CD19 CAR T-Cell Therapy in Autoimmune Disease - A Case Series with Follow-up.

BACKGROUND: Treatment for autoimmune diseases such as systemic lupus erythematosus (SLE), idiopathic inflammatory myositis, and systemic sclerosis often involves long-term immune suppression. Resetting aberrant autoimmunity in these diseases through deep depletion of B cells is a potential strategy for achieving sustained drug-free remission. METHODS: We evaluated 15 patients with severe SLE (8 patients), idiopathic inflammatory myositis (3 patients), or systemic sclerosis (4 patients) who received a single infusion of CD19 chimeric antigen receptor (CAR) T cells after preconditioning with fludarabine and cyclophosphamide. Efficacy up to 2 years after CAR T-cell infusion was assessed by means of Definition of Remission in SLE (DORIS) remission criteria, American College of Rheumatology-European League against Rheumatism (ACR-EULAR) major clinical response, and the score on the European Scleroderma Trials and Research Group (EUSTAR) activity index (with higher scores indicating greater disease activity), among others. Safety variables, including cytokine release syndrome and infections, were recorded. RESULTS: The median follow-up was 15 months (range, 4 to 29). The mean (±SD) duration of B-cell aplasia was 112±47 days. All the patients with SLE had DORIS remission, all the patients with idiopathic inflammatory myositis had an ACR-EULAR major clinical response, and all the patients with systemic sclerosis had a decrease in the score on the EUSTAR activity index. Immunosuppressive therapy was completely stopped in all the patients. Grade 1 cytokine release syndrome occurred in 10 patients. One patient each had grade 2 cytokine release syndrome, grade 1 immune effector cell-associated neurotoxicity syndrome, and pneumonia that resulted in hospitalization. CONCLUSIONS: In this case series, CD19 CAR T-cell transfer appeared to be feasible, safe, and efficacious in three different autoimmune diseases, providing rationale for further controlled clinical trials. (Funded by Deutsche Forschungsgemeinschaft and others.).

Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study.

BACKGROUND: Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. METHODS: We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. FINDINGS: Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1-8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0-19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8-78·0) patients and a complete response by 136 (53%, 46·8-59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. INTERPRETATION: Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.

Interim Phase 2 ZUMA-5 Results Show Promise for Axi-Cel in R/R iNHL.

Results from an interim analysis of the phase 2 ZUMA-5 study showed that axicabtagene ciloleucel (axicel;Yescarta) demonstrated significant and durable clinical benefit in patients with relapsed or refractory indolent non-Hodgkin lymphoma, with high overall response rate (ORR) and complete response (CR) rate observed. It also had a manageable safety profile.

Progressive multifocal leukoencephalopathy after CAR T therapy.

Progressive multifocal leukoencephalopathy (PML) remains a life-threatening central nervous system infection in immunocompromised patients. Although outcomes have improved in cases that immune reconstitution is feasible with anti-retroviral therapy (ART) in HIV + patients or natalizumab removal in those with multiple sclerosis, in individuals with hematological malignancies, the prognosis is usually dismal. Anti-viral treatments have been largely ineffective, but immunotherapy-based approaches with checkpoint inhibitors and adoptive virus-specific T cells' transfer are currently explored in clinical trials. PML has not been described as a cause of encephalopathy after CAR T therapy. We report the first case of PML 7 months after lymphodepleting chemotherapy with fludarabine/cyclophosphamide and anti-CD19-directed CAR T therapy in a patient with relapsed diffuse large B-cell lymphoma who relapsed fast after a previous autologous hematopoietic stem cell transplant. She remains alive 12 months after diagnosis with stabilization of her symptoms with a combination of therapies targeting viral replication and immunotherapy.

CAR T-Cell-Associated Neurotoxicity: Current Management and Emerging Treatment Strategies.

