Use of a versatile platform for coating adenoviral vectors with cell membrane carrying tumor antigens

• Grant number: 22/04622-5
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2022
• End date: October 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Bryan Eric Strauss
• Grantee: Gabriel Borel Marinho
• Host Institution: Instituto do Câncer do Estado de São Paulo Octavio Frias de Oliveira (ICESP). São Paulo , SP, Brazil
• Associated research grant: 15/26580-9 - Cancer gene therapy: strategic positioning for translational studies, AP.TEM

Abstract

One of the goals for cancer treatment is the induction of oncolysis and antitumor immune response. For example, radiotherapy and chemotherapy drugs are known to induce immunogenic death. In the same way, gene therapy can also be used for this purpose, such as using oncolytic viruses, whether by the action of viral replication or the function of transgenes encoded by the vector. Previous work by our group showed that non-replicating adenoviral vectors encoding p19Arf (a functional partner of p53) and interferon-beta (IFNb, pleiotropic cytokine) cooperate to induce immunogenic death and antitumor immune response. However, this approach lacks mechanisms to direct the response to tumor antigens expected to be critical targets for an effective antitumor immune response. Recent data from our laboratory have shown that the delivery of target antigens in the form of peptides has improved the effectiveness of treatment with adenoviral vectors. Here we propose a solution not only for the provision of antigens in a versatile, easy, and economical way but also as a resource to increase the efficiency of the gene transfer process. Coating the viral particle with a cell membrane-derived from tumor cells protects the particle against the body's defenses, especially neutralizing antibodies, increases transduction efficiency, and possibly directs the vector to tumor cells. In addition, the cell membrane serves as a carrier for proteins that can serve as antigens to strengthen the antitumor immune response. For this, we will use a plasmid vector that encodes a transmembrane protein adapted to include peptides of interest. The resulting fusion protein is located in the cell membrane and the peptide of interest is exposed to the extracellular medium through the transmembrane loop of tetraspanin. These cells will serve as donors of the cell membrane donors that will be used to coat adenovirus encoding p19Arf and IFNb. When used for in situ gene therapy in immunocompetent mice, we expect to see an immune response against the peptide presented on the cell membrane. As a proof of concept, we will start this study with the peptide OVA (SIINFEKL) derived from chicken ovalbumin. With the success of thisproject, we will have a promising molecular tool for the creation of further prototypes of a new approach to immunotherapy.