Abstract
Introduction: Relapsed, refractory (R/R) primary (PCSNL) and secondary central nervous system lymphoma (SCNSL) are difficult to treat diseases with poor clinical outcomes. We recently reported a high level of expansion of dual targeted lentiviral transduced anti-CD20/anti-CD19 (LV20.19) CAR T-cells into the CNS in a cohort of patients (pts) with R/R MCL (Shah et al. JCO 2025). Accordingly, we amended an ongoing single center multi-cohort clinical trial of LV20.19 CAR T cell therapy to include an arm for high-dose (HD) methotrexate R/R PCNSL or SCNSL.
Methods: We conducted a Phase 1/2 single center, multi-cohort prospective trial (NCT04186520) evaluating LV20.19 CAR T-cells at a fixed dose of 2.5x10e6 cells/kg for pts with R/R B-cell non-Hodgkin Lymphoma. CAR T-cells were all manufactured on site utilizing the CliniMACS Prodigy device for a flexible 8 or 12-day manufacturing (MF) process with the goal of fresh CAR T cell infusion. Lymphodepletion was standard fludarabine/cyclophosphamide conditioning. Cohort E was added to the multi-arm trial to include pts with R/R primary or secondary CNS lymphoma involvement who had seen prior high-dose methotrexate. International Primary CNS Lymphoma Collaborative Group (IPCG) criteria from Abrey et al. JCO 2005 was used for evaluation of response.
Results: To date, six pts have enrolled including four pts with PCNSL and two with SCNSL (DLBCL and MCL). All pts had parenchymal disease with enhancing lesions by MRI and two pts had concurrent leptomeningeal disease before LV20.19 CAR T cell therapy. The median age was 63 (range 42-80) and five of six patients were male. All pts received prior HD methotrexate and over 50% of pts received at least four lines of prior therapy. Three pts had prior thiotepa conditioned autologous transplants. Two pts had prior whole brain radiation. All LV20.19 CAR-T products were manufactured in 8 days, and five pts received a fresh product. One pt had his CAR T cells cryopreserved and received the product later, due to rapid CNS decline after apheresis requiring intubation and whole brain radiation. The Day 28 overall response rate (ORR) was 100% (CR=5 pts, PR=1 pt), and only one of the six patients relapsed with a median follow-up of eight months. Day 28 lumbar punctures were assessed for LV20.19 CAR T cells in four patients with all having detectable CAR T cells within the CSF. The toxicity profile of this product was in line with prior trials; 83% (n=5) experienced Grade 1-2 CRS, and no patient experienced ICANS. All pts remain alive to date.
Conclusions: In this early analysis of Cohort E consisting of pts with R/R PCNSL and SCNSL, LV20.19 CAR T cell therapy demonstrates promising clinical activity with high response rates, manageable toxicity, and detectable CNS penetrance of the CAR T cells. Importantly, no patient developed ICANS and CRS was low-grade and manageable. These findings highlight the feasibility, safety, and encouraging efficacy of LV20.19 CAR T cell therapy in this high-risk patient population with historically limited treatment options and poor prognosis. This data supports further investigation of dual-targeted LV20.19 CAR T therapy in CNS lymphoma.
