And the other possibility is to do that in writing in the question and answer window that you can also see in your screen I will receive those questions and I will read them so the doctor can answer them As you know the talk was going to be given by Dr. Samastaglio, but because of a last minute issues he can attend this webinar So finally this webinar is going to be given by Dr. Matteo Carava a hematology and bone marrow transplantation unit San Rafael Scientific Institute in Milan, Italy on behalf of my alumna patients Europe Dr. Carava, I would like to thank you for your kind collaboration and also for your time And forgive this overview about gut sale treatment Thank you. I met people this kind invitation and on behalf of professor Chichuri I apologize for his absence, but he had a family problem So can you hear me? Yes, I got you perfectly. You can start whenever you want Okay, so today we will speak about new frontiers in immunotherapy for hematological cancers focusing on CAR-T cells so let me go ahead and CAR-T cells are the newest form of cancer immunotherapy and We will address the issue of on what is immunotherapy Why is it all about T cells? What is CAR-T cell therapy? Why are people so excited about it? I have a problem But this is not my computer So what is immunotherapy immunotherapy uses our immune system to fight against cancer and it works by immunotherapy aims at Improving the capacity of the new system to recognize and attack cancer cells and As most of you probably know T cells are key players in immunosystem They are like the pivot of all the immune response the immune system and in particular this Immune the capacity of the immune system to recognize specifically an antigen that is the specificity which characterizes a Bacteria and even a tumor cells is tailored by T cells In particular T cells are cells that generates from the bone marrow from the stem cell which is characterized by the presence of CD-44 Antigen which is in the bone marrow and which can differentiate in T cell and in B cell Which are in many other type of cell but T and B cell are the two group of cells which Confirm specificity to the capacity of our immune system to recognize specific targets T cells develop in the team of during the development and in the shielded and they differentiate in various group which In particular two main type are CD4 positive T cells and this CD8 positive T cells are Cytolithic T cells that eliminates the target by lesion CD4 T cells are the somehow the organizer of the T the of the immune response Be another important line for Which we will not focus today, but we must keep in mind that exist and that was important in our capacity to generate the CAR T cells is the B cell compartment B cells are the one which produce antibodies and various class of antibody in in real life in the body B and T cells strictly collaborate and Cellular responses and antibody responses are somehow coordinated by T cells itself so T cells recognize and promote the elimination of use but they're into more cells each T cells is different from The other in the normal physiology and each T cells as a specific T cell receptor that Recognizes the foreign peptides loaded on antigen presenting cells that are cells which for example during a viral infection Most of you have experienced pain in their throat This is due to the fact that the antigen that is the virus is Captured by macrophages and other cell of the new system is processed and Presented to T cells the T cells Which have the specific receptor to recognize this virus Expands produce cytokines and these cytokines Modulates the end coordinates the response against this virus in order to have an efficient clearance of the pathogen Somehow the same occurs when Immune response against tumor cells are generated Importantly T cells are responsible for the long term memory of infection If We are protected somehow against infection like flu or other flu because other T cells Have encountered the antigen during shoot the voodoo during The last season of flu for example and this T cells persist The persistence of the T cells makes the response against this antigen that we have encountered during Our life particularly rapid and efficiently. This is due to a soup of T cells Which are memory T cells which are antigen specific with the specific receptor which Persist for a long time and even the old life So you can understand the importance to have T cells that are potentially capable to recognize A tumor antigen which persists Due to the life long of an individual T cells can live for years and The memory T cells are those responses for the rapid immune response but If this system was perfect and No tumors or voodoo cure in the real life Tumor which are Autologous data mean that are not like a Bacteria or virus acquired by from the environment but Are press are generated by Cells of the same Individual which monitor the response somehow are very Efficiently in Or should have Hidden themselves from T cell recognition Overwise they would not have developed So The Our capacity to Generate or redirect T cells against tumor Could be particularly important in Fighting cancer and Eliminating it even if the tumor Was able to escape from the original Or the control of our physiological Immune system and T cells There are different phasing in the response that are The encounter with the the virus is captured as I told you by Macrofactor and the process and presented the tool Now if the lymphocyte which expanded as I told you and the coordinated the Productions of antipodes and of CD8 T cells that are capable to Recognize and eliminate the the antigen and after antigen elimination Only memory T cells survives and are ready to fight the ones The potential Pathogen represent T cell Physiological here is represented a city 40 cells as Specific receptor that is here represented that is called T cell receptor Which is has a lot of receptor but the most important and the one which