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期刊来源：Nat Med

原文链接：https://doi.org/10.1038/s41591-024-02851-9

摘要内容如下：

引发针对肿瘤特异性新抗原的细胞毒性T细胞应答的治疗性疫苗有望为癌症患者提供长期的临床益处。在一项正在进行的晚期/转移性实体瘤患者的1/2期研究中，我们评估了一种治疗性疫苗的安全性和耐受性，该疫苗编码来自选定的常见致癌驱动突变的20种共享新抗原，作为主要终点。次要终点包括免疫原性、总缓解率、无进展生存期和总生存期。如果符合条件的患者的肿瘤表达疫苗中包含的人类白细胞抗原匹配的肿瘤突变之一，且大多数患者（18/19）携带KRAS突变，则选择符合条件的患者。由黑猩猩腺病毒（CHAD68）和自我扩增mRNA（SAMRNA）与免疫检查点抑制剂ipilimumab和nivolumab联合组成的疫苗方案显示耐受性良好，观察到的治疗相关不良事件与基于病毒载体的疫苗和免疫检查点阻断预期的急性炎症一致，多数为1/2级。两名患者出现了3/4级严重治疗相关不良事件，这些不良事件也是剂量限制性毒性。总有效率为0%，中位无进展生存期和总生存期分别为1.9个月和7.9个月。相对于患者肿瘤表达的KRAS新抗原，T细胞应答偏向于疫苗中编码的人类白细胞抗原匹配的TP53新抗原，这表明以前未知的新抗原免疫优势等级可能影响多表位共享新抗原疫苗的治疗效果。这些数据导致了专门针对KRAS衍生的新抗原的优化疫苗的开发，该疫苗正在临床研究2期的患者亚群中进行评估。ClinicalTrials.gov注册：NCT03953235。

英文原文如下：

Abstracts

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

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