Fueling Antitumor Immunity Using Oncolytic Viruses Encoding Metabolic Modulators

Despite the promising results with current approved immunotherapies, all patients do not have the same level of response, and recent efforts have focused on understanding and avoiding immunotherapy resistance. Our lab and others have recently proposed that the metabolic state of tumor infiltrating lymphocytes, either preexisting or adoptively transferred, can compromise T cell function and consequently antitumor immunity. This suggests that the understanding of metabolic mediators and systemic metabolic disorders can contribute to the improvement of current immunotherapies as well as understanding therapeutic responses. Furthermore, understanding the mechanism of action in metabolic disorders can allow us to harness their inflammatory potential. Leptin affects a wide range of metabolic processes as well as being a pro inflammatory mediator, can be utilized as a means to remodel the metabolic state of the tumor microenvironment, consequently modulating immunotherapy response. Our data shows that leptin overexpressing tumors have increased T cell infiltration compared to control tumors, and these TIL are metabolically and functionally superior. We next wanted to translate tumor-specific expression of leptin into a therapeutic model. Oncolytic viruses are an attractive therapeutic modality promoting tumor specific killing, inducing an anti-tumor immune response, as well as the capacity to deliver genetic payloads potentially enhancing their anti-tumor activity. We designed an oncolytic Vaccinia virus that expresses leptin and used it to treat aggressive genetically-induced melanomas. While wild-type oncolytic Vaccinia showed some response, leptin-engineered Vaccinia had superior therapeutic efficacy inducing complete regressions in 30% of mice. TIL from these tumors have improved T cell infiltration and function. Single cell RNAseq and TCR sequencing immune infiltrates revealed the influx of new T cells by vaccinia while leptin-expressing virus showed specific clonal expansion. Most importantly we observed a strong memory response when complete responders where rechallenged with tumor cells. Taken together, these data suggest that understanding metabolic modulators in metabolic disorders, like leptin, can inform on therapeutic outcomes as well as taking advantage of these molecules for novel therapeutic modalities.

Learning Objectives:

1. Understand the role metabolic pressures play on the function of tumor infiltrating lymphocytes.

2. Identify metabolic mediators as potential therapeutic targets.

3. Learn about oncolytic viruses and their mechanisms of action as immunotherapeutic modalities.