Metabolomics and Cell Biology Platforms, Gustave Roussy Cancer Center, Université Paris Saclay, Villejuif, France.
Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138 and CNRS SNC 5096, Institut Universitaire de France, Paris, France.
Oncoimmunology. 2022 Jun 24;11(1):2093518. doi: 10.1080/2162402X.2022.2093518. eCollection 2022.
Preclinical experimentation revealed that established cancers treated with the immunogenic cell death (ICD) inducer oxaliplatin are sensitized to immune checkpoint inhibitors targeting PD-1. In contrast, no such sensitizing effect is observed when cisplatin, a non-immunogenic cell death inducer is used. Two randomized phase III clinical trials targeting unresectable gastric and gastro-esophageal junction carcinomas apparently validate this observation. Thus, oxaliplatin-based chemotherapy (together with capecitabine or 5-fluorouracil plus leucovorin) favorably interacted with nivolumab, yielding improved outcome. In contrast, the outcome of cisplatin-based chemotherapy (together with capecitabine or 5-fluorouracil) failed to be improved by concomitant treatment with pembrolizumab. These clinical findings underscore the importance of choosing appropriate ICD-inducing cytotoxicants for the development of chemoimmunotherapeutic regimens. Unfortunately, the FDA and EMA have approved PD-1 blockade in combination with "platinum-based chemotherapy" without specifying the precise nature of the platinum-containing drug. This is a non sequitur. Based on the available clinical data, such approvals should be restricted to the use of oxaliplatin.
临床前实验表明，用免疫原性细胞死亡（ICD）诱导剂奥沙利铂治疗的已建立的癌症对针对 PD-1 的免疫检查点抑制剂敏感。相比之下，当使用非免疫原性细胞死亡诱导剂顺铂时，不会观察到这种致敏作用。两项针对不可切除的胃和胃食管交界处癌的随机 III 期临床试验显然验证了这一观察结果。因此，奥沙利铂为基础的化疗（与卡培他滨或氟尿嘧啶加亚叶酸钙联合使用）与纳武单抗有利地相互作用，改善了结果。相比之下，顺铂为基础的化疗（与卡培他滨或氟尿嘧啶联合使用）未能通过与 pembrolizumab 同时治疗而改善。这些临床发现强调了为开发化疗免疫治疗方案选择合适的 ICD 诱导细胞毒素的重要性。不幸的是，FDA 和 EMA 已批准 PD-1 阻断与“铂类化疗”联合使用，而未具体说明含铂药物的确切性质。这是不合逻辑的。基于现有临床数据，此类批准应仅限于奥沙利铂的使用。
