title: Local secretion of anti-CTLA-4 enhances the therapeutic efficacy of a cancer immunotherapy with reduced evidence of systemic autoimmunity.
abstract: Promising anti-tumor responses have been observed in the clinic using monoclonal antibodies (mAbs) that block immune checkpoints. One concern with these therapeutic agents remains the potential induction of immune breakthrough events (IBEs) resulting from the disruption of T cell homeostasis or the breaking of tolerance to self antigens. As an approach to maintaining anti-tumor responses but decreasing the likelihood of these events, the local expression of a mAb in combination with a GM-CSF-secreting cancer immunotherapy was evaluated. Using anti-cytotoxic T lymphocyte antigen (CTLA)-4 as a model antibody to test this hypothesis, tumor cell lines were generated that expressed the full-length mAb in addition to GM-CSF. Evaluation of these cell lines in two therapeutic tumor models revealed that local, cell-mediated delivery of anti-CTLA-4 from a GM-CSF-secreting tumor cell immunotherapy activated potent anti-tumor responses and prolonged overall survival at significantly lower serum mAb levels in the host. Furthermore, lowering the systemic exposure of the host to the immune modulatory mAb correlated with reduced evidence of systemic autoimmunity. This approach has broad utility for the delivery of mAbs or proteins locally from cellular immunotherapies to minimize IBEs while retaining the potent therapeutic effects of such combination treatments.
authors.affiliation: Cell Genesys, Inc., 500 Forbes Blvd, South San Francisco, CA 94080, USA. andrew.simmons@cellgenesys.com
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Simmons
authors.forename: Marina
authors.initials: M
authors.lastname: Moskalenko
authors.forename: Jennifer
authors.initials: J
authors.lastname: Creson
authors.forename: Jianmin
authors.initials: J
authors.lastname: Fang
authors.forename: Saili
authors.initials: S
authors.lastname: Yi
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: VanRoey
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.forename: Karin
authors.initials: K
authors.lastname: Jooss
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000235:genetics; D015703:Antigens, CD / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D060908:CTLA-4 Antigen; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006825:Hybridomas / Q000276:immunology; D007167:Immunotherapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor