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Targeting a Mimotope Vaccine to Activating Fc Receptors Empowers Dendritic Cells to Prime Specific CD8⁺ T Cell Responses in Tumor-Bearing Mice¹

Margaret Gil,^* Magdalena Bieniasz,^* Andrzej Wierzbicki,^* Barbara J. Bambach, Hanna Rokita, and Danuta Kozbor^2*

^*Department of Immunology and Department of Pediatrics² Roswell Park Cancer Institute, Buffalo, NY 14263; and Faculty of Biochemistry, Biophysics, and Biotechnology, Jagiellonian University, Kraków, Poland

A major challenge for inducing antitumor immune responses with native or modified tumor/self-Ags in tumor-bearing hosts relates to achieving efficient uptake and processing by dendritic cells (DCs) to activate immune effector cells and limit the generation of regulatory T cell activity. We analyzed the ability of therapeutic DC vaccines expressing a CD166 cross-reactive mimotope of the GD2 ganglioside, 47-LDA, to selectively expand adoptively transferred, tumor-specific T cells in NXS2 neuroblastoma tumor-bearing syngeneic mice. Before the adoptive cell transfer and DC vaccination, the tumor-bearing mice were lymphodepleted by nonmyeloablative total body irradiation or a myeloablative regimen that required bone marrow transplantation. The 47-LDA mimotope was presented to DCs either as a linear polypeptide in conjunction with universal Th epitopes or as a fusion protein with the murine IgG2a Fc fragment (47-LDA-Fc2a) to deliver the antigenic cassette to the activating Fc receptors. We demonstrate that immunization of adoptively transferred T cells in tumor-bearing mice with the 47-LDA mimotope expressed in the context of the activating Fc fusion protein induced higher levels of antitumor immune responses and protection than the 47-LDA polypeptide-DC vaccine. The antitumor efficacy of the therapeutic 47-LDA-Fc2a-DC vaccine was comparable to that achieved by a virotherapy-associated cancer vaccine using a recombinant oncolytic vaccinia virus expressing the 47-LDA-Fc2a fusion protein. The latter treatment, however, did not require total body irradiation or adoptive cell transfer and resulted in induction of antitumor immune responses in the setting of established tolerance, paving the way for testing novel anticancer treatment strategies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grants R21EB008071 (to D.K.), Association for Research of Childhood Cancer, Inc., (D.K. and B.B.), and Roswell Park Alliance Foundation (D. K. and B.B.).

² Address correspondence and reprint requests to Dr. Danuta Kozbor, Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263. E-mail address: danuta.kozbor{at}roswellpark.org

³ Abbreviations used in this paper: DC, dendritic cell; ACT, adoptive cell transfer; BM, bone marrow; EGFP, enhanced GFP; rOVV, recombinant oncolytic vaccinia virus; TBI, total body irradiation; Teff, effector T cell; TK, thymidine kinase; Treg, regulatory T-cell; VGF, vaccinia growth factor.