Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies
Zheng Zhang, Caroline Markmann, Ming Yu, Divyansh Agarwal, Susan Rostami, Wei Wang, Chengyang Liu, Huiwu Zhao, Trini A. Ochoa, Kalpana Parvathaneni, Xiao‐Ming Xu, Eric Li, Vanessa Gonzalez, Roman H. Khadka, Jennifer Hoffmann, James J. Knox, John Scholler, Brooke Marcellus, David Allman, Joseph A. Fraietta, Benjamin Samelson-Jones, Michael C. Milone, Dimitri Monos, Alfred L. Garfall, Ali Naji, Vijay Bhoj
Abstract
Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.