Abstract 5563: Harnessing pre-existing viral immunity for development of a broadly applicable tumor immunotherapy
Authors: Cuburu Nicolas , Bialkowski Lukas , Pontejo Sergio M. , Bell Alexander , Kim Rina , Thompson Cynthia D. , Lowy Douglas R. , Schiller John T. 
Published: September 2020

Abstract
The availability of high throughput DNA sequencing provides an opportunity to generate a potent immune stimulation against unique antigens expressed by tumors. Although such approaches have led to increased immune responses in certain individuals, it is often limited to a small patient population and is associated with high development and implementation costs. Therefore, there is an unmet need for an immunotherapy that is easy to manufacture at affordable cost and applicable across many different tumor types. Here, we propose a unique approach to leverage pre-existing anti-Human Cytomegalovirus (CMV) immunity using a defined cocktail of viral epitopes, to both directly kill the tumor cells and induce a secondary T cell response to tumor neoantigens. We chose to recruit CMV immunity because CMV infection is highly prevalent, reaching approximately 90% of the population by the age of 80 years, and because of the naturally-occurring inflation of anti-CMV T cell responses with age leads to high levels CMV-specific T cells. Consequently, in elderly individuals, CMV-specific T cells recognizing a limited number of viral epitopes constitute approximately 10% of all systemic CD4 and CD8 T cells, a level rarely achieved by conventional vaccination. Additionally, in contrast to other chronic viral infections, CMV-specific T cells remain highly functional. In our experimental model, mice persistently infected with Murine Cytomegalovirus (mCMV) were subcutaneously challenged with TC-1 tumor cells (expressing human papillomavirus E6 and E7 oncogenes) or colon adenocarcinoma MC38 tumor cells, followed by intratumoral injections of mCMV peptide antigens together with a Toll-like receptor 3 (TLR3) agonist poly(I:C). Intratumoral injection of mCMV MHC-I or MHC-II restricted epitopes alone led to local and systemic recall of mCMV-specific T cells, and a potent local immune activation resulting in complete rejection of TC-1 and MC38 tumors in a subset of animals. Coinjection of both MHC-I and MHC-II peptides resulted in complete tumor clearance is most animals. Clearance was associated with antigen spreading, as evidenced by protection from secondary tumor challenge and ex vivo IFN-gamma ELISPOT responses to tumor-specific epitopes. Our preclinical studies provide a proof of concept of a first-in-class tumor antigen-agnostic immunotherapy based on recruitment of pre-existing antiviral T cells. The approach induced rapid tumor regression, profound changes in the tumor immune environment, epitope spreading, and resulted in long-term tumor protection. We are currently investigating the contribution of other cell types including NK cells and B cells to the anti-tumor effect of our approach.
Citation Format: Nicolas Cuburu, Lukas Bialkowski, Sergio M. Pontejo, Alexander Bell, Rina Kim, Cynthia D. Thompson, Douglas R. Lowy, John T. Schiller. Harnessing pre-existing viral immunity for development of a broadly applicable tumor immunotherapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5563.