Abstract PR01: Oncolytic adenoviruses expressing metabolic targets can improve viro-immunotherapy with bispecific T cell engagers through reducing acidosis in an in vitro model

Abstract

Abstract Oncolytic viro-immunotherapy holds huge promise for cancer treatment. While oncolytic viruses can robustly trigger immune activation, negative feedback is often upregulated in the tumor microenvironment (TME), an issue that is often neglected in early evaluation in vitro. Lactate accumulation and the resulting acidosis are commonly associated with viral infections and has been reported to be a key factor in shaping the immunosuppressive TME through various mechanisms which favor suppressive Tregs and MDSCs whilst polarizing macrophages towards an immunosuppressive state Given that the success of oncolytic viro-immunotherapy is now widely agreed to rely upon the induction of an immune response either from a transgene or from the release of DAMPs and PAMPs as opposed to direct cell lysis, understanding the impact of the increased acidosis upon immune cells and generating oncolytic viruses capable of avoiding or correcting acidosis is very promising. We found that infection with an oncolytic adenovirus led to a significant increase in lactic acid accumulation and acidosis in keeping with prior reports. An immunotherapeutic that shows promising results is the bispecific antibodies known as bispecific T cell engagers (BiTEs). Although BiTEs have particular success in hematological cancers, they have often shown negligible effects in solid tumor models. Here we show that BiTEs can robustly activate T cells resulting in target cell lysis; however, both T cell activation and BiTE-directed cytotoxicity are reduced when lactate concentrations increase or when acid is added to the media in vitro. Using media from virally infected cells, we show that acidosis following infection of tumor cells with an oncolytic adenovirus also negatively impacted T cell stimulation with BiTEs. Building on previously published results which show that inhibiting glycolysis can improve oncolytic viral infection, we have created oncolytic adenoviruses which inhibit acidosis at various stages through the expression of transgenes targeting this pathway. These next-generation oncolytic viruses were able to replicate whilst inhibiting glycolysis, or acidosis, and were able to halt the production of excess lactic acid following infection of tumor cells, ultimately allowing a rescuing of BiTE-mediated T cell activation. These findings provide a rationale for arming oncolytic viruses with anti-acidity agents, alongside those with T cell-activating abilities, which may offer a novel approach to overcome metabolic barriers of the tumor microenvironment and combat immune evasion. Citation Format: Arthur Dyer, Sally Frost, Flurin Caviezel, Len Seymour. Oncolytic adenoviruses expressing metabolic targets can improve viro-immunotherapy with bispecific T cell engagers through reducing acidosis in an in vitro model [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR01.