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Combination Therapy with Anti–CTL Antigen-4 and Anti-4-1BB Antibodies Enhances Cancer Immunity and Reduces Autoimmunity

¹ Division of Cancer Immunology, Department of Pathology, ² Division of Surgical Oncology, Department of Surgery, and ³ Center for Biostatistics, The Ohio State University Medical Center, Columbus, Ohio

Requests for reprints: Yang Liu, Division of Immunotherapy, Department of Surgery, Program of Molecular Mechanisms of Diseases and Cancer Center, University of Michigan Medical Center, BSRB 1818, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200. E-mail: yang1{at}umich.edu.

The majority of cancer antigens identified thus far have limited expression in normal tissues. It has been suggested that autoimmune disease is a necessary price for cancer immunity. This notion is supported by a recent clinical trial involving an anti–CTL antigen-4 (CTLA-4) antibody that showed significant clinical responses but severe autoimmune diseases in melanoma patients. To selectively modulate cancer immunity and autoimmunity, we used anti-CTLA-4 and anti-4-1BB antibodies to treat mice with a preexisting cancer, MC38. The combination of the two antibodies led to CD8 T-cell-mediated rejection of large established MC38 tumors and long-lasting immunity to the same tumor cells, although the same regimen was not effective for B16 melanoma. More importantly, whereas individual antibodies induced inflammation and autoimmune manifestations, combination therapy increased cancer immunity while reducing autoimmunity. The reduction of autoimmune effects correlates with an increased function of regulatory T cells. Our results suggest a novel approach to simultaneously enhance cancer immunity and reduce autoimmunity. (Cancer Res 2006; 66(14): 7276-84)

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