Axicabtagene ciloleucel and tisagenlecleucel are 2 chimeric antigen receptor (CAR) T-cell immunotherapies targeting CD19 for the treatment of B-cell acute lymphoblastic leukemia and non-Hodgkin lymphoma. Two commonly recognized complications associated with CAR T-cell therapies are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). ICANS can occur in isolation or concomitantly with CRS following CAR T-cell therapy and may be due to disruption of the blood-brain barrier and the effects of elevated cytokine levels on the central nervous system. Presently, the optimum management of ICANS remains elusive, as there lacks consensus guidelines. The objective of this review is to provide a comprehensive summary of ICANS and strategies for prompt identification and management of patients presenting to the intensive care unit with this syndrome.

Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR.

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1-5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40-60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19- clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9-11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1-4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively.

Is it a Chimera? A systematic review of the economic evaluations of CAR-T cell therapy.

Introduction: The new category of chimeric antigen receptor T - cell raised hopes for a more effective treatment of large B cell lymphoma and acute lymphoblastic leukemia. Nevertheless, their soaring acquisition costs will stretch the fiscal capacity of the health systems worldwide. To this direction, the scope of this study is to provide a systematic review of their economic evaluations. Areas covered: A systematic review of the economic evaluations of tisagenlecleucel and axicabtagene was performed. Expert opinion: The available data indicate that these products demonstrate a potentially favorable cost-effectiveness ratio. Nevertheless, their budget impact is of overriding importance and it should be incorporated in any economic evaluation. Moreover, more affirmative clinical data are imperative in order to mitigate uncertainty.

Glial injury in neurotoxicity after pediatric CD19-directed chimeric antigen receptor T cell therapy.

OBJECTIVE: To test whether systemic cytokine release is associated with central nervous system inflammatory responses and glial injury in immune effector cell-associated neurotoxicity syndrome (ICANS) after chimeric antigen receptor (CAR)-T cell therapy in children and young adults. METHODS: We performed a prospective cohort study of clinical manifestations as well as imaging, pathology, CSF, and blood biomarkers on 43 subjects ages 1 to 25 who received CD19-directed CAR/T cells for acute lymphoblastic leukemia (ALL). RESULTS: Neurotoxicity occurred in 19 of 43 (44%) subjects. Nine subjects (21%) had CTCAE grade 3 or 4 neurological symptoms, with no neurotoxicity-related deaths. Reversible delirium, headache, decreased level of consciousness, tremor, and seizures were most commonly observed. Cornell Assessment of Pediatric Delirium (CAPD) scores ≥9 had 94% sensitivity and 33% specificity for grade ≥3 neurotoxicity, and 91% sensitivity and 72% specificity for grade ≥2 neurotoxicity. Neurotoxicity correlated with severity of cytokine release syndrome, abnormal past brain magnetic resonance imaging (MRI), and higher peak CAR-T cell numbers in blood, but not cerebrospinal fluid (CSF). CSF levels of S100 calcium-binding protein B and glial fibrillary acidic protein increased during neurotoxicity, indicating astrocyte injury. There were concomitant increases in CSF white blood cells, protein, interferon-γ (IFNγ), interleukin (IL)-6, IL-10, and granzyme B (GzB), with concurrent elevation of serum IFNγ IL-10, GzB, granulocyte macrophage colony-stimulating factor, macrophage inflammatory protein 1 alpha, and tumor necrosis factor alpha, but not IL-6. We did not find direct evidence of endothelial activation. INTERPRETATION: Our data are most consistent with ICANS as a syndrome of systemic inflammation, which affects the brain through compromise of the neurovascular unit and astrocyte injury. ANN NEUROL 2019.

Long-term Survival and Cost-effectiveness Associated With Axicabtagene Ciloleucel vs Chemotherapy for Treatment of B-Cell Lymphoma.

