Cytokine Release Syndrome Symptoms Research Articles

Use of bispecific antibodies (BsAbs) in community practices: Key attributes to develop logistics and workflow for management of cytokine release syndrome (CRS).

e13575 Background: Establishing workflows to monitor and manage CRS in community practice settings presents unique challenges that may not be encountered in more specialized centers. Real world experience was gathered from OneOncology specialists to understand key steps, common challenges, and best practices to establish CRS workflows in community practices. Methods: Qualitative data were gathered via a 90-minute focus group and follow-up interviews. Participants were MD or PharmD community heme-oncology providers in physician-owned practices with 10-20 physicians. As of January 2024, participants had treated over 30 patients with commercially available BsAbs. Theme matrix techniques facilitated data analysis and presentation. Results: Catalysts for developing CRS workflows were the addition of BsAbs to the practice formulary, identification of practice leaders willing to drive protocol development, and education of clinic and hospital staff who would manage patients treated with BsAbs. Key steps in the workflow included defining lines of communication within the practice during and after office hours, designating leads to oversee staff training, and creating practice-specific management plans. A process for potential inpatient admission for moderate/severe CRS was developed in collaboration with hospital administrators and nursing leaders. Lines of communication between the treating practice, pharmacy, and hospital care staff before, during, and after treatment were established, and methods to ensure availability of necessary medications were identified. Finally, patient support and the logistics of patient/caregiver education on BsAb therapy, symptoms of CRS, and how and when to access care was highlighted. Conclusions: Use of BsAbs in the community requires thoughtful coordination between oncology practices and hospitals. Keys to success include defining flexible, practice-specific workflows for managing CRS, transitioning patients efficiently from clinic to inpatient setting, and careful training of staff, patients, and caregivers. [Table: see text]

Reduced Cytokine Release Syndrome and Improved Outcomes with Earlier Immunosuppressive Therapy in Haploidentical Stem Cell Transplantation

The optimal timing of immunosuppression and post-transplantation cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) is unknown. However, cytokine release syndrome (CRS) following haplo-HSCT is associated with worse transplantation outcomes, and the incidence of CRS may be affected by the timing of immunosuppression and PTCy. In this study, we compared CRS and other transplantation outcomes in 2 cohorts receiving different immunosuppression and PTCy schedules following haplo-HSCT. This was a retrospective cohort study of 91 patients who underwent haplo-HSCT at the Intermountain Health Blood and Marrow Transplant Program. The original or standard haplo-HSCT GVHD prophylaxis regimen included PTCy on days +3 and +4, with mycophenolate mofetil (MMF) and tacrolimus starting on day +5. The modified regimen adopted in November 2020 changed PTCy to days +3 and +5, with earlier introduction of tacrolimus and MMF, on day -1 and day 0, respectively. Grade ≥1 CRS occurred in 32% of patients in the modified regimen, in 82% of patients in the standard regimen (P <.0001), and 65% overall. Likewise, grade ≥2 CRS was lower with the modified regimen (16% versus 57%; P = .0002). The mean duration of CRS symptoms was longer with the standard regimen (3.14 days versus 1.44 days; P = .0003). The incidence of acute graft-versus-host disease grade III-IV or extensive chronic GVHD (cGVHD) at 1 year was lower in the modified regimen (6% versus 32%; P = .0068). No differences between the standard and modified regimens were seen in overall survival, relapse, or GVHD-free relapse-free survival (GRFS), although there appeared to be a trend toward improved GRFS with the modified regimen. Post hoc analysis comparing GRFS in patients with CRS and those without CRS found that CRS was associated with lower GRFS at 1 year (36% versus 63%; P = .0138). The duration of broad-spectrum antibiotic therapy was decreased by 7.5 days (P = .0017) and the time to hospital discharge was reduced by 7.1 days (P = .0241) with the modified regimen. This is the first analysis to evaluate and find a difference in CRS with early initiation of immunosuppressive therapy in haplo-HSCT. Our results suggest that this modified GVHD regimen benefits patients by reducing CRS and high-grade GVHD compared to the standard PTCy-based GVHD prophylaxis regimen in haplo-HSCT. Additionally, this novel regimen did not appear to negatively impact outcomes.

Real-World Treatment Outcomes of Teclistamab Under an Outpatient Model for Step-up Dosing Administration

