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 ζ chain (TCR-ζ) 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-ζ 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.