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Induction of Therapeutic T-Cell Immunity by Tumor Targeting with Soluble Recombinant B7-Immunoglobulin Costimulatory Molecules¹

Immunochemistry Unit [M. M., S. P., P. T., G. C., P. D.], Immunobiotechnology Unit, DIBIT [A. M. G., A. C.], Tumor Immunology Laboratory [M. B.], Biostatistic Unit [F. V.], and Cancer Immunotherapy and Gene Therapy Program [M. M., A. M. G., S. P., M. B., P. T., A. C., G. C., P. D.], H. San Raffaele Scientific Institute, I-20132, Milan, Italy

Tumor targeting with immunomodulatory molecules is an attractive strategy to enhance the host’s antitumor response. Expression of CD80 (B7-1) and CD86 (B7-2) costimulatory molecules in tumor cells has proven to be an efficient way to enhance their immunogenicity. Here, we studied the effects of tumor targeting with biotinylated recombinant soluble B7-1- and B7-2 immunoglobulin G molecules (bio-B7-IgG) using a pretargeting approach based on the sequential use of a biotinylated antitumor monoclonal antibody and avidin. Mouse RMA T-lymphoma cells bearing either bio-B7-1-IgG or bio-B7-2-IgG on their surface prime in vitro naive CD8⁺ CTLs, which are highly effective in adoptive immunotherapy, and induce therapeutic immunity when injected in tumor-bearing animals. In vivo targeting of established RMA tumors with bio-B7-IgG either cures tumor-bearing mice or significantly prolongs their survival. The antitumor response induced by targeted bio-B7-IgG depends on both CD4⁺ and CD8⁺ T cells. Moreover, tumor targeting with bio-B7-IgG in vivo is critical for both expansion in lymphoid organs and mobilization into the tumor of tumor-specific CD8⁺ CTLs. When targeting is performed on poorly immunogenic TS/A mammary adenocarcinoma, only bio-B7-1-IgG primes naive CTLs in vitro and cures or significantly prolongs the survival of tumor-bearing mice in vivo, confirming that the two costimulatory molecules are not redundant with this tumor. Altogether, these data suggest that tumor avidination and targeting with soluble bio-B7-IgG may represent a promising strategy to enhance the antitumor response in the host.

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