Intraventricular immune checkpoint inhibition with nivolumab in relapsed primary central nervous system lymphoma

Abstract

Sequencing studies have deciphered the genetic landscape of primary central nervous system lymphoma (PCNSL) paving novel therapeutic avenues in recent years.1,2 Frequent 9p24.1 copy number gains, the genetic locus of programmed cell death protein 1 (PD-1) ligands PD-L1 and PD-L2, were detected and suggestive of immune evasion via activation of PD-1 signaling.1 Systemic nivolumab, a monoclonal PD-1 antibody, was hence evaluated in a small retrospective PCNSL cohort yielding promising long-term responses.3 Intracranial efficacy of systemically administered monoclonal antibodies may however be impeded by an intact blood-brain barrier (BBB) resulting in lower cerebrospinal fluid (CSF) penetration. To bypass the BBB and reduce systemic toxicities, intraventricular/intrathecal immunochemotherapy is being investigated. Intrathecal nivolumab combined with its systemic administration was recently found safe and effective in melanoma with leptomeningeal dissemination,4 prompting us to evaluate intraventricular nivolumab for recurrent primary CNS lymphoma (PCNSL) in an elderly patient unable to tolerate aggressive systemic polychemotherapy. Intraventricular nivolumab achieved a lasting (>12 months) complete remission including parenchymal lesions distant from cerebrospinal fluid spaces. No toxicities or adverse events related to the mode of administration were noted. Our case suggests intraventricular nivolumab is active in recurrent parenchymal PCNSL. Together with detected 9p24.1 gains this argues for further prospective evaluation, for which our treatment protocol provides a framework.