CAR T-Cells for CNS Lymphoma: Driving into New Terrain?

Abstract

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.

Keywords: adoptive; central nervous system; immunotherapy; refractory; relapsed; survival.

Figure 1

CAR design, route of CAR T-cell administration, and CAR cells. (A) Example of a second-generation CAR T-cell design used in the published clinical trials, incorporating a single-chain variable fragment (scFv) as an extracellular ligand recognition domain providing tumor antigen specificity, a transmembrane domain, an intracellular T-cell activating domain that includes a CD3 zeta chain (CD3ζ), and a co-stimulatory domain (CD28/4-1BB), included into the manufacturing process to ensure a more persistent CAR T-cell activity. (B) Only intravenous injection of CAR T-cells for lymphoma has been conducted so far. The blood–brain barrier may hamper delivery of CAR T-cells to the tumor environment whereas locally delivered CAR T-cells can travel to distant sites within the cerebrospinal fluid but can also be found in the systemic circulation. (C) CAR T-cells, natural killer cells, and macrophages all induce antigen targeted tumor cell elimination. CAR NK-cells recruit additional immune cells such as macrophages, T-cells, and dendritic cells, therefore improving anti-tumor activity. CAR-macrophages express proinflammatory cytokines and demonstrate antigen-specific phagocytosis, thereby presenting tumor antigens to regular T-cells. Abbreviations: CAR—chimeric antigen receptor; CAR NK—CAR natural killer cells; CAR T—CAR T-cells; CAR M—CAR-macrophages; DC—dendritic cell; scFv—single-chain variable fragment.