Abstract 4742: Anti-tyrosinase related protein 1 (TRP1) antibody combined with cyclophosphamide induces adaptive immunity against melanoma
Authors: Saenger Yvonne M. , Pan Michael , Hashimoto Daigo , Glodny Bradley , Shah Shaily , Houghton Alan N. , Merghoub Taha , Wolchok Jedd D. , Merad Miriam 
Published: June 2012

Abstract
Monoclonal antibodies targeting tumor antigens are an effective anti-cancer immunotherapy, with well established benefit against multiple tumor types. They are most potent when given in combination with chemotherapy. The mechanisms underlying the efficacy of combination therapy, however, are poorly understood.1 Tyrosinase-related protein 1 (TRP1) is a protein implicated in pigment formation. TRP1 is found primarily in the melanosome, but surface expression can be detected in vivo. An antibody targeting TRP1 is currently in clinical testing. In mice, anti-TRP1 prophylaxis controls subsequent growth of B16 melanoma, but has minimal activity as a single agent against established disease.2 We have previously shown that anti-TRP1 enhances T cell responses induced by DNA vaccination.3 We now report that anti-TRP1 enhances the cytotoxic effect of cyclophosphamide chemotherapy in the treatment of established cutaneous B16 melanoma. We find considerable efficacy when anti-TRP1 is combined with cyclophosphamide chemotherapy with treatment initiated at timepoints up to day 7 when tumors are palpable with long term disease control observed in some animals. Treatment is ineffective in mice deficient in the Fc receptor common γ chain. Combination therapy is associated with increased infiltration of tumors by CD8+ T lymphocytes visualized by immunofluorescence (IF) and flow cytometry. Mice receiving combination therapy have increased infiltration by CD4+foxp3- T cells, but not by CD4+foxp3+ T cells. Therapeutic efficacy was decreased but not abrogated in animals depleted of CD8+ T cells through injection of anti-CD8 IgG. Surprisingly, although B16 is a non-immunogenic tumor, surviving mice treated with cyclophosphamide and ‘passive’ immunization with anti-TRP1 displayed resistance to repeat inoculation with B16 melanoma. These data strongly implicate a role for adaptive immunity in the therapeutic efficacy of anti-tumor antibodies combined with chemotherapy and has implications for design of future clinical trials using these agents and for the development of novel strategies to induce adaptive anti-tumor immunity.
1. Ferris RL, Jaffee EM, Ferrone S. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity, and immunoescape. J Clin Oncol 2010;28:4390-9.
2. Hara I, Takechi Y, Houghton AN. Implicating a role for immune recognition of self in tumor rejection: passive immunization against the brown locus protein. J Exp Med 1995;182:1609-14.
3. Saenger YM, Li Y, Chiou KC, et al. Improved tumor immunity using anti-tyrosinase related protein-1 monoclonal antibody combined with DNA vaccines in murine melanoma. Cancer Res 2008;68:9884-91.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4742. doi:10.1158/1538-7445.AM2011-4742