CMVPepVax to Protect HCT Recipients from Cytomegalovirus Infection

描述（由申请人提供）：造血干细胞移植（HCT）是化疗难治性白血病和其他恶性肿瘤令人印象深刻的治愈率的原因。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提高HCT后恢复期的发病率和死亡率，降低了HCT的全部治愈潜力。限制CMV病毒血症的抗病毒药物需要付出包括肾功能不全、中性粒细胞减少和免疫抑制在内的发病率的代价。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结果。该疫苗由与来自CMV的HLA-A2限制性CTL表位共价连接的HLA混杂破伤风T辅助表位组成，当与单链寡脱氧核苷酸佐剂和TLR 9激动剂PF 03512676（Pfizer）组合时，该表位在健康成人和HCT接受者（HCT-R）中刺激强烈的免疫应答。在健康成人中完成1b期试验后，我们在匹配的相关（MRD）和无关（URD）供体HCT-R中启动了一项随机化2组先导1b期试验（先导）。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，疫苗组具有更高的CMV特异性免疫力，CMV再激活和慢性GVHD的发生率更低。在本申请中，我们将与明尼苏达大学联合开展2项随机、盲法和安慰剂对照的2期试验，以预防HCT-R中的CMV再激活，从而推进该疫苗概念（CMVPepVax）。在具体目标（SA）1中，我们将进行试验1，即 检验MRD-HCT中CMV再激活和疾病减少的主要终点的把握度。CMV阳性HCT-R将随机分配至疫苗（VA）和安慰剂（PA）组，间隔4周进行2次注射，而供体将同时随机分配至干细胞采集前2-5周接受单次疫苗接种。供体疫苗接种对改善HCT-R结局的影响将是次要终点，从而允许高达67%的供体下降，但仍有能力对HCT-R结局产生影响。免疫学20终点将通过使用HLA多聚体的CMV特异性T细胞的频率测量和使用T-box转录因子、T-bet和Eomes的功能研究来定量。重要的是，这项研究将测试我们的新观察结果，即NK细胞通过激活特定的NKG 2C+持久（记忆）反应来响应HCT后的CMV再激活，该反应可以使用CMVPepVax模拟，这将对该领域产生重大的一般影响。在SA 2中，试验2将测试CMVPepVax在高风险URD和脐带血（UCB）受体中的保护功能。本试验将采用与试验1相同的形式，除了没有供体参与以解决广泛的URD设置或较少匹配的UCB移植物，所有这些都导致CMV再激活和疾病的风险高于MRD。我们的目标是通过进行2期研究来利用我们的CMVPepVax 1期成功，这不仅将确定HCT-R在CMV感染并发症风险中的治疗益处，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.