Emerging Landscape of Immunotherapy for Primary Central Nervous System Lymphoma

SIMPLE SUMMARY: Primary central nervous system lymphoma (PCNSL) is characterized by its location in the central nervous system comprising the brain, the eye, the cerebrospinal fluid and the spinal cord and a poor prognosis with the current chemotherapies. Immunotherapies represent a new paradigm in the care of patients with B-cell lymphoma, but, till recently, immunotherapies studies excluded patients with PCNSL because of the lack of knowledge on the immune network in the brain. Recent studies shed a new light on the origin and characteristics of the CNS immune cells. We review the current experimental preclinical and clinical developments of immunotherapies in CNS lymphoma as well as the effects of targeted therapies on the brain microenvironment. We provide perspectives for improving the efficacy of immunotherapies in the specific setting of PCNSL for a better prognosis of this disease. ABSTRACT: Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell (non-GCB) origin. It is associated with a poor prognosis and an unmet medical need. Immunotherapy has emerged as one of the most promising areas of research and is now part of the standard treatment for many solid and hematologic tumors. This new class of therapy generated great enthusiasm for the treatment of relapsed/refractory PCNSL. Here, we discuss the challenges of immunotherapy for PCNSL represented by the lymphoma cell itself and the specific immune brain microenvironment. We review the current clinical development from the anti-CD20 monoclonal antibody to CAR-T cells, as well as immune checkpoint inhibitors and targeted therapies with off-tumor effects on the brain microenvironment. Perspectives for improving the efficacy of immunotherapies and optimizing their therapeutic role in PCNSL are suggested.