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

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.

• Authors: Michele W L Teng, Michael H Kershaw, Maria Moeller, Mark J Smyth, Phillip K Darcy
• Journal: Human gene therapy (Hum Gene Ther) Vol. 15 Issue 7 Pg. 699-708 (Jul 2004) ISSN: 1043-0342 [Print] United States
• PMID: 15242530 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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