AbstractNeoadjuvant PD-1 inhibitor is promising in cutaneous melanoma but remains unknown in acral melanoma (AM). This phase Ib trial study (Clinicaltrials.gov NCT04197882) assessed the efficacy and safety of the combination of neoadjuvant oncolytic virus orienX010 (ori) and anti-PD-1 toripalimab (tori) for resectable AM.

摘要新辅助PD-1抑制剂在皮肤黑色素瘤中很有前景，但在肢端黑色素瘤（AM）中仍然未知。这项Ib期临床试验研究（Clinicaltrials.gov NCT04197882）评估了新辅助溶瘤病毒orienX010（ori）和抗PD-1托利帕利单抗（tori）联合治疗可切除AM的疗效和安全性。

Thirty patients of stage III/IV received neoadjuvant therapy of ori and tori for 12 weeks before surgery, followed by adjuvant treatment with tori for 1 year. Primary endpoints were radiographic and pathological response rates, with secondary endpoints of 1- and 2-year recurrence-free survival (RFS) rates, event-free survival (EFS) rates, and safety.

30例III/IV期患者在手术前接受ori和tori的新辅助治疗12周，然后用tori辅助治疗1年。。

Twenty-seven completed surgery and tori adjuvant treatment and median follow-up was 35.7 months. Radiographic and pathological response rates were 36.7% and 77.8%, with complete response rates of 3.3% and 14.8%, 1- and 2-year RFS rates of 85.2% and 81.5%, and 1- and 2-year EFS rates of 83% and 73%, respectively.

27例完成了手术和tori辅助治疗，中位随访时间为35.7个月。影像学和病理学缓解率分别为36.7%和77.8%，完全缓解率分别为3.3%和14.8%，1年和2年RFS率分别为85.2%和81.5%，1年和2年EFS率分别为83%和73%。

Adverse events occurred in all patients, mainly grade 1–2. There was no correlation between PET/CT evaluation and pathological response or progression-free survival/overall survival. Patients with pathological response showed tumor beds with high tertiary lymphoid structures (TLSs) and tumor-infiltrating lymphocytes (TILs).

所有患者均发生不良事件，主要是1-2级。PET/CT评估与病理反应或无进展生存期/总生存期之间没有相关性。有病理反应的患者显示肿瘤床具有高三级淋巴结构（TLS）和肿瘤浸润淋巴细胞（TIL）。

Cytokines and chemokines analysis showed the combination therapy significantly increases the secretion of proinflammatory cytokines and chemokines in both responders and non-responders. Therefore, neoadjuvant ori and tori demonstrated promising antitumor activity with high response rates and high 2-year RFS/EFS for AM with acceptable tolerability..

细胞因子和趋化因子分析显示，联合治疗显着增加了应答者和无应答者中促炎细胞因子和趋化因子的分泌。因此，新辅助ori和tori表现出有希望的抗肿瘤活性，对AM具有高反应率和高2年RFS/EFS，具有可接受的耐受性。。

IntroductionAcral melanoma (AM) is an aggressive subtype of melanoma.1 It has a low incidence in the Caucasian population, but a high incidence in the Chinese population, accounting for about 40% of melanoma cases.2 Despite notable advances in melanoma treatment, patients with AM have received limited benefit from popular immunotherapies, and lack established neoadjuvant therapeutic regimens.3 Thus, the prognosis for AM remains poor and shows a significantly severe immunosuppressive state.4 In addition, tumor mutational burden (TMB) was significantly different between acral and cutaneous melanoma, which makes AM less immunogenic and less responsive to immunotherapy.5 The treatment response of advanced AM to anti-PD-1 immunotherapy is significantly lower than that of cutaneous melanoma.6,7,8 A retrospective study showed that patients with AM treated with checkpoint inhibitors had a median overall survival (OS) of 17 months, significantly shorter than that of patients with cutaneous melanomas (median OS of 46 months P = 0.047).9 However, the response was even worse in Asian populations.

