4.6 Review

Targeted Therapies and Immune Checkpoint Inhibitors in Primary CNS Lymphoma

Journal

CANCERS
Volume 13, Issue 12, Pages -

Publisher

MDPI
DOI: 10.3390/cancers13123073

Keywords

primary CNS lymphoma; PCNSL; ibrutinib; lenalidomide; immune checkpoint inhibition; PD-1; nivolumab; pembrolizumab

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Primary central nervous system lymphoma is a rare disease with limited treatment options, but emerging strategies include small molecule inhibitors, immunomodulatory agents, and immune checkpoint inhibitors. This review article discusses mechanisms, clinical study results, ongoing trials, and future prospects for these developments in CNS lymphoma treatment.
Simple Summary Primary central nervous system lymphoma is a rare disease with limited therapeutic options. A more profound understanding of the molecular mechanisms that underlie this disease has fostered the development of novel therapeutic approaches. Key developments for the treatment of primary central nervous system lymphoma were made in the field of small molecule inhibitors, i.e., drugs that were designed to specifically target the molecular backbone of cancer. Prominent examples include inhibitors of Bruton's tyrosine kinase or mammalian target of rapamycin, as well as immune modulatory thalidomide analogues. Along the same lines, another major strain of drug development for primary central nervous system lymphoma comprises of immune checkpoint inhibitors, i.e., monoclonal antibodies designed to unleash anti-cancer immune reactions. This review article discusses these ongoing clinical developments, including biological rationale as well as preliminary toxicity and efficacy, and provides an outlook for future developments. This review article outlines the current development of emerging treatment strategies for primary central nervous system lymphoma, a rare brain tumor with, thus far, limited therapeutic options. Small molecule targeted tyrosine kinase inhibitors, immunomodulatory agents, and immune checkpoint inhibitors will be discussed. The mechanisms of action, results of completed clinical studies, ongoing clinical trials, and future perspectives are summarized. Among the most promising clinical developments in the field of CNS lymphomas is ibrutinib, an inhibitor of Bruton's tyrosine kinase, which relays activation of nuclear factor kappa B upon integration of constitutive B cell receptor and Toll-like receptor signals. Down-stream of nuclear factor kappa B, the thalidomide analogs lenalidomide and pomalidomide exert immunomodulatory functions and are currently explored against CNS lymphomas. Finally, immune checkpoint inhibitors, such as drugs targeting the PD-1 pathway, may become novel therapeutic options to unleash anti-tumor immunity in patients with primary CNS lymphoma.

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