Targeting RNF2 to Synergize with Oncolytic Immunovirotherapy to Induce Anti-Cancer Immunity in Medulloblastoma

Medulloblastoma (MB) is the most common brain cancer and a leading cause of cancer deaths in children. Mortality frequently results from leptomeningeal spread within the central nervous system. Effective, less-toxic therapies for MB and leptomeningeal disease (LMD) represent an unmet need; survival has not improved significantly for decades and patients who are cured are afflicted with lifelong treatment-associated sequalae. Our overarching goal is to change the clinical practice paradigm by developing less-toxic, more effective therapies to improve survival and quality of life for children with MB and LMD. To this end, we recently reported in New England Journal of Medicine that engineered oncolytic herpes simplex virus (oHSV) G207 was safe with promising efficacy and generated a robust intratumoral cytotoxic T cell immune response in a pediatric high- grade glioma (pHGG) phase 1 trial (NCT02457845). Further, in preclinical studies in MB-LMD, we demonstrated safety and heightened efficacy of G207 (compared to pHGG), leading to an ongoing phase 1 trial in recurrent malignant cerebellar tumors (NCT03911388). Despite favorable results in our studies, most responders unfortunately progressed over time, albeit slower than expected. Therefore, novel strategies to augment and sustain the anti-tumor immune response initiated by G207 and to prevent tumor immune evasion are needed to achieve durable responses. In our recent publication in Nature Cancer, we identified tumor cell expressed Ring Finger Protein 2 (RNF2) as a master immune suppressor. We found that RNF2 is overexpressed in MB and LMD and is associated with a significantly worse prognosis and immune suppression. Deleting tumoral RNF2 in murine cancer models resulted in long term tumor regression mediated by mobilized CD4+ T (Th1 skewed) cell- dependent anticancer immunity. Since mobilized CD4+ T cells are shown to inhibit MB growth and metastases, and to induce, facilitate and support CD8+ CTL response, which G207 stimulates, we hypothesize that RNF2 inhibition will be a novel and effective therapeutic strategy for treating MB-LMD and will synergize with oHSV to achieve durable responses. We will test this hypothesis by accomplishing the following specific aims: Aim 1: investigate the anticancer activity of tumoral RNF2 inhibition in MB-LMD; Aim 2: define the anticancer functions of CD4+ T cells in RNF2 inhibition in MB-LMD; Aim 3: determine the synergy of RNF2 inhibition with oHSV in MB-LMD. Upon completing these aims, we will have demonstrated the safety and effectiveness of targeting tumoral RNF2 alone and combined with oHSV to treat MB-LMD and induce durable anticancer immunity. This contribution will be significant and innovative since it will establish a new tumor target (RNF2) in MB-LMD, leading to the development of an innovative combinatorial immunotherapy and resulting in new clinical trials to treat children afflicted with MB-LMD, who desperately need improved, targeted treatments. Our findings will likely be applicable to other pediatric brain and solid tumors, increasing the overall impact. Project Number: 1R01NS146081-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: GREGORY FRIEDMAN (+1 co-PI) | Institution: UNIVERSITY OF TX MD ANDERSON CAN CTR, HOUSTON, TX | Award Amount: $421,361 | Activity Code: R01 | Study Section: Translational Immuno-oncology Study Section[TIO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11271139