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CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248.

Background: Three CD19 directed CAR-T products have gained FDA approval for systemic large B-cell lymphoma. Due to heightened concerns of immune cell associated neurotoxicity syndrome (ICANS), patients with primary CNS lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. Consequently, all three products carry a limitation of use in the PCNSL patient population per their FDA labels . Due to these exclusions, little is known about the treatment-related toxicities and therapeutic potential of the currently available CD19 directed CAR-T products in this challenging patient population with significant unmet need. Methods: Based on our prior experience of tisagenlecleucel in secondary CNS lymphoma (PMID: 31320380) we conducted a pilot study with expansion of tisagenlecleucel in adults with relapsed or refractory PCNSL (NCT04134117). Patients had to be 18 years of age or older and have had progression or relapse following methotrexate-based therapy. All patients needed a confirmed diagnosis of PCNSL without evidence of systemic disease. Patients received a standard regimen of fludarabine (25 mg/m 2) and cyclophosphamide (250 mg/m 2) daily on days -5, -4, and -3 of infusion and a dose of 0.6-6.0 x 10 8 tisagenlecleucel CAR+ T-cells. Patients who had progressed on prior BTKi were allowed to continue given its beneficial effect on CAR-T expansion and function with cessation by month 3. The primary endpoint of this study was tolerability and toxicity including the rate and grade of CRS and ICANS per the 2019 ASTCT (American Society of Transplantation and Cellular Therapy) consensus criteria. Secondary endpoints included overall response rate and complete response rate to tisagenlecleucel per the international PCNSL Collaborative Group (IPCG) criteria which included MRI and CSF assessments. Exploratory endpoints included long-term efficacy, expansion, persistence and phenotype of tisagenlecleucel, cytokine profiling of the blood and CSF and CNS trafficking of CAR-T cells. Results: As of April 1, 2021, 10 subjects (ages 35-70 years) were enrolled and 9 were infused with a median age of 67 years (range, 34-81). Of the 9 infused patients, the median time from leukapheresis to infusion was 30 days (range, 27-37). Patients were heavily pretreated prior to study enrollment and received a median of 4 prior lines of anti-neoplastic therapy. All patients had progressed or failed first line high-dose methotrexate (HD-MTX); two had a history of prior thiotepa based autologous stem cell transplant (ASCT). Eight out of 9 patients had progressed following a prior BTKi and/or an immunomodulatory drug (IMiD) as part of TEDDI-R (temozolomide, etoposide, doxil, dexamethasone, ibrutinib and rituximab, n = 3), ViPOR (venetoclax, ibrutinib, prednisone, obinutuzumab and Revlimid, n = 3), or as monotherapy (n = 5) and 2 patients had received prior stereotactic radiotherapy. All patients had measurable disease at time of lymphodepletion (pre-infusion). Grade 1 CRS was observed in 6 patients with a median onset of 4 days (range, 1-5) following tisagenlecleucel and no patients required intervention for CRS. ICANS developed in 5 out of the 9 patients, only a single case of grade 3 ICANS, with a median time of onset was 5 days (range, 3-11). With a median follow-up of 7.43 months for survivors, 6/9 patients were alive with 4/9 showing ongoing responses (Figure 1). Expansion of tisagenlecleucel was demonstrated in the peripheral blood and CSF. Nanostring and RNA pathway analysis of CSF infiltrates demonstrated higher degrees of CNS CAR-T penetration in responding patients and increased T-cell and macrophage gene signatures. Peripheral and CSF cytokines were assessed. Conclusion: Tisagenlecleucel in r/r PCNSL was safe and efficacious in a highly refractory group of patients with significant unmet need. The majority of patients demonstrated a response per IPCG, including responses beyond 12 months. Tisagenlecleucel was found to expand in the peripheral blood and CNS with CSF gene signatures suggestive of higher CAR-T cell infiltrates in responding patients. Full trial safety data as well as additional follow-up and correlative studies will be presented. Figure 1 Figure 1. Disclosures Frigault: Editas: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Kite: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BMS: Consultancy. Dietrich: Unum: Consultancy; Blue Earth Diagnostics: Consultancy; Magnolia: Consultancy; Gamaka Bio: Consultancy; Beacon Biosignals: Research Funding; Boehringer Ingelheim: Research Funding; BMS: Research Funding; Medimmune: Research Funding; Acerta: Research Funding; Orbus: Research Funding. Jordan: CereXis: Consultancy; Recursion: Consultancy; Navio Theragnostics: Consultancy. Forst: Eli Lilly: Current holder of individual stocks in a privately-held company. Plotkin: AstraZeneca: Consultancy; Akuous: Consultancy; NFlection Therapeutics: Other: Co-founder; NF2 Therapeutics: Other: Co-founder. Spitzer: Qihan Bio: Consultancy; Bluebird Bio: Consultancy; Jazz Pharmaceuticals: Consultancy; Syneos Health: Consultancy. Defilipp: Omeros, Corp.: Consultancy; Incyte Corp.: Research Funding; Regimmune Corp.: Research Funding; Syndax Pharmaceuticals, Inc: Consultancy. Maus: Tmunity: Consultancy; Novartis: Consultancy; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Kite Pharma: Consultancy, Research Funding; GSK: Consultancy; Intellia: Consultancy; In8bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; Cabaletta Bio (SAB): Consultancy; BMS: Consultancy; Bayer: Consultancy; Atara: Consultancy; AstraZeneca: Consultancy; Astellas: Consultancy; Arcellx: Consultancy; Agenus: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy. Chen: Gamida: Consultancy; Incyte: Consultancy.

Chimeric antigen receptor (CAR) T cells have emerged as a promising class of cell-based immunotherapy in refractory malignancies. Neurotoxicity represents a common and potentially life-threatening adverse effect of CAR T cells, and clinical experience is limited. Here, we describe the clinical presentation and management of 25 adult patients who presented with neurotoxic syndromes after CAR T-cell therapy at the Massachusetts General Hospital. This cohort includes 24 patients treated with CD19-directed CAR T cells for non-Hodgkin lymphoma (n = 23) and acute lymphoblastic leukemia (n = 1), and 1 patient treated with α-fetoprotein–directed CAR T cells for hepatocellular carcinoma (n = 1). Twelve of the 25 patients (48%) developed grade 1-2 neurotoxicity and 13 patients (52%) presented with grade 3-4 neurotoxicity. We found that lower platelet counts at time of CAR T-cell infusion were associated with more severe neurotoxicity (P = .030). Cytokine release syndrome occurred in 24 of 25 patients (96%). Serum levels of ferritin peaked with onset of neurologic symptoms, and higher ferritin levels were associated with higher neurotoxicity grade. Grade 3-4 neurotoxicity correlated negatively with overall survival (OS) (P = .013). Median OS of the entire cohort was 54.7 weeks. Eight patients (32%) with grade 3-4 neurotoxicity were deceased at database closure, whereas none died with neurotoxicity grade 1-2. High pretreatment lactate dehydrogenase was frequently encountered in lymphoma patients with grade 3-4 neurotoxicity and correlated negatively with progression-free survival (P = .048). We did not find evidence that steroid use ≥7 days altered the patient’s outcome when compared with