Department of Medical Oncology, City of Hope National Medical Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.
Department of Immuno-Oncology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Clin Transl Oncol. 2019 Mar;21(3):363-372. doi: 10.1007/s12094-018-1932-2. Epub 2018 Aug 9.
Vaccination of cancer patients with p53-expressing modified vaccinia Ankara virus (p53MVA) has shown in our previous studies to activate p53-reactive T cells in peripheral blood but without immediate clinical benefit. We hypothesized that the immunological responses to p53MVA vaccine may require additional immune checkpoint blockade to achieve clinically beneficial levels. We therefore conducted a phase I trial evaluating the combination of p53MVA and pembrolizumab (anti-PD-1) in patients with advanced solid tumors.
Eleven patients with advanced breast, pancreatic, hepatocellular, or head and neck cancer received up to 3 triweekly vaccines in combination with pembrolizumab given concurrently and thereafter, alone at 3-week intervals until disease progression. The patients were assessed for toxicity and clinical response. Correlative studies analyzed p53-reactive T cells and profile of immune function gene expression.
We observed clinical responses in 3/11 patients who remained with stable disease for 30, 32, and 49 weeks. Two of these patients showed increased frequencies and persistence of p53-reactive CD8 T cells and elevation of expression of multiple immune response genes. Borderline or undetectable p53-specific T cell responses in 7/11 patients were related to no immediate clinical benefit. The first study patient had a grade 5 fatal myocarditis. After the study was amended for enhanced cardiac monitoring, no additional cardiac toxicities were noted.
We have shown that the combination of p53MVA vaccine with pembrolizumab is feasible, safe, and may offer clinical benefit in select group of patients that should be identified through further studies.
我们之前的研究表明，给癌症患者接种表达 p53 的改良安卡拉痘苗病毒（p53MVA）可以在外周血中激活 p53 反应性 T 细胞，但没有立即的临床获益。我们假设 p53MVA 疫苗的免疫反应可能需要额外的免疫检查点阻断来达到临床有益的水平。因此，我们进行了一项 I 期临床试验，评估了 p53MVA 和 pembrolizumab（抗 PD-1）联合治疗晚期实体瘤患者的效果。
11 名患有晚期乳腺癌、胰腺癌、肝细胞癌或头颈部癌的患者接受了多达 3 次每 3 周的疫苗接种，同时联合使用 pembrolizumab，此后每 3 周单独使用，直到疾病进展。评估患者的毒性和临床反应。相关研究分析了 p53 反应性 T 细胞和免疫功能基因表达谱。
我们观察到 3/11 名患者出现临床反应，其中 3 名患者的疾病稳定持续了 30、32 和 49 周。这 2 名患者的 p53 反应性 CD8 T 细胞频率和持久性增加，并且多个免疫反应基因的表达升高。7/11 名患者的 p53 特异性 T 细胞反应边界或无法检测到，与没有立即的临床获益有关。第一名研究患者发生了 5 级致命心肌炎。在对研究进行修改以加强心脏监测后，没有发现其他心脏毒性。
我们已经证明，p53MVA 疫苗与 pembrolizumab 联合使用是可行的、安全的，并且可能为选择的患者群体提供临床获益，这需要通过进一步的研究来确定。
