The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. To overcome the intrinsically weak immunogenicity of carbohydrate antigens and tolerance to self/tumor-associated antigens in a tumor-bearing host, we have generated a mimotope of GD2 ganglioside, designated 47-LDA. Our rational for this immunization strategy is that since the 47-LDA mimotope is structurally similar but not identical to GD2 ganglioside, it may stimulate T cell clones that recognize GD2 but have not been deleted during the establishment of self-identity because of their lower affinity for the antigen. We are proposing to express the 47-LDA mimotope together with universal T helper (Th) epitopes in the context of Fc region of IgG antibodies for targeting the antigenic cassettes to activating Fc gamma receptors (Fc?Rs) on antigen presenting cells. For immunization, the 47-LDA-Fc fusion proteins will be delivered by dendritic cell (DC) vaccination or by our newly developed recombinant modified vaccinia Ankara (rMVA) viral vector/liposomal complex. We hypothesize that targeting the 47-LDA-Fc fusion proteins to activating Fc?Rs on DCs will enhance the magnitude of protective immunity against GD2+ tumors.
The Specific Aims are: i) We will generate 47-LDA-Fc fusion proteins with murine IgG1, IgG2a, and IgG3 Fc regions to evaluate their abilities to elicit antitumor immune responses in mice and select the most efficacious construct; ii) We will express the most efficacious 47-LDA Fc-fusion protein by rMVA virus covalently attached to tresylmonomethoxypolyethylene glycol (TMPEG)-modified cationic liposomes (rMVA47-LDAFc/ TMPEG/liposomes) for systemic and mucosal immunizations; and iii) We will compare antitumor efficacy of 47-LDA-Fc fusion protein-pulsed DC vaccine with that of rMVA47-LDA-Fc/TMPEG/liposomes using a combination of adoptive cell transfer (ACT) therapy and vaccination in GD2+ tumor-bearing mice. As the next generation of ACT-based immunotherapies might rely on the ability to endow 'fit' tumor-specific cells that are capable of proliferating and trafficking to tumor lesions, the use of potent vaccines to enhance adoptively transferred T cells may represent a promising new approach for cancer treatment. ? ? Public Health Relevance: The GD2 ganglioside expressed on neuroectodermally derived tumors, including neuroblastoma and melanoma, is weakly immunogenic in tumor-bearing patients and induces predominantly IgM antibody responses in the immunized host. To overcome the intrinsically weak immunogenicity of carbohydrate antigens and tolerance to self/tumor-associated antigens in a tumor-bearing host, we have generated a mimotope of GD2 ganglioside, designated 47-LDA. We are proposing to express the 47-LDA mimotope together with universal T helper epitopes in the context of Fc region of IgG antibodies for targeting the antigenic cassettes to activating Fc gamma receptors on antigen presenting cells. ? ? ?
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| Gil, Margaret; Bieniasz, Magdalena; Wierzbicki, Andrzej et al. (2009) Targeting a mimotope vaccine to activating Fcgamma receptors empowers dendritic cells to prime specific CD8+ T cell responses in tumor-bearing mice. J Immunol 183:6808-18 |
| Wierzbicki, Andrzej; Gil, Margaret; Ciesielski, Michael et al. (2008) Immunization with a mimotope of GD2 ganglioside induces CD8+ T cells that recognize cell adhesion molecules on tumor cells. J Immunol 181:6644-53 |