characterizes T cell is this T cell receptor which recognize the antigen that are The Imaginary virus or a party is the virus which is cut in is part in very small part and this specific part are Presented to the T cell through the T cell receptor in the context of a molecule Which is called the MAHC molecule class 2 for city 40 cell which is present on the nitric cell or macrophage the encounter of The specific Epitope in the context of MAHC cell and T cell receptor together with the trigger of Specific signal which are called costimulatory signal lead to the production of IL2 or other cytokine by city 40 cell which Activate the immune response here is the CD8 T80 cells which is an effector cell which are capable to eliminate both the Presenting cell and the cell which are for example infected by the virus or which are tumor cell in case of tumor So you understand how important could be the development of What we call adoptive T cell therapy that is the capacity to instruct T cell of a given individual to recognize a specific antigen this effort Took as taken several years several decades in which in particular for cancer patients This effort was where aimed to Reactivate the capacity of T cell or induce the capacity of T cell to recognize and eliminate the tumor If you search on clinicaltrial.gov You can Find More than ten thousands of studies for cellular Therapies around the world as you can see most of the study are Conducted in the US in Europe and but also in China. There is a growing interest in this in this type of So now let's come to CAR T cell. What is a CAR T? A CAR T is a T cell in which the T cell receptor has been Substituted or even better in this moment maybe in the future completely substituted in this moment is Introduced in the C cells A specific Chimeric antigen receptor The acronym of CAR cell Chimeric which is composed by the valuable part of an antibody And with Costimulatory signals which Demonstrated to be very important in the capacity of this cell and eliminating their target So patient T cells are generally genetically modified to express a car on surface The car which is this receptor the car Binds to its target on cancer cell and the T cell no longer requires antigen presentation to become Active because are activated by the The specific target without the need of actually and the tumor antigen presentation This is an effort which took More than a decade The first generation CAR T Reproduce the original T cell receptor Unvailable part of the specificity of an antigen with ACG free signaling domain This CAR T Didn't work so good and the result whereas the result came when To this construct was combined a costimulatory signaling domain And the second generation CAR T were Prepared data which are available in clinical now derives from the second generation CAR T and of Particular interest from my point of view is the possibility In the next few years To have data from Optimized the generation CAR T are ready for the fourth generation CAR T Which are which were designed according to our knowledge of immunotherapy So we can data now about second generation CAR T, but third and fourth generation CAR T are ready Or are going to be ready to do for clinical testing So CAR T cell therapy Which most of the data about were conducted on the few large B cell lymphomas and Acute lymphoblastic leukemia and in particular Were conducted with CAR T which were Constructed against a B cell antigen to fight these B cell malignancies Where CAR T is where a big effort because requires the removal From the blood of the patient of T cells Then T cells should be engineered in laboratory And it should be insert the gene for CAR in this CAR T And so that they can express the chimeric antigen receptor These cells should be expanded in the laboratory then should be sent back to the Clinic and infused in the patient where they expand and go directly to recognize The cell in the cancer cells Which express the antigens against which The engineer the receptor was introduced in them So in the real life what does it happen There is an outpatient and possibly an outpatient And sorry I go back of one slide because there is another point which is particularly important As you can guess from this slide this process requires time Now it requires around 4-6 weeks in which the patient should remain somehow in acceptable condition To receive this therapy which as we will see may have an important toxicity And the disease should remain somehow controlled by the possible therapy In order to have that the patient condition do not deteriorate too much in the period in which the CAR T are prepared So in the real life a potential patient Should be carefully selected and first of all should have an indication that is a disease for which a CAR T existed That is capable to recognize the cell of this disease or potentially recognize this place Then the patient should be carefully evaluated for eligibility That is we must find out a patient who can probably not only benefit from CAR T but also can make all the procedure visible That is condition are good enough to face this complex and time requiring process Then if the patient is judge a legible, a leucopharyngeal schedule and in which the T cells are collected These cells are shipped to the manufacturing It takes 4-6 weeks for preparing the CAR T and the CAR T are sent back to the center And infused by a central venous cotator after that the patient has received a conditional chemotherapy Which is aimed not at controlling the disease itself Most of the studies were conducted in patients which were chemorefractory or relapsing after chemo But to reshape the immune system and the T cell repertoire in order to be able to accept the CAR T cells And let these cells expand and work in the best condition as possible After this therapy, which is made mostly for most of the protocol by Fudarabin and Cyclo-Postamin At day zero after premedication the CAR T is infused Then the patient, at least