Background Teclistamab, the first-in-class B-cell maturation antigen (BCMA) x CD3 bispecific therapy was recently approved by the FDA for the treatment of triple-class exposed relapsed or refractory multiple myeloma (MM) after ≥ 4 prior lines of therapy. Because of the risk of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), the step-up dosing (SUD) of teclistamab is commonly administered in an inpatient setting among early users. Mayo Clinic has a well-established hospital-based outpatient program for novel immunotherapies. Since the FDA approval, teclistamab SUD has been administered as part of this program. Each dose of the SUD is administered in an outpatient setting, and the patient is given a remote monitoring kit to regularly measure vital signs and stay connected with the command center for signs and symptoms of CRS and ICANS throughout the entire SUD period. This study aimed to evaluate early safety outcomes and healthcare resource utilization during SUD in real-world (RW) patients who initiated teclistamab under the outpatient administration model across 3 Mayo Clinic locations (Rochester, MN, Phoenix/Scottsdale, AZ, Jacksonville, FL). Methods This was a retrospective study using Mayo Clinic's electronic medical records from October 26, 2022 to June 12, 2023. Eligible patients were adults diagnosed with MM who had initiated commercial teclistamab at any of the 3 Mayo Clinic locations. Patient characteristics, rates and severity of CRS and ICANS, as well as healthcare resource utilization during SUD were described. Time between teclistamab administration and patient check-out was reported for SUD and treatment doses, respectively. Results At the time of data cutoff, 39 patients received at least 1 teclistamab dose across the 3 locations (median age 67.2 years; male: 74%; White: 87%; non-Hispanic: 92%), including 36 patients who initiated teclistamab SUD directly in an outpatient setting. A total of 8 (21%) patients had MM with high-risk cytogenetics and 14 (36%) had prior exposure to other BCMA-targeted therapies. Prevalent comorbidities prior to receiving teclistamab included anemia (77%), hypertension (56%), lytic bone lesions (51%), neutropenia (49%), and hypogammaglobulinemia (41%). Renal impairment or failure was observed in 31% of the patients (Table 1). Almost all patients received acetaminophen (95%), diphenhydramine (95%), and dexamethasone (92%) as pre-medications on the same day as teclistamab administrations during SUD. Of the teclistamab doses with clinic time data, the majority (62%) of doses during SUD required 30 minutes to 1 hour of clinic time for monitoring between administration and check-out. After SUD, the clinic time for weekly treatment doses decreased to less than 30 minutes for most (79%) doses (Figure 1). In patients who completed SUD by data cutoff (n = 37), most patients (70%) received the SUD on a 3-day dose interval (i.e., day 1, 4, 7). The mean time between the first and third doses was 6.3 days. Among the 37 patients with complete SUD, 12 (32%) developed CRS. The highest CRS grade was grade 1 for 10 patients; 1 patient had a grade 2 CRS, and 1 patient had a grade 4 CRS. The patient with grade 4 CRS concurrently decompensated during a dialysis session and all symptoms were considered for CRS grading. A total of 6 patients had recurrent CRS, including 1 patient with 3 events during SUD. All patients who developed CRS during SUD (n=12) were admitted to the hospital for treatment, with a total of 19 admissions across all patients and a median length of stay of 1.7 days per admission. Among patients who were admitted for CRS (n=12), the majority were treated with acetaminophen (92%), diphenhydramine (83%) and dexamethasone (83%); tocilizumab was given to the 2 patients with CRS grade 2 or higher. Only 1 ICANS event (grade 2) was observed in 1 patient during SUD, after dose 3, and the patient was admitted to the hospital for treatment. Conclusion This study evaluated early RW safety outcomes of teclistamab under an outpatient administration model and found the CRS rate and severity to be comparable with other RW evidence generated from various data sources. Outcomes related to teclistamab SUD from Mayo Clinic supported the safety and feasibility of outpatient administration model as a potential option to reduce healthcare resource utilization and improve treatment experiences.

Initial Dose Escalation of ISB 1442, a Novel CD38 Biparatopic x CD47 Bispecific Antibody, in Patients with Relapsed / Refractory Multiple Myeloma (RRMM)

Introduction: ISB 1442 is a fully human bispecific, biparatopic antibody that targets CD38 and CD47, generated using Ichnos' Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform. ISB 1442 is designed to kill CD38-expressing tumor cells through multiple mechanisms of action including blocking CD47-signal regulatory protein alpha (SIRPα) axis to increase several antibody effector functions: antibody-dependent cellular phagocytosis (ADCP), antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) through optimized architecture, affinity to targets, and Fc engineering. ISB 1442 has 2 Fab domains binding to distinct CD38 epitopes that do not compete functionally with daratumumab. ISB 1442 is expected to have optimized tolerability with low potential for adverse effects on red blood cells (RBC) such as hemagglutination, platelet aggregation and RBC depletion (Sammicheli at al., ASH 2021, Blood (2021) 138 (Supplement 1): 73). We report here initial findings from the early dose-escalation portion of an ongoing, multi-center, open-label, single-agent phase 1/2 study (NCT05427812) of ISB 1442 in patients with RRMM. Methods: Adult patients with relapsed refractory multiple myeloma (RRMM) to prior therapies, including a proteasome inhibitors (PIs), an immunomodulatory drugs (IMiDs), and an anti-CD38 antibodies received subcutaneous (SC) doses of ISB 1442 weekly (QW) in 28-day cycles. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation began at 6 mg dose with single patient accelerated titration phase for the first 3 cohorts, followed by a standard titration phase with a “3 + 3” design. The primary study objective for phase 1 is to assess the safety and tolerability to determine the maximum tolerated dose (MTD) and select the recommended phase 2 dose (RP2D) of ISB 1442. For phase 2 the primary study objective is to evaluate efficacy of ISB 1442. Secondary objectives include evaluation of pharmacokinetics (PK) and immunogenicity of ISB 1442. Exploratory objectives include assessment of minimal residual disease (MRD), assessment of cellular biomarkers in blood and bone marrow, and soluble factors in blood, and their correlation with efficacy, safety and other clinical endpoints of interest. Results: As of July 18, 2023, based on preliminary data from ongoing clinical database, 10 subjects had received once weekly SC injections of ISB 1442 in 4 dose-escalation groups from 6 mg to 150 mg. The majority were male (60%) and white (90%). The median age was 67 years (range 57-79). The median number of prior anti-myeloma lines of therapy was 6 (range 3-7); 70% were exposed to 5 drugs (2PIs, 2IMiDs, and CD38). The median number of ISB 1442 cycles was 1(range 1-2). Eight subjects (80%) experienced treatment-related adverse events (TRAEs), all were grade 1 or 2: cytokine release syndrome (CRS) (50%), injection site reactions (injection site erythema 20%, injection site bruising 10%), anemia (10%, 1 subject, grade 2) (Table 1). No grade 5 TRAE was observed. Following QW SC injection, ISB 1442 was slowly absorbed into the systemic circulation with T max generally occurring on day 2 of dosing. The ISB 1442 serum concentrations generally remained quantifiable over the entire dosing duration from 20 mg and above. The available PK data suggest an approximately dose-linear increase in serum concentration up to DL 3 (60 mg), followed by a supra-proportional increase in serum levels in subjects treated at DL 4 (150 mg). To date, 5 subjects treated at DL4 (150 mg) have experienced clinical symptoms of CRS (Grade 1-2) following the first dose of ISB 1442. Assessment of a panel of 63 soluble factors (including multiple cytokines, chemokines and growth factors) in the peripheral blood revealed that several subjects at DL3-4 exhibited transient increases (&amp;gt;10-fold) in macrophage inflammatory protein-1b (MIP-1b/CCL4) within 24h after treatment with ISB 1442, consistent with a macrophage-associated mechanism of action. Conclusions: Treatment with ISB 1442 was well tolerated at the dose levels evaluated. The observed clinical CRS events were moderate and potentially related to macrophage activation following ISB 1442 administration. Updated clinical, biomarker and PK data will be presented for this ongoing study.

