Systemic Immune Correlates of Long-term Survival after Delta-24-RGD Based on the Therapeutic Adenovirus for Recurrent Glioblastoma Effect Trial (TARGET)

The aim of the study is to evaluate the combination of intratumoral Delta-24-RGD and subcutaneous interferon gamma (IFNγ) in patients with high-grade glioma (HGG), based on the rationale that augmenting the immune response with IFNγ will increase the efficacy of Delta-24-RGD treatment.

In this phase Ib, multicenter, randomized trial (NCT02197169), we evaluated the combination of intratumorally injected Delta-24-RGD with subcutaneously administered IFNγ, a potent activator of Th1 CD8+ cell immune response, in 37 patients with recurrent HGG and investigated systemic immune correlates of long-term survival. Twenty-seven patients were randomized 2:1 into two cohorts: Delta-24-RGD (via standard biopsy needle) with IFNγ or Delta-24-RGD alone (via standard biopsy needle). In an expansion cohort, 10 patients received intratumorally injected Delta-24-RGD via the MEMS cannula.

Although the addition of IFNγ to Delta-24-RGD did not significantly increase the percentage of long-term survivors (LTS) compared with Delta-24-RGD alone, the IFNγ cohort had the longest-surviving patients [overall survival (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 revealed that levels of circulating anti-adenovirus-specific IgG and CD8+ natural killer T (NKT)-like cells 2 months after treatment with Delta-24-RGD distinguished LTS from short-term survivors.

Immunologic fitness, assessed by an anti-adenoviral-specific antibody response and higher levels of activated CD8+ NKT-like cells after Delta-24-RGD treatment, may have utility as an early surrogate of a robust systemic immune response that correlates with long-term survival.