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三年大疫，让大家领教了病毒之毒。不过，病毒也可被改造为消灭肿瘤的专业杀手。溶瘤病毒是具有复制能力的肿瘤杀伤型病毒，能够特异性感染肿瘤细胞，并在肿瘤细胞内大量复制增殖并破坏肿瘤细胞，而对正常细胞无杀伤作用。溶瘤病毒疗法利用基因工程手段对溶瘤病毒进行改造，使其失去毒性并保留病毒的复制能力，可杀伤肿瘤细胞，达到治疗的目的。当肿瘤细胞被病毒感染后破裂死亡时，新生成的病毒颗粒被释放，进一步感染周围的肿瘤细胞。从机理来看，溶瘤病毒不仅能对肿瘤进行直接杀伤，还有望刺激人体的免疫反应，增强抗肿瘤效果。 2023年2月9日，英国《自然》旗下《自然医学》在线发表美国南佛罗里达大学莫菲特癌症中心MCC-18621研究报告，首次探讨了粒细胞和巨噬细胞集落刺激因子编码基因工程溶瘤单纯疱疹病毒T-VEC联合蒽环类＋紫杉类标准新辅助化疗对早期三阴性乳腺癌术前患者的有效性和安全性。MCC-18621 (NCT02779855): Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer (A Phase 1/2 Study of Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer) 该单中心单组非对照二期临床研究于2018年5月1日～2020年4月15日入组2～3期三阴性乳腺癌术前患者40例，接受5次肿瘤内注射T-VEC，联合紫杉醇→多柔比星＋环磷酰胺新辅助化疗，随后通过手术切除乳腺原发肿瘤和区域淋巴结评定残癌负荷指数。主要终点为残癌负荷指数为0。次要终点为残癌负荷指数为0～1率、复发率、毒性反应和免疫相关性。 结果，37例患者完成研究。常见的T-VEC毒性为发热、寒战、头痛、疲劳、注射部位疼痛。新辅助化疗毒性符合预计。发生血栓栓塞事件4例。 残癌负荷指数为0占45.9%，残癌负荷指数为0～1占65%。 2年无复发生存率为89%，残余癌负荷指数为0～1的患者均未复发（间接比较KEYNOTE-522研究结果：早期三阴性乳腺癌术前新辅助化疗±帕博利珠单抗，3年无复发生存率为84.5%比76.8%）。 因此，该单中心小样本非对照研究结果表明，早期三阴性乳腺癌术前T-VEC联合新辅助化疗可能提高残癌负荷指数为0～1的患者比例，故有必要进一步开展多中心大样本随机对照研究进行验证。Nat Med. 2023 Feb 9. IF: 87.241Oncolytic T-VEC virotherapy plus neoadjuvant chemotherapy in nonmetastatic triple-negative breast cancer: a phase 2 trial.Hatem Soliman, Deanna Hogue, Hyo Han, Blaise Mooney, Ricardo Costa, Marie C. Lee, Bethany Niell, Angela Williams, Alec Chau, Shannon Falcon, Aixa Soyano, Avan Armaghani, Nazanin Khakpour, Robert J. Weinfurtner, Susan Hoover, John Kiluk, Christine Laronga, Marilin Rosa, Hung Khong, Brian Czerniecki.Moffitt Cancer Center, Tampa, FL, USA.Talimogene laherparepvec (T-VEC) is an oncolytic virus hypothesized to enhance triple-negative breast cancer (TNBC) responses to neoadjuvant chemotherapy (NAC). This article describes the phase 2 trial of T-VEC plus NAC (ClinicalTrials.gov ID: NCT02779855). Patients with stage 2-3 TNBC received five intratumoral T-VEC injections with paclitaxel followed by doxorubicin and cyclophosphamide and surgery to assess residual cancer burden index (RCB). The primary end point was RCB0 rate. Secondary end points were RCB0-1 rate, recurrence rate, toxicity and immune correlates. Thirty-seven patients were evaluated. Common T-VEC toxicities were fevers, chills, headache, fatigue and injection site pain. NAC toxicities were as expected. Four thromboembolic events occurred. The primary end point was met with an estimated RCB0 rate = 45.9% and RCB0-1 descriptive rate = 65%. The 2-year disease-free rate is equal to 89% with no recurrences in RCB0-1 patients. Immune activation during treatment correlated with response. T-VEC plus NAC in TNBC may increase RCB0-1 rates. These results support continued investigation of T-VEC plus NAC for TNBC.DOI: 10.1038/s41591-023-02210-0
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