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

Abstract

Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphoma 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.

Systemic Relapse in a Young Adult Patient with Primary CNS Diffuse Large B-Cell Lymphoma

“…Two patients were noted to have CR at day +90 and day +180 respectively, while two patients died within 30 days secondary to disease progression [ 30 ]. Several ongoing clinical trials [ 32 , 33 ] are exploring the use of CAR-T in PCNSL ( Table 1 ).…”

A Case of Relapsed Primary Central Nervous System Lymphoma Treated with CD19-directed Chimeric Antigen Receptor T Cell Therapy

“…The first problem is antigen loss. In patients with B-cell leukemia, 7%-25% of relapsed patients lost CD19 expression, 18 ) which resulted in the loss of target antigen. Thus, some PCNSL was treated with dual targeting CAR-T, such as CD19, CD22, or CD70 ( Table 1 ).…”

Primary extranodal diffuse large B‐cell lymphoma: Molecular features, treatment, and prognosis

“…105,106 The most clinically used products of this gene-modified cellular therapy are CAR-T cell targeting CD19 with encouraging results, while products targeting additional targets are in extensive clinical trials. [105][106][107][108]…”

“…In terms of immunotherapy, immune checkpoint inhibitors are not efficacious in DLBCL, while Chimeric antigen receptor (CAR)‐T‐cell therapy with significant implications in the treatment of relapsed or refractory DLBCL and represents a new direction of exploration 105,106 . The most clinically used products of this gene‐modified cellular therapy are CAR‐T cell targeting CD19 with encouraging results, while products targeting additional targets are in extensive clinical trials 105–108 …”