Chapters Transcript Video Cellular Therapy for Diffuse Large B Cell Lymphoma right. Hi, I'm Dr Christine Ho. I'm one of the system professors of Ecology on the transparent cellular therapy team at Roswell Park Comprehensive Cancer Center. And today I will be talking about exciting topic of seller therapy for diffuse large B cell lymphoma. So non Hodgkin's lymphoma is 1/7 leading cause of new cancer cases in the United States. NHL accounts for approximately 3% of cancer related deaths in the U. S. There are several subtypes of NHL, including the fuselage B cell lymphoma at the most prevalent at 32.5% followed by follicular lymphoma at 17.1% and Mantle Cell lymphoma at 3 to 5%. Within the subtype of diffuse large B cell lymphoma, there are several other subtypes that associate with higher risk disease, including MK Rearranged, the L BCL High Grade B cell lymphoma with Mick BCL two or B sell rearrangements and activated B cell D L BCL. So for those patients who are diagnosed with a few sort to B cell lymphoma, two typically undergo front line chemotherapy, and about 60% will achieve a cure. However, about 40% will have relapse refractory disease for those who relapse refractory disease, they will typically undergo salvage chemotherapy. For those who are chemo sensitive, they will typically undergo autologous stem cell transplant. But for those who are chemo resistant, they can potentially qualify for car T cell therapy, which will be the focus of my talk today. So I'm going to start off with a brief background of car T cells. This slide shows the anatomy of a car T cell, which is comprised of three domains. The actor domain is the antigen recognition domain. Formed from a single chain variable fragment form from the antigen binding regions of both heavy and light chains of monoclonal antibody, this region will typically have high affinity and specificity for its target. The active domain is then connected to a trans membrane domain, which is then connected to the end of domain, which is the signaling domain derived from CD three, which will ultimately transmit activation and co stimulatory signals to the T cells. So over time there have been several generations of car T cells that have been developed. The first generation card T cells on Lee have a CD three signaling chain, but show limited efficacy in clinical trials due the lack of long term T cell expansion. This led to the development of the second generation car T cells, which used the first generation cars at the backbone and includes an additional coast military domain. So now there are two signals to activate the T cells. These T cells have been shown to have enhanced persistence and proliferation compared to the first generation cars and have shown to have clinical efficacy with several disease types. The third generation car T cells have a CD three domain along with two coastal military molecules, and these have been shown to have enhanced clinical efficacy in the car T cell therapy process. The patient will typically undergo local for Isis as the first step where the T cells are isolated from the patient, the T cells and then engineered to express cars that will recognize certain tumor antigens. These modified T cells and then grown and expanded and culture and will ultimately be infused back into the patient alongside Olympio depleting chemotherapy regimen, which will serve to reduce T rag mediated inhibition and enhanced production of cytokines that will favor expansion of the infuse cells. So as of February of 2020. There have been several cellular products that have been approved for the treatment of diffuse large B cell lymphoma. The first is Tease a cell, also known as camera, which is produced from Novartis. In August of 2017, it was approved for relapse refractory B Cell Precursor, A L L for pediatric or young adult patients less than equal to 25 years old. In May of 2018, it was approved for adult patients with relapse refractory large B cell lymphoma after greater than or equal to two lines. The systemic treatment the next product is actually sell. Also notice Yes Carta, which is produced by Kite. And in October 2017 it was approved for adult patients with realized refractory large B cell lymphoma after greater than or equal to two lines of systemic treatment. And lastly, we have Liza's all produced by B. M s, and as of February 2020 it had FDA party review for relapse refractory large basil informa. So I'm going to start off by describing the clinical trial that led to the approval of ACSI Cell for relapse refractory large B cell lymphoma published in The New England Journal of medicine. So this trial is called Azuma one trial. So in the phase one portion of this trial, a total of seven patients with refractory the fuselage B cell lymphoma, primary media cycle B cell lymphoma and transformed follicular lymphoma were enrolled. The results showed that access L could be centrally manufactured at a minister safely. The overall response was seen in five patients with a complete response seen in four patients in ongoing CR was seen in three patients at one year. This led to the development of the face to portion of this trial, where a total of 101 patients were enrolled. This trial was split into two cohorts with cohort one enrolling Onley, refractory deal, BCL patients and Cold War to enrolling refractory primary media, stand up yourself lymphoma patients and transformed follicular lymphoma patients. Refractory disease was defined as progressive or stable disease as the best response to most recent chemotherapy or disease progression or relaxed within 12 months after autologous stem cell transplant. The conditioning regimen that was used consisted of flu Dara being at adults of 30 mg per meter squared and cyclophosphamide at 500 mg per meter squared on days minus five minus four and minus three. Access L was administered at a target dose of two times, 10 to the sixth per kilogram on day zero. So we regard the patient characteristics that were enrolled in this trial. On the charts of the left, a majority of patients have received greater than or equal to three lines of therapy. 