Examining the Role of Nono Pathway on the Innate Immunity Against Oncolytic Adenoviruses - PROJECT SUMMARY / ABSTRACT Recent clinical trials in adults and children with brain tumors from our group and others have shown that oncolytic viruses prolong the survival of a small percentage of patients (<20%). Importantly, these studies have also demonstrated that viroimmunotherapy induces Tcell infiltration into brain tumors. Such findings support the paradigm-shifting concept that complete tumor debulking by virotherapy requires the elicitation of antitumor immune responses following the initial oncolytic effect. Therefore, further enhancement of the immune arm of this treatment approach may be required to increase the percentage of positive responders. In a clinical trial developed by the MDACC team, 20% of GBM patients treated with the oncolytic adenovirus Delta-24-RGD showed complete response and survival longer than three years (NCT00805376). Although these studies have illustrated that robust immune responses can be invoked using oncolytic virotherapy, they have also shown that viruses are eliminated early during infection and thus preventing the development of an efficacious anti- tumor immune response in the majority of the patients. The first mechanism that is activated to eliminate the virus is the innate immune response. Mitigation of this response should result in the permanence of more viruses and during a longer period within the infected tumor, increasing the window of opportunity for the development of an anti-tumor immune response. During a screening of the factors regulating the anti- adenovirus innate immune response using RNA sequencing, we discovered that the NONO pathway, which was not previously connected with adenovirus infection, was significantly upregulated following infection. Based on this seminal information, we hypothesize that NONO pathway is an essential sensor of adenovirus DNA and capsid proteins in infected cells and that plays a key role in the modulation of an effective innate immune response against oncolytic viruses. To test this hypothesis and achieve the objectives of the project, we proposed the following two specific aims: Specific aim 1: To examine the NONO pathway in glioma cells treated with oncolytic adenoviruses. We hypothesize that NONO functions as a viral capsid sensor in response to adenoviral infection and interacts with players of the host’s innate immune response. Specific aim 2: To determine the immunomodulatory functions of NONO during oncolytic adenovirus treatment. We hypothesize that evading innate immune defenses allows for enhanced adenovirus replication and lysis, functionally tipping the scale towards anti-cancer immunity. Therefore, we will test the therapeutic efficacy of Delta-24-RGD oncolytic, as well as monitor the flux of cancer-specific T-cells and innate immune activation in the context of differential NONO expression. If successful, our project should propel the exploration of viral capsid-based recognition and NONO-cGAS crosstalk in the design of new oncolytic adenovirus strategies. This project is part of our long-term goal of legitimizing oncolytic adenoviruses as part of the conventional treatment for malignant gliomas and other solid tumors.
