Immunotherapy targeting B cells and long-lived plasma cells effectively eliminates pre-existing donor-specific allo-antibodies

Cell Rep Med. 2023 Dec 19;4(12):101336. doi: 10.1016/j.xcrm.2023.101336.

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.

Keywords: BCMA; CAR T cells; CD19; TACI; allo-antibodies; desensitization; immunotherapy; long-lived plasma cells; rejection; transplantation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies
  • B-Cell Maturation Antigen
  • Humans
  • Immunotherapy
  • Mice
  • Plasma Cells
  • Receptors, Chimeric Antigen*
  • T-Lymphocytes

Substances

  • Receptors, Chimeric Antigen
  • B-Cell Maturation Antigen
  • Antibodies

Associated data

  • ClinicalTrials.gov/NCT03549442