title: A conjugate of a tumor-targeting ligand and a T cell costimulatory antibody to treat brain tumors.
abstract: T cell immunotherapy is a potential strategy for the treatment of brain tumors because it offers a high degree of specificity, the ability to extravasate into solid tumors, and the potential for eliciting a long-term protective immune response. Various approaches have been developed to overcome T cell immune tolerance to cancer, including the use of cytokines and bispecific antibodies. T cell stimulation with the proinflammatory cytokine IL-12 can elicit antitumor immunity. T cell activation can be increased using bispecific antibodies against activating molecules on the surface of T cells and a tumor antigen. We studied the effects of systemic IL-12 administration in combination with a conjugate of an anti-CD28 antibody and a ligand for the folate receptor. The high affinity folate receptor is expressed on endogenously arising choroid plexus tumors of SV11 mice, which are transgenic for large T antigen under the control of the SV40 promoter. SV11 mice are immunocompetent, yet immunologically tolerant to large T antigen expressed by choroid plexus tumors. MRI analysis showed that the administration of IL-12 and anti-CD28 Fab/folate significantly slowed tumor growth. Proliferating CD8(+) T cells were found in choroid plexus tumors of treated animals. Treatment of animals with IL-12 + anti-CD28 Fab/folate prolonged survival compared to IL-12 alone. Cytokine treatment combined with tumor-targeted costimulation may be a useful adjunct treatment.
authors.affiliation: Neuroscience Program and Department of Biochemistry, University of Illinois, Urbana, Illinois 61801, USA.
authors.forename: Ute
authors.initials: U
authors.lastname: Gawlick
authors.forename: David M
authors.initials: DM
authors.lastname: Kranz
authors.forename: Victor D
authors.initials: VD
authors.lastname: Schepkin
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Roy
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D008024:Ligands; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000961:Antilymphocyte Serum; D000970:Antineoplastic Agents; D008024:Ligands