Purpose: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. Patients and Methods: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. Results: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. Conclusions: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.

中文翻译：

---

通过立体定向放射和原位病毒基因治疗增强转移性三阴性乳腺癌免疫检查点阻断的 2 期试验

目的：对转移性三阴性乳腺癌 (mTNBC) 患者进行立体定向放射治疗和原位细胞毒性病毒治疗，然后进行派姆单抗 (STOMP) 的 2 期试验，旨在评估用腺病毒增强单药免疫检查点阻断的双重方法。 mTNBC 患者中单纯疱疹病毒胸苷激酶 (ADV/HSV-tk) 介导的表达加上伐昔洛韦基因治疗和立体定向放射治疗 (SBRT)。患者和方法：在这项单臂、开放标签 2 期试验中，mTNBC 患者接受 ADV/HSV-tk [5 × 1011 病毒颗粒 (vp)] 瘤内注射治疗，然后对注射的肿瘤部位进行 SBRT，然后是派姆单抗（200 毫克，每 3 周一次）。主要终点是临床获益率[CBR；完全缓解 (CR)、部分缓解 (PR)、或根据 RECIST version1.1 在非照射部位疾病稳定 (SD) ≥ 24 周]。次要终点包括治疗持续时间 (DoT)、总生存期 (OS) 和安全性。探索性终点包括通过相关组织和血液生物标志物评估的治疗免疫反应。结果：28 名患者入组并接受治疗。6 例患者 (21.4%) 出现 CBR，其中 2 例 CR (7.1%)、1 例 PR (3.6%) 和 3 例 SD (10.7%)。具有临床获益的患者具有持久的缓解，中位 DoT 为 9.6 个月，OS 为 14.7 个月。总人口的中位 OS 为 6.6 个月。该组合具有良好的耐受性。飞行时间细胞计数 (CyTOF) 和成像质量流式细胞术 (IMC) 的相关研究表明，应答者中 CD8 T 细胞和无应答者中骨髓细胞显着增加。结论：具有临床获益的患者的中位 OS 增加了 2 倍以上。对于接受过多次治疗的 mTNBC 患者来说，该疗法是一种耐受性良好的治疗方法。早期检测到效应和效应记忆 CD8 T 细胞和骨髓细胞的增加分别与反应和无反应相关。