Induction of human T lymphocyte cytotoxicity and inhibition of tumor growth by tumor-specific diabody-based molecules secreted from gene-modified bystander cells.
Infiltrating T cells are found in many malignancies, but they appear to be mostly anergic and do not attack the tumor, presumably because of the absence of activation and/or costimulatory signals. We describe a strategy for cellular antitumor immunotherapy by the in situ production of soluble bifunctional Ab-based molecules that activate and retarget T cells to the tumor. We genetically modified cells to simultaneously secrete two bifunctional molecules, a bispecific diabody directed against the carcinoembryonic Ag (CEA) and the CD3 epsilon chain of the TCR (alphaCEA x alphaCD3), and a fusion protein comprising the extracellular portion of B7-1 fused to a bivalent anti-CEA diabody (B7-alphaCEA). Together, alphaCEA x alphaCD3 and B7-alphaCEA proved potent at inducing the activation, proliferation, and survival of primary human T cells. When producer cells were cocultured with primary T cells and CEA(+) cancer cells, alphaCEA x alphaCD3 and B7-alphaCEA acted in combination to activate and retarget T cell cytotoxicity and completely abrogate tumor growth in the coculture. Furthermore, the introduction of just a few such producer cells at the tumor site efficiently inhibited the growth of established human colon carcinoma xenografts. Despite a cumbersome generation process, the use of autologous gene-modified producer cells opens the way for a new diabody-based gene therapy strategy of cancer.
Blanco
Belén
B
Department of Immunology, Hospital Universitario Clínica Puerta de Hierro, Madrid, Spain.
Holliger
Phillip
P
Vile
Richard G
RG
Alvarez-Vallina
Luis
L
D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D000918:Antibody Specificity / Q000235:genetics; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000235:genetics; D024201:Bystander Effect / Q000235:genetics / Q000276:immunology; D002272:Carcinoembryonic Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D002460:Cell Line; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D018390:Gene Targeting / Q000379:methods*; D005822:Genetic Vectors; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019073:HT29 Cells; D006801:Humans; D008213:Lymphocyte Activation / Q000235:genetics; D016853:Muromonab-CD3 / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000138:chemical synthesis / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014162:Transfection
D018033:Antibodies, Bispecific; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D002272:Carcinoembryonic Antigen; D006131:Growth Inhibitors; D016853:Muromonab-CD3; D011993:Recombinant Fusion Proteins