Genetically targeted T cells eradicate established breast cancer in syngeneic mice.
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.
Wang
Hao
H
International Joint Cancer Institute and Changhai Hospital Cancer Center, The Second Military Medical University, Shanghai, People's Republic of China.
Wei
Huafeng
H
Zhang
Ruiping
R
Hou
Sheng
S
Li
Bohua
B
Qian
Weizhu
W
Zhang
Dapeng
D
Kou
Gen
G
Dai
Jianxin
J
Guo
Yajun
Y
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*
D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D007135:Immunoglobulin Variable Region; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; C114805:scFv fragment SW1