26% were primary factory, 77% were factory toe last therapy, 21% had received a priority target stem cell transplant. A total of 111 patients were enrolled. Access A was manufactured for 110 patients but a minister to only 101 patients. And the reasons why patients did not receive the product where that one had unsuccessful manufacturer four had adverse events. One died from disease progression, two had unmeasurable disease, one had sepsis and one died. For multi factorial issues. The medium time from local four aces to delivery of actually saw to the treatment facility with 17 days. The primary endpoint of this trial was the rate of objective response, which was defined as the combined rates of complete response and partial response secondary and points included duration of response progression, free survival, overall survival, incidents of adverse events and the blood levels of car T cells Inside. In serum side of kinds, Cytokine release syndrome was greeted by the league criteria, and the media follow up was 15.4 months. So in regards to results at a minimum of six months of follow up, the objective response rate was 82%. The complete response for it was 52%. The medium time to response was one month and the medium duration of response was 8.1 months. Response rates were consistent across Kiko variants, including age disease, stage it be scored presence or absence of bulky disease, cell of origin subtype and the use of total is a mob or steroids in regards to results. At a minimum of one year follow up, the overall response was 82%. The complete response was 58%. The medium duration of response was 11.1 months and as you can see from the chart to the left, the medium duration of progression free survival was 85.8 months and on the truck to the rights the media all over survival was not reached. In regards to adverse events, 100% of patients experience an adverse event of any grade, with the most common being Pyrex CIA, 85%. Also, common side effects included, decided Pena's of neutropenia anemia and thrown beside a pina. Other comment Adverse events that were experienced include decided kind release syndrome and euro toxicity, which I will go through in the next slide. So regards to CRS the most common symptoms of CRS of greater than or equal to great. Three. What. Pyrex AEA, hypoxia and hypertension. The time to onset of CRS was two days, and the medium time to resolution of CRS was eight days. As you can see from the chart to the left, a majority of patients at 93% required treatment with total is a map and 43% required treatment with steroids, 13% required raise oppressors and 17% required ice. You admission. Despite that, all events of Sierra's resolved except for one event of great five h l H. In one event of great five cardiac arrest. In regards to neuro toxicity, the most common neurotoxic city events are greater than equal to gray. Three were in simple apathy, confusion all state a fada and somnolence. The medium timeto onset of neuro toxicity was five days and the medium time to resolution with 17 days after infusion. As you can see from the chart to the left, 64% experience all grades of neuro toxicity in 28% experienced great three or four neuro toxicity. And despite that, all neurological events resolved except for four months in regards to expansion and biomarkers, car T cells re peaked in the peripheral blood. Within 14 days of infusion, car T cells were detectable in most patients. At 180 days after infusion, an expansion was significantly associated with response. With a P value of less than 0.1 Peak expansion was significantly associated with neurologic events of greater than or equal to great three, but not with the RS in serum biomarkers that were associated with euro toxicity and CRS included Aisle six, I'll 10 I'll 15 and Grand Zombie, so in guards to conclusions. Responses were ongoing of 42% of patients, including in 40% with a CR with a medium follow up of 15.4 months. Some patients converted to a CR as latest 15 months after treatment. Ongoing durable remissions who observed as far out as 24 months and the overall survival rate was 15 52% at 18 months. Although the medium over Ceravolo had not been reached, CRS in or toxicity would generally reversible and the use of total is a map or steroids did not affect over responses. So this trial concluded the access L is an effective and safe treatment option for patients with relapse refractory large B cell lymphoma after at least two prior therapies. So next I'm going to go into the clinical trial that that led to the approval. Tease a cell for patients with adult with relapse refractory large B cell lymphoma, also published in the New England Journal of Medicine. So this is an open label, multi center international Phase two study of teas, a cell. The eligibility criteria were patients who have previously received at least two lines of therapy, including the toxin and anthrax. Cycling patients had either had a relapse after or ineligible for autologous stem cell transplant, and patients had relapse refractory d L BCL d o B. Still transformed from follicular lymphoma. High grade B cell lymphoma with McCoury Arrangement Plus plus rearrangement of BCL two BCL six or both genes. Patients who were excluded from this study included patients with a diagnosis of primary media, son of the diffuse large B cell lymphoma. Patients who had prior treatment with City 19 directed therapy or have had a prior AL a genetic transplant. And patients with active CNS disease. So, following informed consent, patients typically underwent local for recess for this trial, Bridging therapy is allowed if needed. This is followed by conditioning, chemotherapy and physicians had a choice of either the combination of flood Aravena cyclophosphamide or single agent venom. Osteen. And this is followed by to the cell infusion so that for the patients who are enrolled in this trial, a majority of patients had received multiple lines of chemotherapy. 