Gritstone bio, Emeryville, CA, USA.
Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Med. 2024 Apr;30(4):1013-1022. doi: 10.1038/s41591-024-02851-9. Epub 2024 Mar 27.
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 .
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的临床获益。在这里，我们评估了编码 20 个源自选定常见致癌驱动突变的共享新抗原的治疗性疫苗的安全性和耐受性，这是一项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、总缓解率、无进展生存期和总生存期。如果患者的肿瘤表达疫苗中包含的匹配人类白细胞抗原的肿瘤突变之一，则符合入选条件，大多数患者（18/19）携带 KRAS 突变。疫苗方案由黑猩猩腺病毒（ChAd68）和自我扩增 mRNA（samRNA）与免疫检查点抑制剂伊匹单抗和纳武单抗联合组成，结果显示具有良好的耐受性，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引起的急性炎症一致，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，也是剂量限制毒性。总缓解率为 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。与患者肿瘤表达的 KRAS 新抗原相比，T 细胞反应偏向于疫苗中编码的匹配人类白细胞抗原的 TP53 新抗原，表明存在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。这些数据导致了一种专门针对 KRAS 衍生新抗原的优化疫苗的开发，该疫苗正在临床研究的 2 期部分患者中进行评估。临床试验注册：NCT03953235。
