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's lymphoma (NHL). This modality has not yet been extended to NHL manifesting in the central nervous system (CNS), primarily due to concerns for potential toxicity. CD19CAR T cells administered intravenously (IV) are detectable in cerebrospinal fluid (CSF), suggesting that CAR T cells can migrate from the periphery into the CNS, where they can potentially mediate anti-lymphoma activity. Here, we report the outcome of a subset of patients with primary CNS lymphoma (PCNSL; n=5) treated with CD19CAR T cells in our ongoing Phase 1 clinical trial (NCT02153580). All patients developed at least 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%CI [19%,92%]) appeared to achieve complete remission, as indicated by resolution of enhancing brain lesions, and the remaining 2 patients had stable disease. Although the study cohort was small, we demonstrated that using CD19CAR T cells to treat PCNSL can be safe and feasible.

Epidemiologic Characteristics, Prognostic Factors, and Treatment Outcomes in Primary Central Nervous System Lymphoma: A SEER-Based Study

“…In recent years, novel agents including immune checkpoint inhibitors, immunomodulatory drugs (IMiDs), Bruton tyrosine kinase (BTK) inhibitor, PI3K/ AKT/mTOR inhibitors, and chimeric antigen receptor T cell (CAR-T cell) therapy have been applied in several clinical trials, which exhibit promising clinic outcomes. Even with an impressive clinical response (8)(9)(10)(11), more randomized clinical trials are still needed to verify and identify the optimal therapy for PCNSL patients.…”

Novel insights into the biomarkers and therapies for primary central nervous system lymphoma

“…Even all five patients occurred grade ⩾ 1 CRS and neurotoxicity, and these toxicities were tolerable and manageable. 89 The French LOC reported their first clinical experience of commercial CD19 CAR T-cell therapy for r/r PCNSL, which supported the clinical application of CD19 CAR T-cells. The best response in nine patients was five CR and one PR, with median PFS 122 days (210 days for responders).…”

Systemic Relapse in a Young Adult Patient with Primary CNS Diffuse Large B-Cell Lymphoma

“…Novel targeted therapies, which have demonstrated efficacy both within the CNS and systemically for relapsed-refractory (R/R) PCNSL, should be considered. These agents have been investigated in prospective clinical trials [ 29 , 35 – 56 ], and are summarized below ( Table 2 ). Single-agent temsirolimus, an mTOR inhibitor, demonstrated an ORR of 54% in a study of 37 patients with refractory PCNSL [ 44 ].…”