Outpatient Management of CAR-T and Teclistamab for Patients with Lymphoma and Multiple Myeloma

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset &amp;gt;= 3 days from infusion, CRP&amp;lt;100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

Chylothorax after chimeric antigen receptor T cell therapy for relapsed and refractory diffuse large B-cell lymphoma: A case report.

Anti-CD19-targeted chimeric antigen receptor (CAR) T cell therapy is effective in treating relapsed/refractory diffuse large B-cell lymphoma (DLBCL). This therapy is associated with several side effects that can be life-threatening such as cytokine release syndrome (CRS). However, chylothorax associated with CRS after CAR-T therapy has not been reported. A 23-year-old male diagnosed with DLBCL relapsing after autologous peripheral blood stem cell transplantation was treated with anti-CD19-targeted CAR-T cell therapy. After CAR-T cell transfusion, he developed grade 3 CRS includes fever, dyspnea, tachycardia and hypotension. The symptoms of CRS persisted and chest plain film revealed bilateral pleural effusion. Chylothorax was confirmed by the pleural effusion analysis that triglyceride level was 1061 mg/dL. Bacterial and fungal culture of pleural fluid reported no pathogen was detected. Cytological examination of pleural effusion revealed no malignant cells. The chylothorax resolved after treatment with intravenous administration of tocilizumab. On 30-day follow-up, the patient was in stable clinical condition with complete remission of DLBCL on whole-body positron emission tomography scan. We reported a rare case of CAR-T associated chylothorax in a patient with relapsed and refractory DLBCL. Grade 3 CRS with high interleukin-6 level was presented in our patient. The symptoms of CRS were improved with tocilizumab treatment and the chylothorax resolved later on. It is suggested that high interleukin-6 releases might induce chyle leakage resulting from activations of endothelium and coagulation. Our finding highlights the occurrence of chylothorax during the course of CAR-T cell therapy and the importance of proper monitoring and prompt management of this life-threatening side effect.

Autologous Platelet-Rich Plasma: A Potential Therapy to Mitigate Severe Covid-19 Manifestations

The Chinese Ministry of Health's Chinese Health Protection Centers reported the appearance of COVID-19, a group of pneumonia, in Wuhan toward the end of 2019. Common symptoms found are sore throat, headache, pain, diarrhea, skin lesions, and eye irritation. The immune regulatory system may become dysfunctional as a result of SARS-COV-2, leading to an uncontrolled inflammatory response. These events will then result in lymphocyte activation and dysfunction, lymphopenia, an increase in pro-inflammatory cytokine productions, and abnormalities in granulocytes and monocytes, all of which are symptoms of cytokine release syndrome (CRS). CRS may result in shock, acute respiratory distress syndrome, organ failure, respiratory failure, and even death in COVID-19 patients. In order to avoid this, activated autologous platelet-rich plasma (aaPRP) therapy was created to treat CRS. aaPRP therapy is replicable in a short time, easy, and at a low cost. The numerous growth factors in aaPRP have anti-inflammatory properties that reduce the production of IL-1, IL-6, and TNF. The use of aaPRP treatment may lessen the need for invasive mechanical breathing, avoid alopecia and sepsis, and lessen pulmonary fibrosis. According to the findings of the phase I/II study that were conducted, it shows that aaPRP was given through intravenously and did not cause side effects in COVID-19 patients. To fully comprehend the aaPRP treatment for COVID-19 patients, however, more research is required. This review will go into discuss about the pathophysiology of COVID-19 as well as potential areas for aaPRP therapy.

