In face of the necessity of broadly acting and highly effective vaccines capable of eliminating/preventing human cancers with insufficient mutated antigens, we introduced the concept of Virus-Like Vaccines (VLVs). This strategy combines a replication-deficient retrovirus encoding virus structural proteins. These proteins assemble into secreted virus-like particles (VLPs) that deliver the target antigen to the immune system rising both humoral and cellular immune responses. Here, we use an adenoviral vector encoding the group specific antigen (Gag) and the glycoprotein of the viral envelope (Env) from endogenous retrovirus (ERV). Since ERV Env is reported to have immunosuppressive properties that support tumor establishment and development, we designed a modified vaccine that includes a mutation on the Env immunosuppressive domain (ISD) that prevents the vaccine from being immunosuppressive itself. In our studies, we demonstrate that VLVs are able to induce strong, broad, and long-lasting ERV Env specific CD8+ T cell by flow cytometry and antibody responses by ELISA in mice. Furthermore, the modified vaccine is of special interest to future research as it proved to significantly delay mouse tumor growth in a therapeutic setup. Nevertheless, we now need to address the principal host related developmental uncertainties in translating our achievements into the clinical setting. This goal can be accomplished by raising human T cells capable of targeting human cancers ex vivo. Furthermore, to support the translation of our work, we tested the ability to rise adaptive responses upon vaccination in non-human primates (NHP) which endogenously express ERVs similar to humans (in collaboration with IPB University, Indonesia). Fellowship granted by Innovation Fund Denmark.Disclosure InformationJ. Daradoumis: A. Employment (full or part-time); Significant; InProTher Aps. B. Research Grant (principal investigator, collaborator or consultant and pending grants as well as grants already received); Significant; Innovation Fund Denmark. P.J. Holst: A. Employment (full or part-time); Significant; InProTher Aps. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; InProTher. K.N. Nielsen: A. Employment (full or part-time); Significant; InProTher Aps.
BackgroundMany cancers acquire mechanisms to evade immunosurveillance by activating immune checkpoint pathways, which suppress the antitumor immune responses. Monoclonal antibodies (ab’s) targeting immune checkpoints, such as CTLA-4 and PD-1, have shown excellent results in several cancers and are currently being investigated in clinical trials for various malignancies. The clinically tested a-CTLA-4 (Ipilimumab) and a-PD-1 (Nivolumab and Pembrolizumab) ab’s are fully human or humanized ab’s, respectively. However, most studies conducted in mice utilize a xenogeneic a-PD-1 ab originating from rat, IgG2a RMP1-14 clone. This has been proposed to cause adverse effects in the commonly used 4T1 mammary carcinoma model of triple negative breast cancer (TNBC). Repeated administration of xenogeneic a-PD-1 ab’s in this model results in fatal hypersensitivity reactions in tumor bearing mice, and unlike human TNBC, the 4T1 cell line is generally poorly responsive to immune checkpoint inhibitors. Recently, a semi-syngeneic recombinant a-PD-1 ab has been developed by transferring the variable regions of RMP1-14 onto a murine IgG1e3 constant region.Materials and MethodsTesting xenogeneic and semi-syngeneic a-PD-1 ab with and without a-CTLA-4 ab in BALB/c mice carrying 4T1 luciferase positive tumors.ResultsIn this study, we compared a semi-syngeneic recombinant a-PD-1 ab to the original xenogeneic RMP1-14 clone for treatment of luciferase positive 4T1 carcinomas. Surprisingly, the semi-syngeneic a-PD-1 ab was not able to circumvent the fatal hypersensitivity reactions. Still, the combination therapy of a-CTLA-4 and the semi-syngeneic a-PD-1 ab significantly reduced tumor volume in 4T1-luciferase tumor bearing mice compared to isotype control-treated mice already from day 16 post tumor inoculation (day 8 post treatment-initiation). In contrast, xenogeneic a-PD-1/a-CTLA-4 treated mice did not show significant difference from the control group until 24 days post tumor inoculation and never to the same degree. Furthermore, analysis of the T cell responses towards the murine tumor-associated antigen AH-1, revealed that treatment with syngeneic a-PD-1/a-CTLA-4 ab gave a significantly stronger CD8+ T cell response over both control mice and mice treated with xenogeneic a-PD-1/a-CTLA-4 ab.ConclusionsThese studies indicate that the semi-syngeneic a-PD-1 IgG1e3 ab might be a more efficient and translatable a-PD-1 ab for preclinical in vivo studies, which is important for the future investigation of immune checkpoint inhibitor therapy.Disclosure InformationI. Skandorff Pedersen: A. Employment (full or part-time); Significant; InProTher Aps. K. Orfin: A. Employment (full or part-time); Significant; InProTher Aps. K.N. Nielsen: A. Employment (full or part-time); Significant; InProTher Aps. P.J. Holst: A. Employment (full or part-time); Significant; InProTher Aps. E. Ownership Interest (stock, stock options, patent or other intellectual property); Significant; InProTher Aps.
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