in most of the European center but even in the US Should remain under strict control in the first week Because two major complications have been associated with the activation of these T cells And probably are a direct consequence of these T cells Which are related to the release of cytokine by this T cell And in fact what it has been observed is a cytokine-releasing syndrome In the medial onset of this syndrome is two days after CAR T infusion The release of cytokine is also associated with medial delay of 5-6 days from infusion of CAR T by neurotoxicity Other known toxicity were also reported but the two main toxicity are neurotoxicity and cytokine-releasing So going back to what happens after CAR T infusion Here is the CAR T from the blood goes to the tumor site Recognize the antican and produce cytokine that eliminates tumor cells The production of cytokine induces CRS syndrome which occurs in most of the patients who receive CAR T And the most frequent expression of this syndrome is high fever Fever itself is a physiological response to virus or bacteria And due to the release of cytokines by the immune system In this case the second I released by the CAR T that we infuse and go to their target Recognize it, release cytokine lead to fever, pneumonia, malase, heart failure, edema But also potentially life-threatening symptoms like hypoxia, pulmonary edema, capillary leak, hypotension And almost all organs may be target of this complication Which can be also associated with encephalopathy These are data and neurological and neurological symptoms These are the two products or which there is the greater experience This is chymriam from Novartis and yeskarta from Kaita in the fuselage vision lymphomas and acute lymphoblastic leukemia Also other toxicity are possible after CAR T, in particular tumor-lase syndrome Which is somehow expected or may occur after tumor recognition by the CAR T which eliminates the tumor Of course infection, most of you as you know patients with myeloma for example are prone to infection due to their hematological condition Also allergic reaction and then other that we call on target of tumor toxicity That is the possibility that CAR T eliminates all the cells that express the antigens against which they are directed So if this antigen is for example expressed by a normal counterpart, this counterpart might be eliminated by the CAR T And it is even possible that he is eliminated by the CAR T For example CAR T against CD19 eliminates also CD19 positive B cells which are not malignant So why are people so excited about CAR T cells? There are about more than 700 CAR T, more than 160 trials have been completed and 300-400 trials are enrolling A lot of trials are under preparation, most of the data are so far are on targeting of CD19 Which is I told you before is expressed by acute lymphoblastic leukemia, lymphoma chronic lymphocytic leukemia, LTB cells In myeloma most of the data available which are much more limited that those about CD19 are about the BCMA CAR T BCMA is an antigen expressed by plasma cells And the number of patients is not so big as for CD19 patients but the results which have been recently published on the most important Journal in medicine which is known around the Journal of Medicine are very very interesting Trials have most of the trials that are currently available are quite small and have been generated as I told you on the Salma lineas These are the impressive results that were granted by the Brexpo approval of this therapy by FDA and EMA on acute lymphoblastic leukemia and non-oxygen lymphomas In patients who did not have therapeutic alternatives Many other targets as I told you are under investigation The result of CD19 therapies led to the approval of two products, one from Novartis, Kim Ray and the other from Gilead Yes, Kata, on pediatrics and young adult patients up to 25-year-olds who fail to sell acute lymphoblastic leukemia Refracts or relapses for transplants, or in second rate relapses, or patients with diffusory lymphomas after two or more months Yes, Kata was granted and approved for diffusory lymphoma from her primary mediation therapy after two or more months of systemic therapy The most data on CAR-T available in clinic are those on advanced patients who had poor therapeutic alternatives I would like to point out because many times I am asked if there is a CAR-T self-therapy available, for example myeloma or something else As I told you before, the specificity of CAR-T may lead to several results which can be very different We cannot take per se the result from Kim Ray or Kata and say if I take a CAR-T from myeloma, I will have the same result of these two drugs Exactly with monoclonal antibodies, the specificity of these products may lead to different results And either the characteristic of the product may lead to different results So each product should be, on my point of view, really tested in clinical trials and the results should be validated And moreover what I would like to point out is that these results are from what we call in medical research phase two trials That is trials which were not directly of comparison with the best available therapy in the moment Because these patients received so bad promises that the results have been observed with these two products were judged good enough to introduce them in the market But we lack data really on a large number of patients and we lack data on long-term follow-up Which should be carefully observed in the context of CT-19 and should be generated for all other types of CARs What makes for me a lot of fantasies on this therapy is the possibility to improve and work on the mechanism in order to make this therapy really a step up in our capacity to fight potentially a lot of disease But in this moment I should say potentially So going to relapse refactoring myeloma, some combination drugs, standard for treatment of myeloma may not be effective for particular people as you know And maybe it