Immunotherapy of cancer using systemically delivered gene-modified human T lymphocytes

Hum Gene Ther. 2004 Jul;15(7):699-708. doi: 10.1089/1043034041361235.

Abstract

The use of gene-engineered T cells expressing chimeric single-chain (scFv) receptors capable of codelivering CD28 costimulation and T cell receptor zeta chain (TCR-zeta) activation signals has emerged as a promising treatment regimen for cancer. Using retroviral transduction, primary human T lymphocytes were gene-engineered to express the scFv-CD28-zeta chimeric receptor reactive with the ErbB2 tumor-associated antigen. We demonstrated the ability of these gene-engineered human T cells to produce high levels of cytokines, proliferate vigorously, and mediate lysis of ErbB2(+) tumors in an antigen-specific manner. Furthermore, such gene-engineered human T cells significantly delayed the growth of two distinct subcutaneous ErbB2(+) human tumors in irradiated nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice after systemic administration. These preclinical studies are an important proof of principle that human T cells may be genetically redirected to tumors in cancer patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma / secondary
  • Carcinoma / therapy
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / immunology
  • Colonic Neoplasms / pathology
  • Colonic Neoplasms / therapy
  • Cytokines / biosynthesis
  • Fluoresceins / pharmacology
  • Humans
  • Immunotherapy / methods
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Receptor, ErbB-2 / immunology*
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism
  • Recombinant Fusion Proteins / genetics*
  • Recombinant Fusion Proteins / metabolism
  • Single-Chain Antibodies
  • Succinimides / pharmacology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Thymidine / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • 5-(6)-carboxyfluorescein diacetate succinimidyl ester
  • Cytokines
  • Fluoresceins
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Single-Chain Antibodies
  • Succinimides
  • scFv-CD28-zeta chimeric receptor
  • Receptor, ErbB-2
  • Thymidine