Measles oncolytic virus as an immunotherapy for recurrent/refractory pediatric medulloblastoma and atypical teratoid rhabdoid tumor: results from PNOC005

Pediatric recurrent medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT) are largely incurable and warrant novel therapies. We investigated a) the safety of a measles virus variant, MV-NIS, in a pediatric phase 1 study and b) the mechanisms of MV-NIS and potential benefit of combination with immune checkpoint inhibition (ICI). Pediatric patients with recurrent MB or ATRT were treated with intratumoral injections for local recurrence or via lumbar puncture for disseminated recurrence. We evaluated local immune responses to MV-NIS with and without ICI via single-cell and bulk RNA sequencing in an intracranial, immunocompetent, syngeneic murine model. MV-NIS given intratumorally or via repeat intrathecal dosing was safe. MV-NIS prolonged survival in murine models but did not demonstrate additive benefit with ICI. No changes in tumor-infiltrating immune-cell composition or activation were observed in response to MV-NIS treatment; however, MV-NIS induced local expression of neutralizing antibodies, complement cascade, and phagocytosis-related genes. Single-cell and bulk RNA sequencing were performed to characterize tumor and immune responses to oncolytic measles virus (MV-NIS) therapy in medulloblastoma (MB) and atypical teratoid rhabdoid tumor (ATRT). Single-cell RNA sequencing was used to profile tumor-infiltrating cells from MB PDX tumors derived from CSCG, treated with MV-NIS alone or in combination with anti-PD1. Bulk RNA sequencing was performed on PDX tumors across treatment conditions, including PBS control, heat-inactivated control, mid-treatment, and resistance. In parallel, bulk RNA sequencing was conducted on whole blood and PBMCs from pediatric patients enrolled in the PNOC005 clinical trial, across different MV-NIS treatment regimens. *************************************************************** Due to the human privacy concern we have submitted the raw fastq files to European Genome-phenome Archive (EGA), that can be access through this EGAS50000000811. ***************************************************************