Preclinical development of CD37CAR T-cell therapy for treatment of B-cell lymphoma

Abstract

T cells modified to express chimeric antigen receptor (CAR) targeting CD19 (CD19CAR) have produced remarkable clinical responses in patients with relapsed/refractory B-cell acute lymphoblastic leukemia. CD19CAR T-cell therapy has also demonstrated prominent effects in B-cell non-Hodgkin lymphoma (B-NHL) patients. However, a subset of patients who relapse after CD19CAR T-cell therapy have outgrowth of CD19− tumor cells. Hence, development of alternative CARs targeting other B-cell markers represents an unmet medical need for B-cell acute lymphoblastic leukemia and B-NHL. Here, we confirmed previous data by showing that, overall, B-NHL has high expression of CD37. A second-generation CD37CAR was designed, and its efficacy in T cells was compared with that of CD19CAR. In vitro assessment of cytotoxicity and T-cell function upon coculture of the CAR T cells with different target B-cell lymphoma cell lines demonstrated comparable efficacy between the 2 CARs. In an aggressive B-cell lymphoma xenograft model, CD37CAR T cells were as potent as CD19CAR T cells in controlling tumor growth. In a second xenograft model, using U2932 lymphoma cells containing a CD19− subpopulation, CD37CAR T cells efficiently controlled tumor growth and prolonged survival, whereas CD19CAR T cells had limited effect. We further show that, unlike CD19CAR, CD37CAR was not sensitive to antigen masking. Finally, CD37CAR reactivity was restricted to B-lineage cells. Collectively, our results demonstrated that CD37CAR T cells also can effectively eradicate B-cell lymphoma tumors when CD19 antigen expression is lost and support further clinical testing for patients with relapsed/refractory B-NHL.

Phase I dose escalation study of BI 836826 (CD37 antibody) in patients with relapsed or refractory B-cell non-Hodgkin lymphoma

“…As with our study, the incidence of Grade 3/4 neutropenia (53%) was high; grade 3/4 thrombocytopenia was also common (48%). Further clinical investigation of AGS57E is ongoing [ 14 ], along with preclinical studies investigating CD37 as a target for chimeric antigen receptor T cell therapy [ 14 , 23 ].…”

The Advent of CAR T-Cell Therapy for Lymphoproliferative Neoplasms: Integrating Research Into Clinical Practice

“…Finally, preclinical studies showed that also anti-CD37 CAR T cells can be active against B-cell lymphomas (111,112).…”

In Vitro-Transcribed mRNA Chimeric Antigen Receptor T Cell (IVT mRNA CAR T) Therapy in Hematologic and Solid Tumor Management: A Preclinical Update

“…Accordingly, insertion of CXCR4 or CCR7 mRNA contributes to the homing of CAR T cells towards bone marrow and lymphnodes, respectively, and binding with CD19 surface antigen. Köksal et al demonstrated the killing efficiency and/or tumor growth in vitro and in vivo of CD37-targeting mRNA CAR T cells against human Burkitt's lymphoma cell line BL41 and diffuse large B cell lymphoma cell line U-2932 [13]. In addition to murine models, the feasibility and safety of IVT mRNA CAR T cells has been investigated in canine models.…”

“…in vitro CD19 -Leukemia, lymphoma Cytotoxicity [10] in vivo CD19 Multiple doses 5 × 10 6 ; i.p. lymphoma Tumor growth inhibition [11] in vitro CD19 -Leukemia, lymphoma Degranulation and IFN-γ secretion [12] In vitro and in vivo CD37 Multiple doses 10 7 ; intratumorally Lymphoma Cytotoxicity; tumor growth reduction [13] in vivo Canine CD20-ζ 2.4 ×10 8 , 5.4 × 10 7 , 1.1 × 10 8 cells i.v. ; 1.16 × 10 8 cells i.n.…”