CD19-directed CAR T-cell therapy for treatment of primary CNS lymphoma

Abstract

CD19-directed chimeric antigen receptor (CD19CAR) T-cell therapy has been successful in treating several B-cell lineage malignancies, including B-cell non-Hodgkin lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily as a result of concerns for potential toxicity. CD19CAR T cells administered IV are detectable in cerebrospinal fluid (CSF), suggesting that chimeric antigen receptor (CAR) T cells can migrate from the periphery into the CNS, where they can potentially mediate antilymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n = 5) who were treated with CD19CAR T cells in our ongoing phase 1 clinical trial. All patients developed grade ≥ 1 cytokine release syndrome and neurotoxicity post-CAR T-cell infusion; toxicities were reversible and tolerable, and there were no treatment-related deaths. At initial disease response, 3 of 5 patients (60%; 90% confidence interval, 19-92%) seemed to achieve complete remission, as indicated by resolution of enhancing brain lesions; the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrate that using CD19CAR T cells to treat PCNSL can be safe and feasible. This trial was registered at www.clinicaltrials.gov as #NCT02153580.

Figure 1.

Percentages of CAR T cells in the blood and CSF. (A) Persistence of EGFR⁺ CAR T cells in blood circulation of patients after CAR T-cell infusion on days 0, 1, 7, 14, 21, and 28. The percentage of EGFR⁺ T cells are gated from live CD3⁺ cells. (B) Expansion and persistence of CD19CAR T cells in blood of patients, as measured by Woodchuck post-transcriptional regulatory element (WPRE) copy number per milliliter of blood. (C) Levels of CD19⁺ cells in blood circulation after CAR T-cell infusion. CD19⁺ cells are gated from live cells. (D) Persistence of EGFR⁺ CAR T cells in CSF from unique patient number (UPN) 272 on day 0 and on days 7 and 14 post–T-cell infusion. Absolute cells per milliliter of CSF (left panel) and flow cytometry plots of CD3⁺ cell and EGFR⁺ cells on day 7 (middle panel) and on day 14 (right panel) post–CAR T-cell infusion. (E) Brain MRI series of UPN 475 pre–CAR T-cell infusion (left panel) and post–CAR T-cell infusion (right panel). Images are T1 weighted postcontrast axial. The pretherapy scan shows an enhancing lesion in the left basal ganglia (arrow) that is no longer present at 28 days post–CAR T-cell infusion. SD, stable disease.