T cells expressing CD19-specific Engager Molecules for the Immunotherapy of CD19-positive Malignancies

Sci Rep. 2016 Jun 3:6:27130. doi: 10.1038/srep27130.

Abstract

T cells expressing chimeric antigen receptors (CARs) or the infusion of bispecific T-cell engagers (BITEs) have shown antitumor activity in humans for CD19-positive malignancies. While BITEs redirect the large reservoir of resident T cells to tumors, CAR T cells rely on significant in vivo expansion to exert antitumor activity. We have shown that it is feasible to modify T cells to secrete solid tumor antigen-specific BITEs, enabling T cells to redirect resident T cells to tumor cells. To adapt this approach to CD19-positive malignancies we now generated T cells expressing secretable, CD19-specific BITEs (CD19-ENG T cells). CD19-ENG T cells recognized tumor cells in an antigen-dependent manner as judged by cytokine production and tumor killing, and redirected bystander T cells to tumor cells. Infusion of CD19-ENG T cells resulted in regression of leukemia or lymphoma in xenograft models and a survival advantage in comparison to control mice. Genetically modified T cells expressing engager molecules may present a promising addition to current CD19-targeted immunotherapies.

Publication types

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

MeSH terms

  • A549 Cells
  • Animals
  • Antigens, CD19 / metabolism*
  • Cell Line, Tumor
  • Cytotoxicity, Immunologic
  • Humans
  • Immunotherapy
  • K562 Cells
  • Mice
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / immunology
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / therapy*
  • Single-Chain Antibodies / genetics*
  • Single-Chain Antibodies / metabolism
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD19
  • CD19 molecule, human
  • Single-Chain Antibodies