is necessary to try new combination For some people a treatment that worked well earlier can be repeated with good result The same reasoning applies when a treatment that has been effective no longer appears to work for well known as refactoring myeloma The first time a relapse happens most people will be given more take from it It is usually given in combination with the steroid, the metazone and often with chemotherapy agent like cyclopostramine or Melfan as most of you probably know The drug must often given at a second relapse is renalidimide Usually in combination with the metazone and cyclopostramine, alternatively it may be possible to have a second stem cell transplantation Carfliton is approved in both US and Europe for treatment following a third relapse A number of other new treatments have recently been approved or under consideration to use for relapsing or refactoring myeloma such as paladino stathe, tubumab, Vagvomib and other tubumab And some of these drugs are really important result of impressive data So the patient with myeloma has many therapeutic options in this moment Probably it is still difficult to achieve an eradication in the cure of myeloma but the myeloma can be kept under under under under controlled for many for many years For this reason, CAR-T cells have been tested in multiple myeloma In particular, most of the studies have been conducted with BCMA CAR This CAR is directed against this antigen which is expressed mostly on plasma cells with an important overall response rate It was about 80% according to the study but as you can see in this tab, most of the first messenger not so much patients have been treated This is a study on a relatively small amount of patients, 24, 25, 43, 55, 7, 12 So not many patients have been treated yet with this kind of CAR No direct comparison with other treatment, I have been conducted but a promising overall response rate was observed in advanced patients Moreover, the construct of this CAR was different There are CAR which has some types like CD28 of costimulatory molecules other with 4, 1, 2 So a work is in progress, I would say In this field, these data are very interesting and promising And should be evaluated and are more careful and further evaluation So some of the targets that are in the investigation, as I told you before, BCMA CAR is the one which has been most investigated Then there is CD19 We are working on preparing a trial against CD44D6, which is a molecule expressed in myeloma This is a phase 1 trial There are interesting initial data on targeting CD38 Which is the same antigen which is targeted by Daratumab Work is in progress on taxi But what I would like to say is that you cannot take the promising data on BCMA CAR and say that CD44D6 CAR is the same It's not the same because on this CAR, for example, there are available data on about more than 100 of patients No patients have been treated yet, like on the few ones on this one So the CAR may have a different grade of the mechanism and the type of drug is similar But changing the antigen, the result might be and the benefit and the risk might be different BCMA CAR T-Lesson, clinical manifestation of CRS and neurotoxicity reported in different CAR T-T cell trials in multiple myeloma patients Were similar to those observed with CAR T-C and against CD19 The clinical efficiency of anti-BCMA CAR is very interesting It's very promising Moreover, this is important because the CD19 paradigm can be extended to other antigen And the BCMA CAR offered the first proof that multiple myeloma is generally and potentially treatable to CAR T-C cell therapy Two years ago, we could not say this We are part of a European grant group of a group which was granted by European grant of the Caramba-Consoxum Which is coordinated by the Google University And is an academic CAR T-T directed against SLAMF-7 And which is prepared by Sleeping Beauty Clean Transplant for immunotherapy in multiple myeloma 10 partners are participating to this project, 6 European unit countries Which are close in collaborating to transfer the CAR T-Breakthrough therapy from base to bedside The University of Rup-Bur is the co-ordinating centre The target molecule was chosen based on the fact which is uniformly expressed on all multiple myeloma cells in every patient And the Caramba will be the first clinical trial to target SLAMF-7 This CAR T-T is, from my point of view, a particular intrigue for the fact that Normally CAR T-T, most of the CAR T-T which have been tested in clinical were generated by lentivirus mediated or retrovirus mediated gene transfer For this CAR T-T, Sleeping Beauty technology was used that is an economic and sustainable medicinal product which is virus free And there are safety switch that can be triggered to deplete the CAR T-Cell The CAR T-Cell constructs against SLAMF-7 in order to switch off the cells in case of toxicity Because every time we test a new target, a new antigen as a target we should keep in mind to observe on target of tumor toxicity or other unexpected toxicity So to have mechanism to which of this toxicity is also important A phasor and clinical trial is under preparation and in advance phase of development Which clinical side will participate to the trial and can be contacted for information? The University of Liverpool in Germany, Pamplona, Spain, Milan, Italy and the Central Hospital Regulatory at the University of Berlin What next? So first of all, next there is the trial from my personal point of view and looking at our center Next is the trial with SLAMF-7 and possibly CD44-6 In particular, both of these trials should involve patient with multiple myeloma When they will be open for enrollment and this is the next step These both are phase one trial, first in men, that means that the aim of this trial is not efficacy but the toxicity and the feasibility of this CAR T-Cell therapy in men And then if this part is the dospine feasibility and the safety is good in the first part of