Adverse events during chimeric antigen receptor T-cell (CAR-T) therapy for hematologic malignancies (HM): Real-world, US patient experience.

e18891 Background: CAR-T therapy represents the most significant advancement in the treatment of HM in the past 5 years. Life-threatening complications such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) may occur leading to significant morbidity and mortality. We aimed to describes the frequency of CRS and ICANS and the time to onset of each post CAR-T therapy administration in real-world, U.S. patients. Methods: Patients (pts) with HM who received any FDA-approved CAR-T therapy were identified from a U.S. EMR database containing de-identified healthcare data for &gt; 40M patients from &gt; 500 hospitals and 30 healthcare systems (including academic centers). Confirmation of CAR-t treatment was based on ≥1 procedure code for general administration of CAR-T therapy (e.g., XW033C3, introduction of engineered autologous chimeric antigen receptor t-cell immunotherapy into peripheral vein) or a specific approved CAR-T (I.e., XW033K7, introduction of idecabtagene vicleucel immunotherapy into peripheral vein) between 2017 and 2022. Diagnosis of CRS or any ICAN was based ≥1 related ICD-10 diagnosis code (e.g., CRS = D89.83X). Frequency of occurrence of CRS, symptoms of CRS, ICANS symptoms, and severity of CRS or ICANS is described (severity based on validated clinical algorithm). Time to CRS and ICANS was calculated as the interval from CAR-T administration to first reported diagnosis, respectively. Results: 212 pts met the study criteria including 77 b-cell lymphoma, 64 multiple myeloma, 47 follicular lymphoma, 13 mantle cell lymphoma and 11 acute lymphoblastic leukemia pts. The majority were male (54.7%); median age was 60 years. Overall, 100 (47.2%) pts were diagnosed with CRS (any grade) while 82 (38.7%) pts experienced any ICAN symptoms. The top three CRS symptoms were fever (57.5%), hypotension (31.1%) and tachycardia (21.2%). The top three ICANS symptoms were obtundation (18.4%), confusion (12.7%), and delirium (12.7%). Of CRS pts, 25.0% experienced severe symptoms, including renal insufficiency (10.0%), atrial fibrillation (9.0%), ventricular tachycardia (7.0%), and cardiac failure (2.0%). The median time to development of CRS was 2 days (range 0-23 days). Of pts. experiencing ICANS, 72.0% experienced any mild symptom and 53.7% experienced any severe symptom, including obtundation (47.6%), aphasia (13.4%), and seizures (1.2%). The median time to development of ICANS post CAR-T therapy was 6 days (range 0-26 days). Conclusions: Our study is the first real-world, U.S. evaluation of the frequency and time to toxicities associated with CAR-t therapy across multiple hematologic malignancies. While well-described in RCTs these data highlight the need for the continued development of clinical and therapeutic approaches to minimize their impact on the effectiveness of CAR-T.

Abstract 846: Utilizing quantitative systems pharmacology (QSP) model to understand cytokine release syndrome (CRS) following administration of epcoritamab in DLBCL patients

Abstract Background: Epcoritamab is a novel bispecific antibody that targets CD3 and CD20 and induces T-cell-mediated cytotoxic activity against CD20+ malignant B cells (1). Epcoritamab’s pharmacokinetics (PK), pharmacodynamics, and safety profiles were investigated in GCT3013-01 escalation study across a wide range of doses. CRS is an adverse event of special interest for T cell engagers such as Epcoritamab. As such, step-up dosing (SUD) has been investigated in study GCT3013-01 escalation to minimize release of cytokines and mitigate severe CRS symptoms. Seventeen permutations of SUD were tested, with doses ranging from 0.004 to 60 mg. Based on observed CRS data, a SUD regimen of 0.16/0.8/48 mg was selected. The aim of the analysis was to develop a QSP model capable of predicting cytokine release which can be used to identify potential optimal SUD regimen. Method: Leveraging Epcoritamab preclinical and clinical data, we have developed a QSP platform that captures the observed tumor responses and allows for systemic predictions of biomarkers with the selected SUD regimen. A minimal physiologically based PK model was linked to submodels of T cell activation, proliferation, and cytotoxicity of target-bearing cells, to create an integrated QSP model of the DLBCL system. Epcoritamab-mediated cross-linking of target(s) and CD3 receptor to form trimer complexes drives cell trafficking and cytokine production as well as inducing death of target-bearing cells. The model described the PK, cellular effects, and observed cytokine profiles within the plasma, and simulated similar effects in lymph node(s), tumor, and other peripheral body tissue. Result: After SC administration of Epcoritamab, transient and modest elevation of selected cytokines was observed. Patients’ cytokine profiles were categorized into three different trends based on Cycle 1 data. By accounting for the interaction of receptors and ligands at the nano-scale level (time and physical size) we characterized the dose response and dynamics of T cells, B cells, IL6, and IL10 in patients enrolled in the study by using the QSP model. Conclusions: This analysis integrated underlying mechanisms to predict various systemic biomarkers dynamics including T cells, B cells, IL6 and IL10 following administration of Epcoritamab. The well-studied pathways and mechanisms allow implementation of the model in disease indications other than DLBCL.

