背景：在 VITAL（NCT02346747）試驗中，用 Vigil 維持治療，Vigil 是一種自體腫瘤細胞疫苗，轉染了編碼 GMCSF 和 bishrna-furin 的 DNA 質粒，用於 TGFb 在晚期高級別卵巢癌患者中，一線鉑類化療後的表達控製可提高無複發生存率（RFS）（HR=0.69，90%CI）0.44–1.07，p=0.078），在 BRCAwt 患者中顯著（HR=0.51，90%CI 0.30-0.88，p=0.020）（Rocconi 等人，《柳葉刀腫瘤學》。2020). 在這裏，我們報告了事後 HR 缺乏症（HRD）亞組分析和鑒定的另一個分子亞組敏感守夜治療涉及字符串分析。

Background: In the VITAL (NCT02346747) trial, maintenance therapy with Vigil, an autologous tumor cell vaccine transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin for TGFβ expression control, following frontline platinum-based chemotherapy led to a recurrence-free survival (RFS) benefit in patients with advanced high-grade ovarian cancer (HR=0.69, 90% CI 0.44–1.07, p=0.078) and significantly in BRCA-wt patients (HR=0.51, 90% CI 0.30-0.88, p=0.020) ( Rocconi et al. Lancet Oncol. 2020). Here we report post-hoc HR deficiency (HRD) subgroup analysis and identification of an additional molecular subgroup sensitive to Vigil therapy involving STRING analysis.

方法：這項雙盲、安慰劑對照、2b 期研究隨機選擇 92 例新診斷的Ⅲ/Ⅳ期卵巢癌患者進行臨床研究對前線手術和化療的反應（CR）。患者接受 1 x 10e7 細胞/ml 的守夜或安慰劑皮內每月一次，最多 12 劑或疾病進展。RFS 是盲法獨立中心評價的主要終點。HRD 狀態根據 myChoice-CDx 分析確定（熟練者 HRD 評分<42）。利用腫瘤利用 DNA 多態性數據，構建了蛋白質-蛋白質相互作用網絡字符串數據庫。利用該網絡的拓撲距離和 hub 基因的識別等性質，預測了一個對守夜敏感的目標分子群體。

Methods: This double-blind, placebo-controlled, Phase 2b study randomized 92 patients with newly diagnosed stage III/IV ovarian cancer with a complete clinical response (CR) to frontline surgery and chemotherapy. Patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses or disease progression. RFS was the primary endpoint assessed by blinded independent central review. HRD status was determined according to the Myriad Genetics myChoice CDx assay (HRD score < 42 for proficient). Using tumor annotated DNA polymorphism data, a protein-protein interaction network was constructed using the STRING database. Properties of this network including topological distance and the identification of hub genes were used to predict a target molecular population sensitive to Vigil.

結果：在根據方案人群（PP，n=91），對 62 例 BRCA wt 患者進行 HRD 狀態檢測。45 例患者 HR 熟練（HRP），17 例 HR 缺乏（HRD）。無 HRP 患者在守夜組報告治療相關的 3 級或以上不良事件。從與對照組相比，HRP 患者的隨機中位數 RFS 在 Vigil（n=25）下得到改善安慰劑（n=20）（表 1）。同樣，在守夜組中觀察到總體生存（OS）益處與安慰劑相比（表 1）。改善 RFS 被證明適用於一部分患有糖尿病的患者字符串預測了分子輪廓。

Results: In the per-protocol population (PP, n=91), 62 BRCA-wt patients were tested for HRD status. Forty-five patients were HR proficient (HRP) and 17 patients were HR deficient (HRD). No HRP patients in the Vigil group reported treatment related Grade 3 or higher adverse events. From the time of study randomization median RFS was improved with Vigil (n=25) in HRP patients compared to placebo (n=20) (Table 1). Similarly, overall survival (OS) benefit was observed in the Vigil group compared to placebo (Table 1). Improved RFS was demonstrated for a subset of patients with STRING predicted molecular profile.

Endpoint	HRP (n=45)
	Vigil (n=25)	Placebo (n=20)
Recurrence-Free Survival (RFS)
Median (mo.)	10.6	5.7
95% CI (mo.)	5.9-NA	5.6-14.9
HR (90%CI)	0.386 (0.199-0.750), p=0.007
Overall Survival (OS)
Median (mo.)	NR	26.9
95% CI (mo.)	28.7-NA	17.1-NA
HR (90%CI)	0.342 (0.141-0.832), p=0.019

結論：守夜免疫治療是一線維持 III/IV 期卵巢癌耐受性良好，BRCA 和 wt 均顯示出臨床益處 HRP 分子圖譜。結果表明，一個獨特的分子網絡，提高靈敏度療法。

Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed clinical benefit in both BRCA-wt and HRP molecular profile patients. Results suggest a unique molecular network that enhances sensitivity to Vigil therapy.