Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial

Abstract

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.

Graphical abstract

Figure 1.

Swimmer’s plot of evaluable patients following tisagenlecleucel infusion and associated CRS/ICANS. Response to most recent therapy included in parentheses. 001 (fourth line; PR), 002 (third line; PD), 005 (fourth line; PR), 007 (fourth line; PD), 008 (second line; SD), 011 (fifth line; PD), 014 (sixth line; PD), 004 (fourth line; PD), 015 (sixth line; SD), 003 (fourth line; PD), 012 (fifth line; PD), and 009 (fourth line; PD). PD, progressive disease; PR, partial response; SD, stable disease. *Continued ibrutinib use through month 3.

Figure 2.

Representative magnetic resonance imaging of responders at baseline and initial time point of best overall response. (A) Patient 007 baseline scan demonstrating a 1.6 cm × 1.3 cm × 1.1 cm enhancing mass within the left posterior caudate body bordering the left lateral ventricle with complete resolution of enhancing lesion at month 4. Patient 008 baseline scan demonstrating a 1.4 cm × 1.4 cm × 0.5 cm enhancing mass in the left middle frontal gyrus corresponding to biopsy proven CNS lymphoma with complete resolution at month 3. (B) Patient 011 demonstrating leptomeningeal enhancement within the spinal cord and (C) CD19⁺ CD20⁺ CD5⁻ CD10⁻/dim leptomeningeal disease with monotypic κ immunoglobulin light chain expression at baseline, day +7 and month 1 demonstrating resolution following tisagenlecleucel infusion.

Figure 3.

Peripheral CAR-T expansion and phenotyping. Expansion of tisagenlecleucel in peripheral blood and associated CAR-T phenotyping during peak expansion (day +7) demonstrating variable T_Naïve, T_EMRA, T_EM, T_CM, and T_SCM phenotypes.

Figure 3.

Peripheral CAR-T expansion and phenotyping. Expansion of tisagenlecleucel in peripheral blood and associated CAR-T phenotyping during peak expansion (day +7) demonstrating variable T_Naïve, T_EMRA, T_EM, T_CM, and T_SCM phenotypes.

Figure 4.

CSF and cytokine analysis of pre/post infusion samples. (A) Detection of tisagenlecleucel by RNA (Nanostring) demonstrating higher levels of the WPRE element in patients who achieved a CR. (B) Detection of tisagenlecleucel in the CSF of patient 008 (21 CAR+ cells/μL CSF) on day +7 by flow cytometry. (C) Pathway analysis and differential gene expression of patients who achieved a CR as best response vs others. Increase over non-CRs shown. (D) Representative serum and CSF cytokine analysis showing fold change from preinfusion baseline vs day +7. Grade 3 ICANS event shown in red.