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Chimeric Antigen Receptor T Cells: Toxicity and Management Considerations

Successful Outpatient Treatment and Monitoring Following Administration of Various Anti-CD19 Chimeric Antigen Receptor Therapies in B-Cell Lymphomas

Background: Chimeric Antigen Receptor (CAR) T-cell therapy is available as a salvage option for patients with relapsed/refractory B-cell lymphomas (DLBCL, FL, and MCL). Historically, most CAR T-cell therapy has been administered in the inpatient setting due to the potential need to closely monitor or treat cytokine release syndrome (CRS) and neurologic toxicity (NT). However, the introduction of rigorous outpatient monitoring programs incorporating nurse-driven education, patient/caregiver-driven after-hours reporting, and prophylactic corticosteroids may enable outpatient administration and monitoring of CAR T-cell in a large proportion of patients. Outpatient monitoring can improve quality of life for the patient as well as reduce healthcare costs. Objective: Describe clinical outcomes in a cohort of patients who received a variety of commercial CAR T-cell therapies and were subsequently monitored in the outpatient setting. Study Design: This is a retrospective analysis of 20 patients treated with outpatient CAR T-cell therapy between February 2021 and March 2022 with all patients having at least 100 days of post-infusion follow up. Additional data points included progression free survival, overall survival, HCT-CI score, prior lines of treatment, ECOG scores (before and after treatment), and incidence of cytokine release syndrome and neurological toxicity. Responses to treatment were determined based on radiographic tumor evaluation by metabolic response with PET-CT. Patients were monitored with daily RN triage visits and in the absence of complications, were seen twice weekly by an advanced practice provider (APP) or MD. Patients did not use remote monitoring devices and both patients and caregivers were encouraged to self-report any symptoms of CRS or NT to a 24 hour on-call APP/MD. Results: Of the 20 patients in the cohort, 2, 3, 14, and 1 patients received tisagenlecleucel, axicabtagene ciloleucel, lisocabtagene maraleucel, and brexucabtagene autoleucel, respectively. The median age was 69.5 (range 46-81). 60% of patients were male. 65% (13/20) of patients were treated with prophylactic dexamethasone. 55% of patients had an IPI score of 3-4. 25% (5/20) of patents had an ECOG score of 2 or greater. Median HCT-CI score was 1 and ≥2 in 9/20 (45%) patients (range 0-5). Overall, 10/20 (50%) patients were admitted in the first month of therapy (all initially for management of CRS), and no patients were admitted within the first 72 hours after infusion. The incidence of CRS was 11/20 (55%) with grade 3+ CRS of 5%. The incidence of NT was 9/20 (45%), with grade 3+ NT of 20%. Progression free survival in the cohort was 65% at 6 months and 60% at 1 year, and overall survival was 85% and 75%, respectively. 2 (10%) patients died prior to day 30 of treatment, one due to MRSA bacteremia (which developed >1 week into hospital admission), one due to progressive disease. No patients were admitted directly to the ICU. Conclusions: In a single-center cohort of patients who received CAR T-cell therapy and were subsequently monitored in the outpatient setting without remote monitoring devices, only half of the patients were admitted in the 1st month of therapy and no patients were admitted within the first 72 hours after infusion. 2 patients died in the first month of treatment for reasons unlikely to be related to outpatient monitoring. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Cytokine release syndrome-like serum responses after COVID-19 vaccination are frequent and clinically inapparent under cancer immunotherapy

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0–5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6–23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was >1.5-fold upregulated in 40% (95% CI 23.9–57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.

Abstract 2816: A novel in vivo model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy

Abstract Over the past few years, chimeric antigen receptor T (CAR T)-cell therapy has emerged as a novel treatment option for certain hematologic malignancies. Several CAR T-cell therapies produced highly efficacious responses from patients with hematologic malignancies. However, wider adoption of CAR T-cell therapy is challenged due to the potential development of life-threatening toxicities including cytokine release syndrome (CRS). CRS symptoms can range from mild fever to life-threatening events, including death. Preclinical animal models to assess the efficacy and toxicity of CAR T-cell therapies have been lacking. Here, we developed a novel mouse model to assess the efficacy and toxicity of CAR T-cell therapy simultaneously. Two different PBMC humanized NSG™ variants were used. NSG-MHC Class I/II double knock-out strain is known to have a delayed onset of GvHD, and NSG-SGM3xIL15 strain shows a higher engraftment level of human NK and myeloid cells, in addition to human T cells. Mice were humanized using PBMCs and treated with autologous or allogeneic CAR T cells, and efficacy and toxicity were assessed. Compared to the control treatment, CD19 CAR T-cells caused a decrease in the human CD19+ cell population in the blood and spleen, and induced cytokine release. Both T-cell and myeloid cytokine releases, including IFNgamma, IL-10, RANTES, and MIP-1alpha, were induced in our animal models. The in vivo platform can also be used to determine individual PBMC/CAR T donor differences and show the extent of efficacy and toxicity of each PBMC donor treated with autologous and allogeneic CAR T-cell therapy. We further confirmed anticancer efficacy using luciferase-tagged human B-cell lymphoma Raji tumor cells, which express a high level of CD19. In summary, we have developed a novel in vivo model to test the efficacy and toxicity of both autologous and allogeneic CAR T-cell therapy simultaneously. Citation Format: Jiwon Yang, Won Lee, Jing Jiao, Danying Cai, Heather Gustafson, Rebecca Gardner, Mingshan Cheng, James G. Keck. A novel in vivo model to simultaneously assess efficacy and toxicity of chimeric antigen receptor T-cell immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2816.

