CMVPepVax to Protect HCT Recipients from Cytomegalovirus Infection

描述(申请人提供)：造血干细胞移植(HCT)对化疗、难治性白血病和其他恶性肿瘤的治愈率令人印象深刻。然而，包括巨细胞病毒(CMV)在内的危及生命的机会性感染通过在HCT后恢复期间增加发病率和死亡率而降低了HCT的全部治疗潜力。限制CMV病毒血症的抗病毒药物需要付出包括肾功能障碍、中性粒细胞减少和免疫抑制在内的发病率代价。用刺激多种免疫机制的疫苗替代有毒的抗病毒药物可能会改善HCT的结果。该疫苗由一个HLA杂乱破伤风T辅助表位共价连接到CMV的HLA-A2限制性CTL表位上，当与单链寡脱氧核苷酸佐剂和TLR9激动剂PF03512676(辉瑞)结合时，可在健康成年人和接受HCT-R的人中激发强烈的免疫反应。在健康成人完成1b期试验后，我们在匹配亲属(MRD)和非血缘关系(URD)供者HCT-R中启动了随机双臂试验1b期试验(Pilot)。对HCT-R试验的中期分析支持疫苗概念，因为初步数据显示，与观察组相比，疫苗中CMV特异性免疫力更强，CMV重新激活和慢性GVHD的比率更低。在这项应用中，我们将通过与明尼苏达大学联合进行2个随机、盲目和安慰剂对照的第二阶段试验来推进这一疫苗概念(CMVPepVax)，以防止HCT-R中CMV的重新激活。在特定目标(SA)1中，我们将进行试验1，即 用于测试MRD-HCT中CMV重新激活和疾病减少的主要终点。CMV阳性的HCT-R将被随机分成疫苗(VA)和安慰剂(PA)组，并间隔4周进行两次注射，而捐赠者将同时和联合随机接受干细胞采集前2-5周的单次疫苗接种。捐赠者接种疫苗对改善HCT-R结局的影响将是次要终点，从而允许多达67%的捐赠者下降，但仍有能力影响HCT-R结局。免疫学上的20个终点将通过使用人类白细胞抗原多聚体测量CMV特异性T细胞的频率以及使用T盒转录因子、T-bet和eome进行功能研究来量化。重要的是，这项研究将检验我们的新观察结果，即NK细胞对HCT后CMV重新激活的反应是通过激活特定的NKG2C+长时间(记忆)反应，这种反应可以用CMVPepVax来模拟，这将对该领域产生重大的普遍影响。在SA2中，试验2将测试CMVPepVax在高危URD和脐带血(UCB)接受者中的保护功能。这项试验将采用与试验1相同的形式，除了没有供者参与以解决广泛的URD环境，或匹配较少的脐带血移植，所有这些都导致与MRD相比，CMV重新激活和疾病的风险更高。我们的目标是利用我们在CMVPepVax的第一阶段的成功，进行第二阶段的研究，这些研究不仅将确定存在CMV感染并发症风险的HCT-R的治疗益处，而且还将确定这种保护的免疫学基础。

DESCRIPTION (provided by applicant): Hematopoietic stem cell transplant (HCT) is responsible for impressive cure rates of chemotherapy refractory leukemia and other malignancies. However, life-threatening opportunistic infections including cytomegalovirus (CMV) diminish full curative potential of HCT by raising morbidity and mortality throughout post-HCT recovery. Antiviral drugs which limit CMV viremia exact a cost of morbidity including renal dysfunction, neutropenia and immune suppression. Substituting toxic antivirals with a vaccine that stimulates multiple immune mechanisms may improve HCT outcomes. The vaccine is composed of an HLA promiscuous tetanus T-helper epitope covalently attached to an HLA-A2-restricted CTL epitope from CMV that stimulated a strong immune response in healthy adults and HCT recipients (HCT-R) when combined with a single stranded oligodeoxyonucleo-tide adjuvant and TLR9 agonist, PF03512676 (Pfizer). Subsequent to the completed Phase 1b trial in healthy adults, we initiated a randomized 2-arm pilot Phase 1b trial (Pilot) in both matched related (MRD) and unrelated (URD) donor HCT-R. Interim analysis of the Pilot in HCT-R supports the vaccine concept because preliminary data shows greater CMV-specific immunity, lower rates of CMV reactivation and chronic GVHD in the vaccine versus observational arm. In this application, we will advance this vaccine concept (CMVPepVax) by conducting 2 randomized, blinded and placebo-controlled Phase 2 trials to prevent CMV reactivation in HCT-R jointly with the University of Minnesota. In Specific Aim (SA) 1, we will conduct Trial 1 that is powered to test the primary endpoint of reduced CMV reactivation and disease in MRD-HCT. CMV-positive HCT-R will be randomized into a vaccine (VA) and a placebo (PA) arm, and given 2 injections spaced 4 weeks apart, while donors will be simultaneously and conjointly randomized to receive a single vaccination 2-5 weeks prior to stem cell collection. The effect of donor vaccination on improving HCT-R outcomes will be a secondary endpoint, thereby allowing up to 67% of donors to decline, yet still have power for effect on HCT-R outcomes. Immunologic 20 endpoints will be quantified by frequency measurements of CMV-specific T cells using HLA multimers and functional studies with T-box transcription factors, T-bet and Eomes. Importantly, this study will test our novel observations that NK cells respond to CMV reactivation after HCT by activating a specific NKG2C+ long-lasting (memory) response that can be mimicked using CMVPepVax, which would have significant general impact on the field. In SA2, Trial 2 will test protective function of CMVPepVax in higher risk URD and umbilical cord blood (UCB) recipients. This trial will employ the same format as Trial 1 except no donor involvement to address a broad range of URD settings, or lesser matched UCB grafts, all resulting in a higher risk of CMV reactivation and disease compared to MRD. The goal is to capitalize on our Phase 1 success with CMVPepVax by conducting Phase 2 studies that will not only establish the therapeutic benefit for HCT-R at risk for complications of CMV infection, but as well define the immunologic basis for this protection.