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

patients_and_methods

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).

在这项Ib期、多中心、随机试验(NCT02197169)中，我们评估了37名复发性HGG患者中，瘤内注射Delta-24-RGD与皮下注射IFNγ（一种Th1 CD8+细胞免疫反应的强效激活剂）联合治疗的效果，并研究了长期生存的系统性免疫相关因素。27名患者被随机分为两组，比例为2:1，一组接受Delta-24-RGD（通过标准活检针）联合IFNγ治疗，另一组仅接受Delta-24-RGD治疗（通过标准活检针）。

In an expansion cohort, 10 patients received intratumorally injected Delta-24-RGD via the MEMS cannula.

在一个扩展队列中，10名患者通过MEMS导管接受了Delta-24-RGD的肿瘤内注射。

Results

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].

尽管将IFNγ添加到Delta-24-RGD中并没有显著增加长期生存者（LTS）的比例，与单独使用Delta-24-RGD相比，IFNγ队列中有存活时间最长的患者[总生存期（OS）分别为44.2个月、23.7个月、20.6个月和20.1个月]。

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.

使用病毒噬菌体免疫沉淀测序抗体反应谱（VirScan）对血浆和外周血单个核细胞进行事后分析，以及单细胞RNA测序显示，治疗后2个月，循环中抗腺病毒特异性IgG和CD8+自然杀伤T（NKT）样细胞的水平可以区分长期生存者（LTS）和短期生存者。

Conclusions

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.

通过抗腺病毒特异性抗体反应和Delta-24-RGD治疗后激活的CD8+ NKT样细胞水平评估的免疫适应性，可能作为早期替代指标，反映与长期生存相关的强大系统性免疫反应。