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.

引发针对肿瘤特异性新抗原的细胞毒性 T 细胞反应的治疗性疫苗有望为癌症患者提供长期临床益处。在这里，我们评估了编码 20 种共享新抗原的治疗性疫苗的安全性和耐受性，这些新抗原源自选定的常见致癌驱动突变，作为正在进行的针对晚期/转移性实体瘤患者的 1/2 期研究的主要终点。次要终点包括免疫原性、总体缓解率、无进展生存期和总体生存期。如果患者的肿瘤表达疫苗中包含的与人类白细胞抗原匹配的肿瘤突变之一，则选择符合条件的患者，其中大多数患者（18/19）携带KRAS突变。该疫苗方案由黑猩猩腺病毒 (ChAd68) 和自扩增 mRNA (samRNA) 以及免疫检查点抑制剂伊匹单抗 (ipilimumab) 和纳武单抗 (nivolumab) 组成，显示出良好的耐受性，观察到的与治疗相关的不良事件与预期的急性炎症一致基于病毒载体的疫苗和免疫检查点封锁，大多数为 1/2 级。两名患者经历了 3/4 级严重的治疗相关不良事件，也是剂量限制性毒性。总体缓解率为 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 细胞反应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会影响多表位共享新抗原疫苗的治疗效果。这些数据促使开发出一种专门针对 KRAS 衍生新抗原的优化疫苗，该疫苗正在临床研究第 2 阶段的一部分患者中进行评估。 ClinicalTrials.gov 注册：NCT03953235。