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Improved Tumor Immunity Using Anti-Tyrosinase Related Protein-1 Monoclonal Antibody Combined with DNA Vaccines in Murine Melanoma

¹ The Swim Across America Laboratory, Immunology Program, ² Department of Medicine, Memorial Sloan-Kettering Cancer Center, and ³ Weill Medical College of Cornell University, New York, New York; and ⁴ State University of New York Downstate College of Medicine, Brooklyn, New York

Requests for reprints: Jedd D. Wolchok, Melanoma-Sarcoma Service, Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, Room Z-1462, New York, NY 10021. Phone: 646-888-2395; Fax: 646-422-0453; E-mail: wolchokj{at}mskcc.org.

Key Words: melanoma • monoclonal antibody • vaccine • CD8+ T cells • Fc receptors

Passive immunization with monoclonal antibody TA99 targeting melanoma differentiation antigen tyrosinase-related protein-1 (Tyrp1; gp75) and active immunization with plasmid DNA encoding altered Tyrp1 both mediate tumor immunity in the B16 murine melanoma model. We report here that TA99 enhances Tyrp1 DNA vaccination in the treatment of B16 lung metastases, an effect mediated by immunologic mechanisms as Tyrp1 has no known role in regulating tumor growth. TA99 is shown to increase induction of anti-Tyrp1 CD8+T-cell responses to DNA vaccination against Tyrp1 as assessed by IFN- ELISPOT assays. Immunohistochemistry studies reveal that TA99 localizes rapidly and specifically to B16 lung nodules. Augmentation of T-cell responses is dependent on the presence of tumor as well as on activating Fc receptors. Furthermore, TA99 enhances DNA vaccination against a distinct melanoma antigen, gp100(pmel17/silver locus), improving antitumor efficacy, augmenting systemic CD8+ T-cell responses to gp100, and increasing CD8+ T-cell infiltration at the tumor site. Epitope spreading was observed, with CD8+ T-cell responses generated to Tyrp1 peptide in mice receiving gp100 DNA vaccination in the presence of TA99. Finally, we show that TA99 improves therapeutic efficacy of DNA vaccination combined with adoptive T-cell transfer in treatment of established subcutaneous B16 melanoma. In conclusion, TA99 enhances DNA vaccination against both the target antigen Tyrp1 and a distinct melanoma antigen gp100 in an Fc receptor–dependent mechanism, consistent with enhanced cross-presentation of tumor-derived antigen. Monoclonal antibodies should be tested as vaccine adjuvants in the treatment of cancer. [Cancer Res 2008;68(23):9884–91]