45% have relapse. After last therapy, 55% had refractory the L BCL A 49% had a prior autologous stem cell transplant. Prior to infusion, 92% of the patients received bridge and chemotherapy, 73% received Ladera being and cyclophosphamide, 20% received by the machine and 100 11 patients received an infusion of teas itself. The primary and point of this trial was the best overall response rates, defined as a combined percentage of patients who had a C R or P R secondary endpoints included the response duration, overall survival, safety and cellular kinetics. And there was also an exploratory analysis consisting of the evaluation of biomarkers. In regards the results, 93 patients were included in the efficacy analysis. Thes patients had greater than or equal to three months of follow up. The best over response for it was 52% with a complete response of 40% and a partial response of 12%. A conversion from partial to complete response occurred in 54% of patients, with some occurring 15 to 17 months after the initial response. Among patients who were in a CR three months, the estimated probability of remaining in a CR at 12 months was 81%. Response rates did not differ across major demographic or prognostic subgroups. The medium duration of response was not reached. Durable responses were observed for up to 18.4 months after infusion, the median progression. Free survival was not reached. For patients in a CR, the estimated rate of progression free survival a 12 months was 83%. For patients who had a C, R or P R at three months, the media Malvo survival was 12 months and the estimated probability of survival a 12 months was 49% for all patients and 90% for patients in a CR persistent car. Transition levels were detected for up to two years after infusion. In patients with durable responses, clinical responses were observed across barriers. Doses for both responders and non responders, expansion, concentration and medium time to maximum transition levels were similar in regards to safety, the most common adverse events of any grade was see arrested, 58% anemia at 48% and fever, a 35% medium tone from infusion to onset of CRS was three days and the medium duration with seventies and patients were typically treated with either total is map alone or a combination of total is a mob plus steroids. Nora toxicity occurred in 21% of patients with a medium duration of 14 days. Nine patients with great three or four neurologic events also had conquering CRS, and the treatment consisted of a combination of supportive care plus steroids. So in regards to the conclusions, durable responses were seeing what they used to t the self for adults with real after refractory d l BCL, the best overall response rate was 52% in long term persistence of Jesus. L was president for up to two years. So the conclusion of this trial was that he's a cell is an effective and safe treatment option for patients with relapse or refractory large B cell lymphoma after at least two prior therapies. So for the next few sides, I wanted to show you a comparison between the two commercial products for diffuse ought to B cell lymphoma so that you have a better understanding of the differences between two products. So, currently, the U. S FDA indication for access l includes D l BCL primary media, son of B cell lymphoma, high grade B cell lymphoma and if you start to B cell lymphomas arising from particular lymphoma. This is in contrast to tease a cell where the only indication for use currently is for diffuse large B cell lymphoma in regards to the info depleting chemotherapy for actually sell. We're currently using food A Rabin with cyclophosphamide, as opposed to tease the cell with physicians have a choice between the combination of fluid Rabin and Cyclophosphamide versus Bend amassing alone. Bridging therapy is not allowed for XSL, whereas it is allowed for tea is a cell in regards to the patient characteristics. They were pretty comparable between the two products with most patients haven't received multiple lines of therapy. Majority of patients having primary factory disease and refractory to the last therapy and patients haven't had received the prior autologous stem cell transplant. So regards the survival rates for both products for actually sell the 18 month progression free survival was 40% versus 64% for tea is a cell and the 18 month over survival for access L was 53% vs 43% for tea is a cell and most importantly in regards to toxicities, looking at both sides kind of release syndrome and euro toxicity for actually sell. The majority of patients required either treatment with total is a mob or steroids, and 93% and 43% respectively, This is in contrast to tease a cell where 58% received treatment. Total is a map and 16% treatment with steroids. So in regards to neuro toxicity, a significantly higher proportion of patients experience no toxicity of all grades or grade three or four. No toxicity for actually sell at 64% in 28%. This is in contrast to tease a cell where 20% experienced all grades of neuro toxicity and 11% experienced great three or four in a row toxicity. So although these two products are currently commercially available for the treatment of the few source to be cell lymphoma, there still areas of ongoing research, including a comparative analysis off Axis L vs TSL Clinical outcomes between patients who are transplant naive versus post transplant infect his complications and patterns with car T cell therapy. Prolong side opinions with car T cell treatment and toxicities of car T cell treatment, including risk factors and management. So for the last few sides, I'm gonna go over the unique toxicities associated with car T cell treatment and talk about the management associated with each. So these toxicities will include cytokine release syndrome, and neuro toxicity so Santa can release syndrome is the most common toxicity and adopted T cell therapy. It typically occurs within a few