Coagulopathy related to CAR-T cell therapy

Chimeric antigen receptor (CAR) T-cell therapy has become the standard of care for some B-cell malignancies due to its high antitumor efficacy. However, adverse events specific to CAR T-cell therapy, such as cytokine release syndrome (CRS), are frequently observed. Typical clinical manifestations of CRS include hyperthermia, hypotension, hypoxemia, and increased vascular permeability. Coagulopathy may also be observed along with to the typical symptoms of CRS. Previous studies, including ours, have revealed that the increase in interleukin-6 levels associated with CRS promotes production of plasminogen activator inhibitor-1 from the vascular endothelium, resulting in suppressed fibrinolysis and hypercoagulability and an exhaustible decrease in fibrinogen. Continuous monitoring of coagulation parameters is necessary during CAR T-cell therapy, and adequate provision of fresh-frozen plasma or cryoprecipitate is recommended if the patient is evaluated to be at high risk for severe CRS.

A Phase 1 Dose Escalation Study of Igm-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies

A Phase 1 Dose Escalation Study of Igm-2323, a Novel Anti-CD20 x Anti-CD3 IgM T Cell Engager (TCE) in Patients with Advanced B-Cell Malignancies

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Safety and Efficacy of Two Anakinra Dose Regimens for Refractory CRS or Icans after CAR T-Cell Therapy

Treatment-Related Adverse Events of Chimeric Antigen Receptor T-Cell (CAR T) in Clinical Trials: A Systematic Review and Meta-Analysis.

Simple SummarySuccessful treatment of hematological malignancies with chimeric antigen receptors T (CAR-T) cells has led to much enthusiasm for the wide clinical usage and development of novel CAR-T therapies. However, it also challenges physicians and investigators to recognize and deal with treatment-associated toxicities. We conducted a systematic review and meta-analysis from 84 eligible study and a total of 2592 patients to identify the comprehensive incidences and severity of CRS and neurological symptoms (NS) as well as the potential differences in AEs across a variety of cancer types, CAR-T targets, and other factors, thereby offering a significant implication on its future application and research.Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24–36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23–37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.

CAR T-cell therapy for solid tumours

Chimeric antigen receptor (CAR) T-cell therapy has fundamentally changed the therapeutic landscape for haematological malignancies. CAR T-cell therapy involves the collection of a patient's T cells, ex-vivo genetic modification of the cells to encode a synthetic receptor that binds a specific tumour antigen, and then re-infusion of these cells back into the patient. The clinical success of CAR T-cell therapy in blood cancers has generated enthusiasm for testing the technology in solid tumours. However, the biology of solid tumours is more complex than that of haematological malignancies. Unfortunately, CAR T-cell therapy for solid tumours suffered a setback on June 2, 2021, when Tmunity Therapeutics stopped its phase 1 clinical trial in men with prostate cancer because two patients died from immune effector cell-associated neurotoxicity syndrome (ICANS). Tmunity Therapeutics had been developing prostate-specific membrane antigen (PSMA)-directed, TGF-β-insensitive CAR T cells. Prostate cancer cells secrete TGF-β as an immunosuppressive factor, so the investigators hypothesised that using a PSMA-directed CAR T cell with coexpression of a dominant-negative TGF-β receptor would enhance antitumour immunity in patients with prostate cancer. Early trial results had shown no dose-limiting toxicities, and only one, reversible, case of cytokine release syndrome (CRS). ICANS, however, although seen less frequently than CRS, has been reported in up to half of all patients receiving CAR T-cell therapy for various haematological cancers and thus was also a risk in solid tumour trials. ICANS needs prompt diagnosis and appropriate management to avoid rapid clinical deterioration. Unlike CRS, the precise underlying pathophysiology of ICANS remains poorly understood, and although the acute symptoms of CRS and ICANS are generally reversible with supportive care, steroids, and immunosuppressive drugs, they can be associated with substantial morbidity, with some patients requiring admission to an intensive care unit. In addition to CRS and ICANS, the development of CAR T-cell therapy for solid tumours faces many fundamental challenges, the most difficult being the identification of an ideal target antigen. Haematological cancers typically express a single, specific, tumour-associated antigen, whereas solid tumours have substantial antigen heterogeneity. Of concern, many antigens associated with solid tumours are also expressed on healthy tissue, raising the risk of off-target adverse events. Genetic modification technologies can help to circumvent this risk, but they are not a failsafe solution. Other major challenges include how to traffic the CAR T cells to the tumour bed because of a lack of appropriate cytokines in the tumour milieu; how to prevent CAR T cells from losing their effectiveness over time (so-called T-cell fitness); how to lymphodeplete the tumour to allow for CAR T-cell expansion in the absence of effective lymphodepleting chemotherapies; and, finally, how to overcome the hostile immunosuppressive conditions of the tumour microenvironment. A recent development might help to overcome two of these challenges. Using a new CAR T-cell technology called synthetic Notch (or synNotch), CAR T cells can be made to target specific cancers very precisely. Researchers at the Children's Hospital Los Angeles (Los Angeles, CA, USA) have developed a modified version of a CAR T cell for treating neuroblastoma. The synNotch protein on the surface of the T cell is designed to recognise an antigen called GD2. When it does, the synNotch protein then instructs the T cell to activate its CAR T-cell properties, enabling it to recognise a second antigen called B7H3. This gating property is key to minimising toxicity, as healthy cells sometimes express one of these antigens, but rarely both. Neuroblastoma, however, has both GD2 and B7H3 antigens. Interestingly, synNotch CAR T cells are metabolically more stable than regular CAR T cells, enabling them to target a tumour over a longer timeframe and overcome the problems associated with CAR T-cell fitness. The use of CAR T-cell therapy has yielded excellent early-to-mid-term results in patients with haematological cancers, but the transfer of this technology to solid cancers faces more substantive biological barriers and risks to patients. Despite many ongoing clinical trials, very few have reported any results and all are at early stages. Consequently, many unknowns remain. The potential is evident, but it will only be realised through carefully designed trials incorporating thorough patient monitoring and stringent stopping rules coupled to detailed preclinical translational research.

