Use of BAFFR CAR-T to treat B cell leukemia/lymphoma and auto-immune diseases.

Abstract

6523 Background: BAFFR (B-cell Activating Factor Receptor) is a member of the tumor necrosis factor (TNF) receptor superfamily and is almost exclusively expressed on B cells. Meanwhile, BAFFR is found to be highly expressed on the surface of lymphoma cells. In addition, blocking the BAFF/BAFFR interaction can inhibit the maturation of B cells, which is beneficial for alleviating autoimmune diseases, such as psoriasis, inflammatory bowel disease, multiple sclerosis, and rheumatoid arthritis. These characteristics make BAFFR a promising target for B-cell malignancies and auto-immune diseases. It has been reported that BAFFR CAR-T (PMB-CT01) treated six non-Hodgkin lymphoma (NHL) patients, and all of these patients achieved CR and showed tolerable safety profile. Methods: In the current study, we screened out three different BAFFR antibodies (1312, 1313, and 1315) and constructed them into second-generation CARs, consisting of BAFFR scFv, 4-1BB co-stimulatory domain and CD3ζ. The preclinical efficacy of BAFFR CAR-T cells was evaluated in vitro and in vivo. Results: In vitro experiments showed that all three CAR-T cells effectively killed Raji tumor cells, with 1312-CAR-T demonstrating the strongest cytokine release and cytotoxicity. In vivo tumor-bearing mouse experiments using Raji cells showed that 1312-CAR-T could effectively clear tumor cells in the mice. While the control group all mice died by day 33, and the experimental group remained fully alive. In addition, SLE model using MRL/MpJ-Fas lpr mice showed that BAFFR CAR-T cells could decrease the dsDNA-IgG levels in the serum. Conclusions: The results of this study suggest that BAFFR is an active and promising immunotherapeutic target for B-cell malignancies and auto-immune diseases. In the future, BAFFR CAR-T clinical trials will be conducted to treat B-ALL, lymphoma, and autoimmune diseases. It would be interesting to see whether BAFFR CAR-T can achieve similar or even better results than CD19 CAR-T in treating these diseases.