the trial Then they became a phase two trial in the act of serving and reporting the efficacy So this is the next step Future direction Based on the fact that anti-BCMA CAR T-Cell I have demonstrated or I suggest the efficacy multiple myeloma The main challenge are to improve the duration of response and understand the resistance mechanisms Because most of the patients tend to relapse even after BCMA CAR T-Cell therapy Many advances in CAR T-Cell therapy for multiple myeloma will come from general advances in CAR T-Cell technology What I would like to point out is that is CAR T-Cell technology itself as I told you before A step up from my point of view in the therapeutic possibilities of our patient Then is probably like the first mobile phone if some of you remember They were so big mobile that we laughed when we look at them with an iPhone X So I think that in the CAR T-Cell are somehow in the same condition We are at the beginning of a new era And there is a lot of work to do The CARamba project as I told you is part of this big order which is going to open in the next few years We must keep in mind that standard multiple myeloma therapy improves So the position of CAR T-Cell in this context is to be determined In increasing complex landscape of multiple myeloma therapy Nobody knows now if it is better to target BCMA with a CAR T-Cell or with a B-specific antibody Of course once the data are mature it will be very intriguing to know whether it is better to stimulate the immune system With a B-functional antibody or directly provided to the patient Specific T-Cells directed against the antigens Thank you for your attention Thank you very much for this wonderful explanation about CAR T-Cells Now I will open the floor for questions Just to remind you that there are two ways to make questions One of them is using the microphone in your computer by clicking in the right hand bottom Or just you can just write your question in writing in the Q&A window Which is something that some people are already doing One of the first questions that arrives during your presentation is why chemotherapy if not transplantation is required? Because before CAR T-Cell I guess So because the CAR T-Cells are infused in a context of all other T-Cells Among these T-Cells there are also T-Cells that maybe have a new suppressive effect So it has been observed that depleting the T-Cell repertoire before CAR T-Cell infusion provides better results This was also observing the context for example of allogenic transplantation When we give donor line for site infusion The preparation of the patient with chemotherapy directed in order to modulate the immunological environment Provides a better activation of the T-Cells that we give to the patient Thank you very much This question is from Jaime Cooper which wants to do the question through the microphone So I will unmute you so you can just make your question Go ahead Hello Jaime Cooper I unmute your microphone so you can just make the question to the doctor Well I'm not sure if he's listening to me I cannot listen to the question Well we are going for the next question and if you want to ask again then we will give him the floor So the next question is in England for a child with acute lymphoblastically eukemia received CAR T therapy on the NHL And the treatment is made available to another lymphoma patient Is that the first time it's being used CAR T? For what? For another lymphoma patient? Lymphoblastically eukemia Sorry it's made available to another lymphoma patient So most of the data that are currently available comes from TAYAL in lymphoblastically eukemia and B cell lymphoma So the original patients were the first data were generated at the Pennsylvania University in US Thank you very much The next question is the data on CAR T in myeloma is good but it is incurative Do you think it will work better used in earlier stages of the disease? This is a very important question And I personally think yes but it should be proved This is a very very important question It should be addressed in lymphomas in the field of lymphomas on which there are more mature data What is going to be done is to test this therapy in an earlier phase of disease Because this is an important scientific and clinical question Well thank you very much The next question is what are the reimbursement challenges with CAR T and how can we overcome this? I don't know Very good question I think This is a good question I don't know the answer Okay For the next question I hope that with improving the technologies that the price will go down But of course this may not be one of the biggest questions I must leave in a few minutes unfortunately So it's time probably for two or three questions Okay then I'm going to ask you the last question Will patients still need a hematopoietic stem cell transplantation after CAR T cell treatment? CAR T cell infusion Okay you do very very good questions My answer is again I don't know This also should be tested It should be also tested if the different type of CAR T Because the CAR T as I told you before are not the same There are CAR T which have been found in the body at medium term Whereas there are CAR T which disappear from the blood And is this the same or not in case the CAR T disappear the transplantation in the other case no In both cases yes So my answer is I don't know We have two preliminary data to answer this question But this is a point that should be addressed by clinical plan in the next years Okay thank you very much We are running out of time so we don't have time for more questions But if you have more questions you can send them to us And we will make sure that those questions are answered by our specialist Thank you very much Dr. Kava for being in this webinar for giving this talk Just remind you all the attendees that this webinar has been recorded and it will be available in the MP website And also in our YouTube channel Thank you very much Dr. Kava Thank you, bye bye