Preliminary Results of UCART19, an Allogeneic Anti-CD19 CAR T-Cell Product in a First-in-Human Trial (PALL) in Pediatric Patients with CD19+ Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

▪BackgroundUCART19 is a genetically modified T-cell product manufactured from non-HLA matched healthy donor cells and aims to provide a ready to use, off-the-shelf allogeneic engineered CAR T-cell product. Lentiviral-transduced CAR T-cells express (1) an anti-CD19 CAR (anti-CD19 scFv- 41BB- CD3ζ), and (2) an RQR8 “safety switch” that is intended to allow targeted elimination of RQR8+ cells by rituximab. UCART19 has been additionally modified to disrupt the T-cell receptor alpha constant (TRAC) and CD52 genes. We previously reported the success of this approach in two infants treated under compassionate use who achieved molecular remissions ahead of allogeneic transplantation and remain in remission with follow-up for 18 and 24 months. Here we describe preliminary results of a Phase 1 trial of UCART19 in pediatric patients (pts) with high risk relapsed refractory (R/R) CD19+ B-ALL and no therapeutic options.MethodsThis study evaluates the safety and tolerability of a fixed dose (2x107 total cells or 1.1 to 2.3x106 cells/kg) of UCART19 and its ability to achieve molecular remission at day (D) 28 to enable allogeneic stem cell transplantation (allo-SCT). Up to 10 subjects with R/R B-ALL aged between 6 months and < 18 years, with morphologically confirmed CD19+ B-ALL or an MRD load ≥ 1x10-3 are eligible. The lymphodepletion regimen combines cyclophosphamide and fludarabine with or without alemtuzumab (FC or FCA). UCART19 is administered thereafter (Day 0) as a single dose infusion. If the patient achieves molecular remission, allo-SCT is scheduled within 6 to 12 weeks (wks) after infusion, and trial period continues for a further 12 months before entry into a long-term follow-up study.ResultsAs of 24 June 2017, 5 children (3 males and 2 females), including two infant leukaemias, aged between 8 months and 16.4 years had been enrolled and treated. Four pts had received 3 or more previous lines of treatment and 2 had undergone a previous allo-SCT. All patients were unsuitable for or had failed generation of an autologous CAR T-cell product. All had received debulking chemotherapy and/or inotuzumab ozogamicin therapy before UCART19. All pts received lymphodepletion with FCA. No immediate infusion related reaction (IRR) related to UCART19 were reported. All pts experienced reversible cytokine release syndrome (CRS) (1 grade (G) 1, 3 G2, 1 G3), with one child requiring 2 doses of tocilizumab. Time to onset of first CRS symptoms was between D4 and D8. Two pts presented mild neurological symptoms that recovered (within 1 to 3 days) without treatment. Acute skin GvHD G1 was reported in two pts (one with biopsy confirmation) and both recovered with topical steroids. Four children experienced viral complications (CMV, ADV, BK, metapneumovirus) related to lymphodepletion, and all experienced neutropenia, which was prolonged in 2/5 pts. By D28-42, 5/5 pts had achieved complete remission with incomplete blood count recovery albeit with hypoplastic marrows (all patients were MRD negative by flow cytometry or qPCR ). UCART19 were detectable from D7 to at least D28 in all subjects by qPCR and/or flow cytometry and by molecular signatures of T-cell donor chimerism. All proceeded to conditioned allo-SCT between 7 to 9 weeks after UCART19 infusion, with no gene-modified cells detectable thereafter. Two children relapsed 3 months after transplantation (one CD19- and one CD19+) and died 7 and 8 months after UCART19 infusion respectively. One subject died in remission from transplant related complications including thrombotic microangiopathy and BK haemorrhagic cystitis and nephritis. Two subjects remain in molecular remission 2 and 2.5 months post-transplant.ConclusionPreliminary results of this first-in-human trial of UCART19 treatment in a high risk R/R B-ALL pediatric population revealed no unexpected toxicities. GvHD seen in 2 patients was mild and self-limiting. Lymphodepletion-related viral complications and persisting neutropenia were encountered. All five treated subjects were rendered either flow or PCR MRD negative enabling allogeneic transplantation to proceed. The trial is ongoing in the UK and further data may be presented (NCT02808442) . DisclosuresQasim:Autolus Ltd: Consultancy, Equity Ownership; Miltenyi: Research Funding; Orchard Therapeutics: Consultancy, Equity Ownership; Servier: Research Funding; Bellicum: Research Funding; NIHR: Research Funding; Cellectis: Research Funding. Lucchini:Alexion: Membership on an entity's Board of Directors or advisory committees. Zinaï:Servier: Employment. Binlich:Servier: Employment. Dupouy:Servier: Employment. Pauly:Servier: Employment. Balandraud:Servier: Employment. Dubois:Servier: Employment. Konto:Bristol-Myers Squibb: Employment, Equity Ownership; Pfizer: Employment, Equity Ownership. Patel:Pfizer: Employment, Equity Ownership. Veys:Bellicum: Research Funding; Servier: Research Funding.

