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的治愈率令人印象深刻的原因。然而，危及生命的机会性感染，包括巨细胞病毒（CMV），通过提高HCT后恢复期间的发病率和死亡率，削弱了HCT的全部治愈潜力。限制巨细胞病毒血症的抗病毒药物必须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的代价。用刺激多种免疫机制的疫苗替代有毒抗病毒药物可能改善HCT的结果。该疫苗由HLA混杂破伤风t辅助表位与CMV HLA- a2限制性CTL表位共价结合组成，当与单链寡核苷酸佐剂和TLR9激动剂PF03512676（辉瑞）结合时，在健康成人和HCT受体（HCT- r）中刺激强烈的免疫反应。在健康成人完成1b期试验之后，我们在匹配的相关（MRD）和非相关（URD）供体HCT-R中启动了一项随机2组先导1b期试验（pilot）。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，疫苗组的CMV特异性免疫力更高，CMV再激活率更低，慢性GVHD发生率更低。在本次申请中，我们将通过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期试验来推进这一疫苗概念（CMVPepVax），以防止CMV在HCT-R中的再激活。在Specific Aim (SA) 1中，我们将进行试验1，即

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.