Immunotherapy of cancer using systemically delivered gene-modified human T lymphocytes.
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.
Teng
Michele W L
MW
Cancer Immunology Program, Sir Donald and Lady Trescowthick Laboratories, Peter MacCallum Cancer Centre, Melbourne 8006, Australia.
Kershaw
Michael H
MH
Moeller
Maria
M
Smyth
Mark J
MJ
Darcy
Phillip K
PK
D000818:Animals; D002277:Carcinoma / Q000556:secondary / Q000628:therapy; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D016207:Cytokines / Q000096:biosynthesis; D005452:Fluoresceins / Q000494:pharmacology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D057127:Single-Chain Antibodies; D013388:Succinimides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000637:transplantation*; D013936:Thymidine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D016207:Cytokines; D005452:Fluoresceins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D013388:Succinimides; D013936:Thymidine; C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; C496415:scFv-CD28-zeta chimeric receptor