Neurological Consequences of Cytokine Release Syndrome Following Subcutaneous Recombinant IL-15 and Haploidentical Donor Natural Killer Cell Therapy for Advanced Acute Myeloid Leukemia

Abstract Cytokine Release Syndrome (CRS) is associated with elevated cytokine levels, macrophage activation, and IL-6 production after antibody or cell-based immunotherapy. We have observed over 200 patients with no CRS following adoptively transferred haploidentical donor natural killer (haplo-NK) cell products after lymphodepleting chemotherapy plus IL-2; and achieved complete remission in 30-50% of patients with refractory AML. To promote NK cell expansion without stimulation of Treg that may compromise NK function, we tested the substitution of IL-2 with the NCI manufactured rIL-15. Using the same lymphodepleting preparative regimen (Fludarabine 25 mg/m2IV for 5 days and Cyclophosphamide 60 mg/kg IV for 2 days) we infused CD3- and CD19-depleted haplo-NK incubated overnight with rIL-15 (10 ng/mL) prior to infusion. Two cohorts received rIL-15; either intravenously x 12 daily doses (at the Phase I MTD of 0.75 mcg/kg) or subcutaneously x 10 doses (5 days on, 2 days off, 5 days on at 2 mcg/kg SQ, the MTD when used as monotherapy in solid tumor patients). CRS was defined by modified CRS grading criteria (Lee et al. Blood, 2014). Results: Forty patients with relapsed/refractory AML were treated with haplo-NK plus IV rIL-15 (n=24) or SQ rIL-15 (n=16). Patients received an average of 11.6 IV doses [9-12, 96% of planned doses] or 7.5 SQ doses [1-10, 75% of planned doses]. Dosing was stopped for toxicity. No CRS events were observed after IV dosing. However, after SQ dosing, 9 of 16 patients [56%] had grade 1-4 CRS; [4 (25%) with grade 3-4 CRS) (Table 1). The median time from NK infusion to onset of CRS was 8 days [2-44]. Six of the 9 CRS patients (66%) had neurological events. Neurological toxicities included grade 1-2 encephalopathy (n=2), intracranial hemorrhage (ICH) (n=2, grade 1 and grade 5), and grade 4 seizures (n=2). One additional event (a patient with a fall resulting in ICH due to pre-existing gait abnormality) without evidence of CRS was not considered as IL-15 associated neurotoxicity CRS. Symptoms resolved in 4 of 5 patients who received treatment for neurologic CRS (3 received both steroids and Tocilizumab, 1 received steroids only, 1 patient did not require treatment as symptoms resolved with stopping IL-15). Non-neurologic toxicity included hypoxia (n=2) and hypotension (n=3). No significant correlations were found between development of CRS and absolute lymphocyte or monocyte count, presence or absence of haplo-NK expansion at day 14, number of rIL-15 doses received, or disease burden at baseline as measured by blast percentage in bone marrow. In the IV rIL-15 cohort, only 2 of 14 patients at the MTD (14%) cleared leukemia and underwent transplantation. In contrast, 8 of 16 patients (50%, P=0.04) in the SQ rIL-15 cohort achieved CR (n=7) or CRp (n=1), with 6 patients proceeding to alloHCT consolidation. CRS did not limit the clinical benefit in the SQ cohort as 4 of 9 [44%] patients with CRS achieved CR/PR compared to 4 of 7 [57%] patients without CRS. Pharmacokinetic data showed slower clearance of rIL-15 in SQ compared to IV dosing, as shown by higher trough levels prior to dose 2 (501 vs. 233 pg/mL, p Download : Download high-res image (163KB) Download : Download full-size image Disclosures Bachanova: Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Seattle-Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Zymogen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oxis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller: Celegene: Consultancy; Oxis Biotech: Consultancy; Fate Therapeutics: Consultancy, Research Funding.