Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia

J Clin Invest. 2016 Nov 1;126(11):4262-4272. doi: 10.1172/JCI84813. Epub 2016 Oct 17.

Abstract

The adoptive transfer of T cells that have been genetically modified to express a CD19-specific chimeric antigen receptor (CAR) is effective for treating human B cell malignancies. However, the persistence of functional CD19 CAR T cells causes sustained depletion of endogenous CD19+ B cells and hypogammaglobulinemia. Thus, there is a need for a mechanism to ablate transferred T cells after tumor eradication is complete to allow recovery of normal B cells. Previously, we developed a truncated version of the epidermal growth factor receptor (EGFRt) that is coexpressed with the CAR on the T cell surface. Here, we show that targeting EGFRt with the IgG1 monoclonal antibody cetuximab eliminates CD19 CAR T cells both early and late after adoptive transfer in mice, resulting in complete and permanent recovery of normal functional B cells, without tumor relapse. EGFRt can be incorporated into many clinical applications to regulate the survival of gene-engineered cells. These results support the concept that EGFRt represents a promising approach to improve safety of cell-based therapies.

Publication types

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

MeSH terms

  • Agammaglobulinemia / drug therapy*
  • Agammaglobulinemia / immunology
  • Agammaglobulinemia / pathology
  • Animals
  • Antigens, CD19 / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Cetuximab / pharmacology*
  • Female
  • Lymphocyte Depletion*
  • Mice
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology

Substances

  • Antigens, CD19
  • CD19 antigen, mouse
  • Cetuximab