Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.
Evaluation of safety and efficacy of p53MVA vaccine combined with pembrolizumab in patients with advanced solid cancers.
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DOI：
10.1007/s12094-018-1932-2
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发表时间：
2019-03
期刊：
影响因子：
--
通讯作者：
Diamond DJ
中科院分区：
文献类型：
--
作者：
Chung V;Kos FJ;Hardwick N;Yuan Y;Chao J;Li D;Waisman J;Li M;Zurcher K;Frankel P;Diamond DJ
我们之前的研究表明，癌症患者接种表达 p53 的改良痘苗安卡拉病毒 (p53MVA) 可以激活外周血中的 p53 反应性 T 细胞，但没有立即的临床益处。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才能达到临床有益的水平。因此，我们进行了一项 I 期试验，评估 p53MVA 和派姆单抗（抗 PD-1）联合治疗晚期实体瘤患者。 11 名患有晚期乳腺癌、胰腺癌、肝细胞癌或头颈癌的患者每三周接受最多 3 次疫苗，同时联合派姆单抗注射，此后每隔三周单独注射一次，直至疾病进展。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。我们观察了 3/11 患者的临床反应，这些患者在 30、32 和 49 周内病情稳定。其中两名患者表现出 p53 反应性 CD8+ T 细胞的频率和持久性增加，以及多种免疫反应基因表达的升高。 7/11 患者中的临界或不可检测的 p53 特异性 T 细胞反应与没有立即的临床获益有关。第一位研究患者患有 5 级致命性心肌炎。在对研究进行修改以加强心脏监测后，没有发现额外的心脏毒性。我们已经证明，p53MVA 疫苗与 pembrolizumab 的组合是可行、安全的，并且可能为特定的患者群体提供临床益处，应通过进一步的研究来确定。
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 three-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 a clinical benefit in select group of patients that should be identified through further studies.
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DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.1158/1078-0432.ccr-17-2709
发表时间：
2018-03-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Hardwick NR;Frankel P;Ruel C;Kilpatrick J;Tsai W;Kos F;Kaltcheva T;Leong L;Morgan R;Chung V;Tinsley R;Eng M;Wilczynski S;Ellenhorn JDI;Diamond DJ;Cristea M
通讯作者：
Cristea M
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
2.4
作者：
Song GY;Srivastava T;Ishizaki H;Lacey SF;Diamond DJ;Ellenhorn JD
通讯作者：
Ellenhorn JD
影响因子：
4.4
作者：
Hadrup, SR;Strindhall, J;Wikby, A
通讯作者：
Wikby, A