days to a few weeks. Post T cell infusion. The instance. Time of onset and severity can vary between different T style products. The PETA physiology of of CRS is thought to be triggered by T cell activation, along with the activation of other immune cells such as macrophages and dendritic cells. In CRS, there's certain elevation seen in certain side of kinds and CRS, including I'll six I'll to interferon gamma and GM CSF in certain accused Face Reactions are also seem to be elevated. The Sierras, including ferreting and C reactive protein. A risk factor for severe CRS is disease burden, so the higher disease burden the higher the risk for severe CRS in regards to presentation. It can range from mild constitutional symptoms such as fever, malaise, biologists and anorexia to more severe life threatening symptoms. Such a circulatory shock requiring pressure support D I C. And aired Yes, see your arrest can affect any organ system, including cardiovascular, respiratory, renal, Humaita, logic, G I and nervous system. The correlation between development of CRS and clinical primers currently is in perfect, so there is a need to identify predicted by predictive biomarkers. There does not seem to be a correlation between the severity of CRS. It's a clinical response, as I mentioned before. They are CRS can affect any organ system in the body, producing a multitude of different symptoms. And so the patients have to be very closely monitored for any potential signs of CRS and treated appropriately if CRS is suspected. So when guards The CRS Management Toes Elizabeth is currently the first line agent used in the treatment of CRS. Total is a map is a humanized monoclonal antibody against the Aisle six receptor I'll six has been shown to be elevated in the serum of patients with CRS and is the main driver of the manifestations of CRS. Total is a map has been shown to effectively aggregate car T cell induced cytokine release syndrome without impairing the activity and efficacy of the T cells. In total is, um Abdo sing and timing of administration varies between centers. Furthermore, systemic steroids can also effectively alleviate symptoms of CRS. There is theoretical evidence that indicates that steroids may interfere with activity of the T cells, especially when given prior to T cell infusion. So our practice is to avoid steroid administration prior to see cell infusion and our practices to utilize steroids with persistent signed the symptoms of Cirrus while receiving total ism of following t cell infusion. So the key points of Sierra's are that early management of CRS is crucial for preventing progression to severe life threatening CRS. Total is a mob is the first sign agent used to treat cirrus and systemic steroids can also be administered, if not responsive to total is um um now moving on to neuro toxicity. Neurologic toxicities can occur con currently with cirrus or can occur alone. The path of physiology is unclear, but hypotheses include the trafficking of T cells into the CNS or did the future of cider kinds into the brain. No toxicity could occur shortly following T cell infusion or a few weeks afterwards, and direction can also vary from a few hours for a few weeks. The management no toxicity differs from that of Sierras in that the therapeutic agent should be able to effectively penetrate the blood brain barrier. Monoclonal antibodies such as total is a map may not have any beneficial effect, whereas Dr Methadone is often in the agent of choice, given its effective CNN's penetration in regards to the signs and symptoms of neuro toxicity. There's also a range of symptoms ranging from relatively milder symptoms of attention deficits. Language the serpents is impaired, hair writing to more severe symptoms of seizures, mental, a foundation and cerebral oedema. The A S P M T. Created in Icann's consensus of grading for adults with neuro toxicity, which includes several factors, including the ice core, the level of consciousness, the presence or absence of seizures. Certain motive findings, including Hemming Parisse, is a pair of paralysis and the presence or absence of elevated intracranial pressure or cerebral oedema. So patients are monitored very closely for these symptoms, possibly to potentially detect neuro toxicity and, if detected nor toxicity needs to be managed appropriately. So if you're a toxicity is expected. Work up will typically include obtaining imaging of the brain with either Emery or C T, obtaining a lumbar puncture for CSF analysis. Performing egg, typically in conjunction with the initiation of anti epileptic and no toxicity, is typically managed in a multidisciplinary fashion with consultation with our neurology colleagues and, if needed, r I C U colleagues. So in regards to the management of neuro toxicity, total ism of treatment may not have any beneficial effects, whereas Dixon methadone is recommended for neurotoxic see treatment. Steroids can be tapered with improvement or resolution of north toxicity, but the optimal duration of Syria treatment is unknown. And even with resolution of symptoms, patients should be monitored very closely for recurrence of neurotoxic symptoms during the Syria taper. If patients are not responding to either steroids or flair with the decks, taper additional agents for no talks to see. Treatment includes tax map and and and a kima, both of which have seen US penetration. So the key points of car T cell therapy are the car. T. Cell therapy is exciting. Your treatment for the few source B cell lymphoma. We must be able to recognize and promptly treat the unique toxicities Cartoons saw therapy. A multidisciplinary approach to management of Carty saw toxicities is important, and as we gain more experience with the use of T cell therapy, it is very likely that our treatment regimens as well as algorithms for the treatment of T cell toxicities will continue to evolve and improve. So that's the end of my talk. Thank you for watching. 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