Tisagenlecleucel Demonstrates Safety, Efficacy and CNS Trafficking in Primary CNS Lymphoma

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 aut