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: Ute Gawlick, David M Kranz, Victor D Schepkin, Edward J Roy
• Journal: Bioconjugate chemistry (Bioconjug Chem) 2004 Sep-Oct Vol. 15 Issue 5 Pg. 1137-45 ISSN: 1043-1802 [Print] United States
• PMID: 15366970 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antilymphocyte Serum
• Antineoplastic Agents
• Ligands

Topics

• Animals
• Antilymphocyte Serum (metabolism)
• Antineoplastic Agents (metabolism, therapeutic use)
• Brain Neoplasms (drug therapy, immunology)
• Cell Line, Tumor
• Drug Delivery Systems (methods)
• Humans
• Ligands
• Mice
• Mice, Transgenic
• T-Lymphocytes (immunology)