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Updated: Aug 6, 2026

A Murine Ommaya Xenograft Model to Study Direct-Targeted Therapy of Leptomeningeal Disease
Published on: January 29, 2021
Rituximab therapy for CNS lymphomas: targeting the leptomeningeal compartment
James L Rubenstein1, Dan Combs, Jay Rosenberg
1Division of Hematology/Oncology, Comprehensive Cancer Center, Cancer Research Institute, Department of Neurosurgery, UCSF, San Francisco, CA 94143, USA. jamesr@medicine.ucsf.edu
Insights
Direct intrathecal administration of rituximab showed no toxicity in monkeys, suggesting a potential new treatment for central nervous system lymphomas. Further studies will investigate its safety and pharmacokinetics in patients.
Area of Science:
- Neuro-oncology
- Pharmacology
- Immunotherapy
Background:
- Central nervous system (CNS) lymphomas are typically CD20-positive B-cell neoplasms.
- Intravenous rituximab achieves low cerebrospinal fluid (CSF) levels (0.1% of serum), limiting its efficacy for CNS disease.
- Lymphomatous meningitis is a common complication of non-Hodgkin lymphoma.
Purpose of the Study:
- To evaluate the safety and pharmacokinetics of direct intrathecal rituximab administration.
- To determine the feasibility of intrathecal rituximab for CNS lymphoma treatment.
Main Methods:
- Cynomolgus monkeys received direct intrathecal administration of rituximab.
- Safety was assessed through observation for acute and delayed toxicity, including neurological effects.
- Pharmacokinetics were analyzed by measuring drug clearance from CSF.
Main Results:
- No significant acute or delayed toxicity, including neurological adverse events, was observed.
- CSF drug clearance exhibited biphasic kinetics.
- The terminal half-life of rituximab in CSF was determined to be 4.96 hours.
Conclusions:
- Direct intrathecal administration of rituximab appears safe in a non-human primate model.
- The pharmacokinetic profile supports further investigation in human clinical trials.
- These findings provide a basis for a Phase 1 study of intrathecal rituximab in patients with recurrent lymphomatous meningitis.
Abstract:
Most lymphomas that involve the central nervous system are B-cell neoplasms that express the cell surface molecule CD20. After intravenous administration, rituximab can be reproducibly measured in the cerebrospinal fluid (CSF) in patients with primary central nervous system lymphoma; however, the CSF levels of rituximab are approximately 0.1% of serum levels associated with therapeutic activity in patients with systemic non-Hodgkin lymphoma. Because lymphomatous meningitis is a frequent complication of non-Hodgkin lymphoma, we have conducted an analysis of the safety and pharmacokinetics of direct intrathecal administration of rituximab using cynomolgus monkeys. No significant acute or delayed toxicity, neurologic or otherwise, was detected. Pharmacokinetic analysis suggests that drug clearance from the CSF is biphasic, with a terminal half-life of 4.96 hours. A phase 1 study to investigate the safety and pharmacokinetics of intrathecal rituximab in patients with recurrent lymphomatous meningitis will be implemented based on these findings.
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