title: Tumor ablation by gene-modified T cells in the absence of autoimmunity.
abstract: Adoptive immunotherapy involving genetic modification of T cells with antigen-specific, chimeric, single-chain receptors is a promising approach for the treatment of cancer. To determine whether gene-modified T cells could induce antitumor effects without associated autoimmune pathology, we assessed the ability of T cells expressing an anti-Her-2 chimeric receptor to eradicate tumor in Her-2 transgenic mice that express human Her-2 as a self-antigen in brain and mammary tissues. In adoptive transfer studies, we demonstrated significant improvement in the survival of mice bearing Her-2(+) 24JK tumor following administration of anti-Her-2 T cells compared with control T cells. The incorporation of a lymphoablative step prior to adoptive transfer of anti-Her-2 T cells and administration of IL-2 were both found to further enhance survival. The reduction in tumor growth was also correlated with localization of transferred T cells at the tumor site. Furthermore, an antigen-specific recall response could be induced in long-term surviving mice following rechallenge with Her-2(+) tumor. Importantly, antitumor effects were not associated with any autoimmune pathology in normal tissue expressing Her-2 antigen. This study highlights the therapeutic potential of using gene-engineered T cells as a safe and effective treatment of cancer.
authors.affiliation: Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors.forename: Leanne X J
authors.initials: LX
authors.lastname: Wang
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Westwood
authors.forename: Maria
authors.initials: M
authors.lastname: Moeller
authors.forename: Connie P M
authors.initials: CP
authors.lastname: Duong
authors.forename: Wei-Zen
authors.initials: WZ
authors.lastname: Wei
authors.forename: Jordane
authors.initials: J
authors.lastname: Malaterre
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Trapani
authors.forename: Paul
authors.initials: P
authors.lastname: Neeson
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Michael H
authors.initials: MH
authors.lastname: Kershaw
authors.forename: Phillip K
authors.initials: PK
authors.lastname: Darcy
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D018106:CD28 Antigens / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000235:genetics; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D016207:Cytokines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins