Tumor gene therapy by MVA-mediated expression of T-cell-stimulating antibodies.
Immune responses to tumor-associated antigens are often dampened by a tumor-induced state of immune anergy. Previous work has attempted to overcome tumor-induced T-cell anergy by the direct injection of vectors carrying the genes encoding one of a variety of cytokines. We hypothesised that the polyclonal stimulation of T cells, preferably through the TCR complex, would result in a cascade of cytokines associated with T-cell activation and would be best able to overcome T-cell anergy. Here we use the highly attenuated MVA poxvirus to express on tumor cells, in vitro and in vivo, either of three membrane-bound monoclonal antibodies specific for murine TCR complex. Using this system, we have expressed antibodies specific for the CD3 epsilon chain (KT3), TCR alpha/beta complex (H57-597), and V beta 7 chain (TR310). Tumor cells bristling with these antibodies are capable of inducing murine T-cell proliferation and cytokine production. When injected into growing tumors (P815, RenCa, and B16F10), these constructs induce the activation of immune effector cells and result in the rejection of the tumor. Histological and FACS analysis of tumor-infiltrating leukocytes reveal that the injection of recombinant virus-expressing antibodies specific for the TCR complex attracts and activates (CD25(+), CD69(+)) CD4 and CD8 lymphocytes. This approach represents a novel strategy to overcome T-cell anergy in tumors and allow the stimulation of tumor-specific T cells.
Paul
Stephane
S
Clinical and Experimental Immunology Laboratory, Transgene, Strasbourg 67082, France. paul@transgene.fr
Regulier
Etienne
E
Rooke
Ronald
R
Stoeckel
Fabienne
F
Geist
Michel
M
Homann
Horst
H
Balloul
Jean-Marc
JM
Villeval
Dominique
D
Poitevin
Yves
Y
Kieny
Marie-Paule
MP
Acres
R Bruce
RB
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D015153:Blotting, Western; D017252:CD3 Complex / Q000235:genetics; D002455:Cell Division; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010641:Phenotype; D011212:Poxviridae / Q000235:genetics; D011485:Protein Binding; D051381:Rats; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D011948:Receptors, Antigen, T-Cell; D011994:Recombinant Proteins