Systemic immune correlates of long-term survival after Delta-24-RGD based on the therapeutic adenovirus for recurrent glioblastoma effect trial (TARGET)

Purpose: Treatment of high grade gliomas, particularly glioblastoma (GBM), with the oncolytic adenovirus Delta-24-RGD has previously produced anti-tumor effects in phase 1 clinical trials. These effects are mediated through direct oncolysis and activation of an anti-tumor immune response. In this study, we combined Delta-24-RGD with interferon gamma (IFN- ), a potent activator of T-helper 1 CD8+ cell immune response. Patients and Methods: In the Phase 1b, multicenter, randomized, study (NCT02197169), we evaluated the combination of intratumoral injected Delta-24-RGD with subcutaneous administered IFN- in 37 patients with recurrent high grade glioma and investigated potential systemic immune correlates of long-term survival. Twenty-seven patients were randomized 2:1 into two cohorts; Delta-24-RGD with IFN- or Delta-24-RGD alone via a standard nashold biopsy needle. In an expansion cohort, 10 patients received intra-tumoral injected Delta-24-RGD via the MEMS Cannula (Neela Therapeutics). Results: Although the addition of IFN- to Delta-24-RGD did not significantly increase the percentage of long term survivors compared to Delta-24RGF alone, the IFN- cohort has the longest surviving patients after treatment (OS 44.2, 23.7, 20.6 and 20.1 months). Post-hoc analysis of plasma and peripheral blood mononuclear cells using viral phage immunoprecipitation sequencing antibody reactome profiling of viral epitopes (VirScan) and single cell RNA sequencing (scRNA seq) revealed that levels of circulating anti-adenovirus specific IgG and CD8+ NKT-like cells 2 months after treatment with Delta-24-RGD distinguished long term survivors from short term survivors. Conclusions: Immunological fitness assessed by an anti-adenoviral specific antibody response and higher levels of activated CD8+ NKT-like cells after Delta-24-RGD treatment could be used as early surrogates of a robust systemic immune response that correlates with rate of tumor growth and long-term survival.