引言肢端黑色素瘤（AM）是黑色素瘤的一种侵袭性亚型。1它在高加索人群中发病率较低，但在中国人群中发病率较高，约占黑色素瘤病例的40%。2尽管黑色素瘤治疗取得了显着进展，但AM患者从流行的免疫疗法中获益有限，并且缺乏既定的新辅助治疗方案。因此，AM的预后仍然很差，并显示出明显的严重免疫抑制状态。4此外，肢端和皮肤黑色素瘤之间的肿瘤突变负荷（TMB）显着不同，这使得AM的免疫原性较低，对免疫疗法的反应较差。5晚期AM对抗PD-1的治疗反应6,7,8一项回顾性研究表明，接受检查点抑制剂治疗的AM患者的中位总生存期（OS）为17个月，显着短于皮肤黑色素瘤患者（中位OS为46个月，P=0.047）[9]。然而，亚洲人群的反应甚至更差。

In Keynote 151 which conducted in China, pembrolizumab monotherapy had an objective response rate (ORR) of 15.8%.10 A multi-center trial in Japan of patients treated with nivolumab reported an ORR of 19%, and a median OS of 15.6 months.11In spite of advances in treatment modalities, patients with stage IIIB-IVM1a melanoma remain at high risk of recurrence after complete surgical resection with curative intent.12 It remains critical to pursue other treatments aimed at improving OS by preventing disease recurrence.13 Theoretically, neoadjuvant immunotherapy has the potential to provoke a more robust immune response, given the heightened presence of tumor antigens compared to adjuvant strateg.

在中国进行的Keynote 151中，pembrolizumab单药治疗的客观缓解率（ORR）为15.8%[10]。在日本进行的一项多中心试验中，用nivolumab治疗的患者的ORR为19%，中位OS为15.6个月[11]。尽管治疗方式取得了进展，但IIIB-IVM1a期黑色素瘤患者在完全手术切除后仍有很高的复发风险[12]。通过预防疾病复发来寻求旨在改善OS的其他治疗仍然至关重要[13]。理论上，新辅助免疫治疗有可能引发更强大的免疫反应，因为与辅助治疗相比，肿瘤抗原的存在率更高。

Data availability

数据可用性

The original contributions presented in this study are included in the article/supplementary files. Further inquiries can be directed to the corresponding author.

本研究中提供的原始贡献包含在文章/补充文件中。进一步的询问可以直接联系通讯作者。

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Download referencesAcknowledgementsWe thank all the patients who participated in this trial and their families. We also thank Shanghai Junshi Biosciences Co. Ltd. for medical editorial support. This work was supported by the National Key Research and Development Program (2023YFC2506404), National Natural Science Foundation of China (82372869, 82272676, and 82073011), Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20220901, QML20231107), Beijing Natural Science Foundation (7242021).Author informationAuthor notesThese authors contributed equally: Jiayong Liu, Xuan Wang, Zhongwu Li, Shunyu GaoAuthors and AffiliationsKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Bone and Soft Tissue Sarcoma, Peking University Cancer Hospital and Research Institute, Beijing, ChinaJiayong Liu & Zhichao TanKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Melanoma and Sarcoma, Peking University Cancer Hospital and Research Institute, Beijing, ChinaXuan Wang, Lili Mao, Jie Dai, Caili Li, Zhihong Chi, Bin Lian, Bixia Tang, Siming Li, Xiaoting Wei, Jun Guo & Lu SiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Pathology, Peking University Cancer Hospital and Research Institute, Beijing, ChinaZhongwu Li & Yumei LaiKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Radiology, Peking University Cancer Hospital and Research Institute, Beijing, ChinaShunyu GaoKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Genitourinary Oncology, Peking University Cancer Hospital and Research Institute, Beijing, ChinaChuanliang Cui, Xinan .

