Background: CD19-directed chimerical antigen receptor T-cell (CAR-T) therapy as an immunotherapy has documented significant clinical results in relapsed or refractory lymphoma patients, especially for diffuse large B-cell lymphoma (DLBCL) patients. Central nervous system lymphoma (CNSL) is classified into primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). Relapsed or refractory (R/R) PCNSL generally has a poor prognosis, with a median survival period of approximately 4 months. The median survival period of SCNSL ranged from 3.9 months to 1.5 years. Further, CNSL patients were excluded from all key CAR-T-based studies. We conducted a phase 1/2 clinical trial of CD19 CAR-T in highly relapsed/refractory CNSL patients where the medical need was not upto the mark.

Objectives: We evaluated the safety and efficacy of CD19 CAR-T in a highly refractory CNSL patients with treatment gaps in a prospective phase 1/2 study. Provide more evidence for CAR-T treatment of CNSL.

Methods: This prospective, open-label, single-center phase I/II clinical trial was conducted March 2019 to July 2024. In an accelerated titration, 6 patients were recruited and received stepwise infusion doses of CAR-T cells at 0.1 × 10⁶/kg, 0.2 × 10⁶/kg, and 0.5 × 10⁶/kg to monitor treatment-related toxicity. In Phase I, a standard 3+3 dose escalation design was used to evaluate the treatment-related toxicity in 9 patients who received the conventional dose range of 1-2 × 10⁶/kg CAR-T cells. If no dose-limiting toxicity (DLT) occurs, additional patients will be included in the Phase II expanded cohort.

The primary endpoint of this study was safety and tolerability, including all adverse events (AE) and serious adverse events (SAE). The main adverse reactions in CAR-T treatment are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). In addition, determine the recommended dose for subsequent Phase II trial. The secondary endpoint was to evaluate the overall response rate (ORR) and complete response rate (CRR) of dosing treatment. Overall survival (OS) and progression-free survival (PFS) probabilities were estimated employing the Kaplan–Meier method. The exploratory endpoint was to explore the transport of CAR-T cells into cerebrospinal fluid.

Results: A total of 69 subjects were enrolled and 45 patients were infused CD19 CAR-T cells. The median time from infusion to data cutoff was 16.01 months (range, 3.19-50.1). 17/45 (37.8%) ) patients were. male A median age of 60 years (range, 29-68) was seen for baseline patient characteristics. In terms of histological subtypes, PCNSL accounted for 23/45 (51.1%). After accelerated titration and the Phase I study of a total of 15 patients, 2e6 cells/kg CD19 CAR-T cells were determined as the infusion dose for the Phase II clinical trial.

Among the 45 patients who received CD19 CAR-T infusion, 24 (53.3%) patients developed Grade 1/2 CRS. There were no cases of grade ≥3 CRS. The median onset time after infusion was 12.95 hours and the median duration was 36 hours in all CRS occurred patients. Six patients (13.3%) developed ICANS, only one patient (2.2%) presented with Grade 4 ICANS. The cause of death was determined to be disease progression.

Of 45 patients, the overall response rate (ORR) was 75.6% (95% CI 60.5-87.1). The complete response rate was 66.7% (95% CI 51.7-79.5). The median time from the start of administration to data cut-off was 16.01 months. At the time of data cutoff, there was no reach of the median overall survival (OS). The median progression-free survival (PFS) was 20.12 months.

Through univariate/multivariate COX regression analysis, it was found that age, gender, the efficacy of bridging treatment, ECOG score, prior treatment and IELSG/IPI score all had significant effects on the prognosis of patients. We conducted a comprehensive analysis of PBMC and CSF samples from patients who received CAR-T treatment. These analyses indicated that CAR-T cells can be transported to the CNS and expand within the CSF, especially in patients who have achieved CR.

Conclusion: The therapeutic potential of CD19 CAR-T therapy for hematological malignancies was documented in this analysis, especially for central nervous system lymphoma results in controllable adverse events and significantly improves the clinical treatment outcome.

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2025
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