Schmitt Michael, Schmitt Anita, Wiesneth Markus, Hückelhoven Angela, Wu Zeguang, Kuball Jürgen, Wang Lei, Schauwecker Peter, Hofmann Susanne, Götz Marlies, Michels Birgit, Maccari Birgit, Wuchter Patrick, Eckstein Volker, Mertens Thomas, Schnitzler Paul, Döhner Hartmut, Ho Anthony D, Bunjes Donald W, Dreger Peter, Schrezenmeier Hubert, Greiner Jochen
Dept. of Internal Medicine V, Heidelberg University Hospital, 69120 Heidelberg, Germany.
German Cancer Consortium/Deutsches Konsortium für Translationale Krebsforschung (DKTK), 69120 Heidelberg, Germany.
Theranostics. 2017 Apr 10;7(6):1705-1718. doi: 10.7150/thno.18301. eCollection 2017.
Patients receiving an allogeneic stem cell graft from cytomegalovirus (CMV) seronegative donors are particularly prone to CMV reactivation with a high risk of disease and mortality. Therefore we developed and manufactured a novel vaccine and initiated a clinical phase I trial with a CMV phosphoprotein 65 (CMVpp65)-derived peptide. Ten patients after allogeneic stem cell transplantation received four vaccinations at a biweekly interval. All patients were monitored for CMVpp65 antigenemia. Flow cytometry for CMV-specific CD8 and γδ T cells as well as neutralizing anti-CMV antibodies were correlated to clinical parameters. The vaccination was well tolerated. Seven of nine patients cleared CMVpp65 antigenemia after four vaccinations and are still free from antigenemia to this day. Two patients with CMV reactivation showed persisting CMV antigenemia. One patient received prophylactic vaccination and did not develop antigenemia. An increase of up to six-fold in frequency of both CMV-specific CD8 T cells and/or Vδ2negative γδ T cells was detected. Titers of neutralizing antibodies increased up to the tenfold. Humoral and cellular immune responses correlated with clearance of CMV. In summary, CMVpp65 peptide vaccination for patients after allogeneic stem cell transplantation at high risk for CMV reactivation was safe, well tolerated and clinically encouraging. A study in solid-organ transplant patients is ongoing.
接受来自巨细胞病毒（CMV）血清学阴性供体的异基因干细胞移植的患者尤其容易发生CMV再激活，疾病和死亡风险很高。因此，我们研发并生产了一种新型疫苗，并启动了一项针对CMV磷蛋白65（CMVpp65）衍生肽的I期临床试验。10名异基因干细胞移植后的患者每两周接受4次疫苗接种。所有患者均监测CMVpp65抗原血症。对CMV特异性CD8和γδT细胞进行流式细胞术检测，并将中和性抗CMV抗体与临床参数相关联。疫苗接种耐受性良好。9名患者中有7名在4次疫苗接种后清除了CMVpp65抗原血症，至今仍无抗原血症。2名发生CMV再激活的患者显示CMV抗原血症持续存在。1名患者接受了预防性疫苗接种，未出现抗原血症。检测到CMV特异性CD8 T细胞和/或Vδ2阴性γδT细胞的频率增加高达6倍。中和抗体滴度增加高达10倍。体液和细胞免疫反应与CMV清除相关。总之，对有CMV再激活高风险的异基因干细胞移植后患者进行CMVpp65肽疫苗接种是安全的，耐受性良好，且在临床上令人鼓舞。一项针对实体器官移植患者的研究正在进行中。