下载参考文献致谢我们感谢所有参与本试验的患者及其家属。。这项工作得到了国家重点研究发展计划（2023YFC2506404），国家自然科学基金（8237286982272676和82073011），北京市医院管理局上升计划（DFL20220901，QML20231107），北京自然科学基金（7242021）的支持。作者信息作者注意到这些作者做出了同样的贡献：刘家勇，王萱，李忠武，高顺宇作者和附属机构北京大学肿瘤医院和研究所骨与软组织肉瘤实验室（教育部），北京大学肿瘤医院和研究所，中国北京，刘家勇，刘志超癌症发生和转化研究坦基实验室（教育部），北京大学肿瘤医院和研究所，黑色素瘤和肉瘤科，北京，王萱，毛丽丽，戴杰，李彩丽，迟志宏，连斌，唐碧霞，李思明，魏晓婷，郭军和路西基癌症发生和转化研究实验室（部）北京大学肿瘤医院和研究所病理学系，北京大学肿瘤医院和研究所，北京，中国顺玉致癌作用和转化研究高重点实验室（教育部），泌尿生殖肿瘤科，北京大学肿瘤医院和研究所，北京，中国崔传良，西安。

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PubMed Google ScholarContributionsL.S. had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. J.L., X.W., Z.-W.L., and S.-Y.G. contributed equally to this work as first authors. Concept and design: Drs J.-Y.L., X.W., Z.-W.L., S.-Y.G.

PubMed谷歌学术贡献l。S、 可以完全访问研究中的所有数据，并对数据的完整性和数据分析的准确性负责。J、 L.，X.W.，Z.-W.L。和S.-Y.G.作为第一作者对这项工作做出了同样的贡献。概念和设计：Drs J.-Y.L.，X.W.，Z.-W.L.，S.-Y.G。

and L.S. Acquisition, analysis, or interpretation of data: All authors. Drafting of the paper: J.-Y.L., X.W., Z.W.L. and S.-Y.G. Critical revision of the manuscript for important intellectual content: L.-L.M., J.D., C.-L.L., C.-L.C., Z.-H.C., X.-A.S., Y.-M.L., Z.-C.T., B.L., B.-X.T., X.-Q.Y., S.-M.L., L.Z., X.-T.W., J.L., J.G., L.S.

和L.S.数据的获取，分析或解释：所有作者。论文起草：J.-Y.L.，X.W.，Z.W.L.和S.-Y.G.重要知识内容手稿的批判性修订：L.-L.M.，J.D.，C.-L.L.，C.-L.C.，Z.-H.C.，X.-A.S.，Y.-M.L.，Z.-C.T.，B.L.，B.-X.T.，X.-Q.Y.，S.-M.L.，L.Z.，X.-T.W.，J.L.，J.G.，L.S。

Statistical analysis: J.-Y.L., X.W., Z.-W.L., S.-Y.G. and L.S. Obtained funding: L.S. Administrative, technical, or material support: J.D. and J.G. Supervision: L.S.Corresponding authorCorrespondence to.

统计分析：J.-Y.L.，X.W.，Z.-W.L.，S.-Y.G.和L.S.获得资金：L.S.行政，技术或物质支持：J.D.和J.G.监督：L.S.对应作者回复。

Lu Si.Ethics declarations

陆思.道德宣言

Competing interests

相互竞争的利益

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jun Guo serves consulting/advisory roles in Merck Sharp & Dohme, Roche, Bayer, Novartis, Simcere Pharmaceutical Group and Shanghai Junshi Biosciences. Lu Si has received speakers’ honoraria from MSD, Roche, Novartis, and Shanghai Junshi Biosciences.

作者声明以下财务利益/个人关系可能被认为是潜在的竞争利益：郭军在默克制药、罗氏、拜耳、诺华、辛切制药集团和上海骏石生物科学公司担任咨询/顾问角色。卢思获得了MSD、罗氏、诺华和上海骏世生物科学公司的演讲者酬金。

The remaining authors declare no competing interests..

其余作者声明没有利益冲突。。

Supplementary informationSupplementary_MaterialsClinical Study ProtocolRights and permissions

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Reprints and permissionsAbout this articleCite this articleLiu, J., Wang, X., Li, Z. et al. Neoadjuvant oncolytic virus orienx010 and toripalimab in resectable acral melanoma: a phase Ib trial.

转载和许可本文引用本文Liu，J.，Wang，X.，Li，Z。等人。新辅助溶瘤病毒orienx010和托利帕利单抗在可切除的肢端黑色素瘤中的应用：Ib期试验。

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