Importance: Axicabtagene ciloleucel, a chimeric antigen receptor T-cell therapy, represents a new and potentially curative treatment option for B-cell lymphoma. It is expected to have long-term survival benefits; however, long-term survival data are limited. Objective: To estimate the long-term survival and cost-effectiveness of axicabtagene ciloleucel for treatment of relapsed or refractory B-cell lymphoma. Design, Setting, and Participants: Economic evaluation study using a survival analysis that digitized and extrapolated survival curves published in the ZUMA-1 trial (Safety and Efficacy of KTE-C19 in Adults With Refractory Aggressive Non-Hodgkin Lymphoma), which enrolled patients between November 2015 and September 2016 and had a maximum follow-up of 24 months. Five different survival models (standard parametric, flexible parametric, 2 mixture cure models, and a flexible parametric mixture model) were used to extrapolate the survival curves to a lifetime horizon from January through June 2018. A cost-effectiveness analysis, from both a trial-based and lifetime horizon, was also conducted to inform the value of this novel therapy. The model was based on data from 111 patients with B-cell lymphoma who were enrolled in the ZUMA-1 trial. Interventions: One-time administration of axicabtagene ciloleucel compared with chemotherapy. Main Outcomes and Measures: Undiscounted and discounted life-years (LYs) and quality-adjusted life-years (QALYs), total costs, and incremental costs per LY and QALY gained. Results: The modeled cohort of 111 patients started at 58 years of age. At the end of the trial, treatment with axicabtagene ciloleucel resulted in 0.48 more LYs and 0.34 more QALYs than chemotherapy, producing a cost-effectiveness estimate of $896 600 per QALY for public payers and $1 615 000 per QALY for commercial payers. Extrapolated long-term survival for patients treated with axicabtagene ciloleucel ranged from 2.83 to 9.19 discounted LYs and from 2.07 to 7.62 discounted QALYs. Incrementally, treatment with axicabtagene ciloleucel was associated with 1.89 to 5.82 discounted LYs and 1.52 to 4.90 discounted QALYs vs chemotherapy. With the use of these incremental estimates of survival, cost-effectiveness estimates ranged from $82 400 to $230 900 per QALY gained for public payers and from $100 400 to $289 000 per QALY gained for commercial payers. Conclusions and Relevance: Treatment with axicabtagene ciloleucel appears to be associated with incremental gains in survival over chemotherapy. The range in projected long-term survival was wide and reflected uncertainty owing to limited follow-up data. Cost-effectiveness is associated with long-term survival, with further evidence needed to reduce uncertainty.

American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group Survey on Chimeric Antigen Receptor T Cell Therapy Administrative, Logistic, and Toxicity Management Practices in the United States.

Administration of immune effector cell (IEC) therapy is a complex endeavor requiring extensive coordination and communication of various healthcare and administrative teams. Chimeric antigen receptor (CAR) T cells are the most established IEC therapy available. As of July 2018 two commercial gene therapy products, tisagenlecleucel and axicabtagene ciloleucel, have been approved by the US Food and Drug Administration. To gain insight into the infrastructure and practices across the country, the American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group conducted an electronic survey on the current administrative, logistic, and toxicity management practices of CAR T cell therapy across the United States. This survey consists of 52 responses from institutions of varying sizes, most of which (∼80%) had previous investigational experience with CAR T cell therapy. Absorbing the energy of this exciting new treatment has challenged hematopoietic cell transplant programs across the country to strengthen department infrastructure, develop new committees and policies, and implement significant education to ensure safe administration. With the variety of experience with CAR T cell therapy, we hope this survey can contribute to the existing published literature and provide support and consensus to established and developing IEC programs and practice guidelines.

Long-term safety and activity of axicabtagene ciloleucel in refractory large B-cell lymphoma (ZUMA-1): a single-arm, multicentre, phase 1-2 trial.

BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. METHODS: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2 × 106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. FINDINGS: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. INTERPRETATION: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. FUNDING: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.

The combination of cyclophosphamide and human T cells genetically engineered to target CD19 can eradicate established B-cell lymphoma.

T cells genetically engineered to express tumour-targeting receptors are attractive anti-cancer therapeutic agents. Human T cells engrafted with a chimeric receptor specific for the B-cell lymphoma antigen CD19 fused to the CD3zeta receptor (aCD19z) are functional in vitro. Current successful clinical protocols targeting melanoma use pre-conditioning chemotherapy in combination with T cells. This study demonstrated that interleukin-2 expanded aCD19z T cells combined with cyclophosphamide effectively treated five-day established Raji B-cell lymphoma in an immunocompromised model system with 50% of mice surviving >100 days. This observation strongly supports the combination of antibody targeted T cells with chemotherapy as a novel approach for the therapy of CD19(+) B-cell malignancies.