title: Genetically targeted T cells eradicate established breast cancer in syngeneic mice.
abstract: OBJECTIVE
  The purpose of the present study was to evaluate the capacity and mechanisms of genetically modified erbB2-specific T cells to eradicate erbB2+ tumors in syngeneic mice.
  
  
  METHODS
  Primary mouse T cells were modified to target the breast tumor-associated antigen erbB2 through retroviral-mediated transfer of a chimeric antigen receptor, termed single-chain antibody (scFv)-CD28-zeta. Antitumor efficacy of scFv-CD28-zeta-modified T cells was analyzed in mice bearing D2F2/E2 breast tumors.
  
  
  RESULTS
  The scFv-CD28-zeta-modified T cells were shown to specifically secrete T cytotoxic-1 cytokines and lyse erbB2+ breast tumor cells following receptor stimulation in vitro. Treatment with scFv-CD28-zeta-modified T cells was able to lead to long-term, tumor-free survival in mice bearing erbB2+ D2F2/E2 breast tumors. Importantly, the surviving mice developed a host memory response to D2F2/E2 tumor cells, and this host response was able to protect against a rechallenge with erbB2+ D2F2/E2 tumor cells and parental erbB2(-) D2F2 tumor cells. In addition, scFv-CD28-zeta T-cell expression of perforin and interferon-gamma were essential for complete antitumor efficacy.
  
  
  CONCLUSIONS
  Treatment with scFv-CD28-zeta-modified T cells was able to induce a host antitumor immunity in syngeneic mice. Complete tumor elimination by scFv-CD28-zeta-modified T cells required T cell-derived interferon-gamma and perforin, indicating that cytotoxicity and cytokine secretion play a role in the in vivo response.
authors.affiliation: International Joint Cancer Institute and Changhai Hospital Cancer Center, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Huafeng
authors.initials: H
authors.lastname: Wei
authors.forename: Ruiping
authors.initials: R
authors.lastname: Zhang
authors.forename: Sheng
authors.initials: S
authors.lastname: Hou
authors.forename: Bohua
authors.initials: B
authors.lastname: Li
authors.forename: Weizhu
authors.initials: W
authors.lastname: Qian
authors.forename: Dapeng
authors.initials: D
authors.lastname: Zhang
authors.forename: Gen
authors.initials: G
authors.lastname: Kou
authors.forename: Jianxin
authors.initials: J
authors.lastname: Dai
authors.forename: Yajun
authors.initials: Y
authors.lastname: Guo
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology*; D018106:CD28 Antigens; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D005260:Female; D018734:Genes, erbB-2; D006801:Humans; D007135:Immunoglobulin Variable Region; D007156:Immunologic Memory; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000276:immunology; D057127:Single-Chain Antibodies; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D007135:Immunoglobulin Variable Region; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C114805:scFv fragment SW1