Transfer of vaccine-induced immunity from immunocompetent stem cell donor as antiviral immunotherapy to protect high-risk transplant recipients from cytomegalovirus reactivation

项目摘要/摘要 造血细胞移植中预防性应用抗病毒药物控制巨细胞病毒血症 受体(HCT-R)是一种治疗进展，同时也增加了毒性。较新的药物，如letermovir (Prevymis)毒性低，疗效高。FDA连续100天批准Prevymis (D)预防措施可将高风险和低风险HCT-R患者的CMV重新激活减少约2倍。抗病毒作用 在没有生存福利的情况下18周后就消退了。我们与NCI共同开发了一种改进的安卡拉牛痘(MVA) 表达CMV免疫优势抗原的三联体疫苗。我们在《健康》杂志上发表了一项安全性研究 志愿者展示了强免疫原性的疫苗(NCT1941056)，这是在一篇发表之前 成功的CMV阳性(P)HCT-R安慰剂对照和随机2期试验(NCT2506933) CMV阳性(CMV-P)或CMV阴性(CMV-N)HCT供者(HCT-D)。第二阶段的试验满足了它的主要要求 通过加速保护性重建，疫苗臂中CMV重新激活的终点减少50% 巨细胞病毒免疫。可以改善三重结局；一种方法是接种具有免疫能力的HCT-D 我们正在进行的试点研究(NCT3560752)的令人印象深刻的初步结果表明 所有接受接种匹配亲属捐赠者(MRD)干细胞的HCT-R(N=12)都受到保护，不会受到 需要PET。我们推测，三联注射HCT-D将通过转移 作为向HCT-R输注干细胞的组成部分的扩增的CMV保护T细胞，在给药前 Prevymis，从而消除了它的需要。在目标1中，我们提出了一项第二阶段随机安慰剂对照试验(in 未为MRD-HCT开Prevymis处方的中心)符合CMV-P HCT-R MRD(中等风险)的资格 接受T细胞全血细胞移植治疗恶性血液病。CMV-P HCT-R将随机接受干细胞移植 来自HCT-D的细胞接受与试点试验相同的单次注射三联或安慰剂。这场审判将证明 单次接种HCT-D疫苗足以取代100天的Prevymis，以防止在MRD-HCT-R中使用PET。 在180d的试验期内，我们将评估PET的使用情况，测量CMV特异性CD8/CD4T细胞，目标是 将频率、记忆表型和基因表达与防止再激活联系起来，导致 病毒血症或疾病。将三重受益扩大到经HCT后环磷酰胺治疗的半相合HCT-R (PTCY)是CMV重新激活的高危人群，在目标2中，我们建议进行两阶段(1b/2阶段)试验来选择 一种最佳的三联疫苗策略，以最小的CMV重新激活促进有效的免疫重建。 所有HCT-D将接种一次三联疫苗，所有HCT-R将在第28天通过3次三联注射加强免疫， 56和100。最初的开放标签1b期片段将让患者戒除Prevymis，或给予 预防用药21d-100d。使用最少的Prevymis但仍不会增加的疫苗接种方案 与标准Prevymis相比，Prevymis将被选为后续随机第二阶段的节段 与没有接种疫苗的标准护理相比，减少或不接种普及率的疫苗接种。

PROJECT SUMMARY/ABSTRACT Preemptive use of antivirals (PET) to control cytomegalovirus (CMV) viremia in hematopoietic cell transplant recipients (HCT-R) was a therapeutic advance balanced by elevated toxicity. Newer drugs such as letermovir (Prevymis) have lower toxicity with increased efficacy. FDA approval of Prevymis was for 100 consecutive days (d) of prophylaxis which reduced CMV reactivation by ~2fold in high and low risk HCT-R. The antiviral effect waned after 18 weeks without a survival benefit. We co-developed with NCI, a modified vaccinia Ankara (MVA) vaccine named Triplex expressing CMV immunodominant antigens. We published a safety study in healthy volunteers showing strong immunogenicity of the vaccine (NCT1941056), which preceded a published successful placebo-controlled and randomized Phase 2 trial (NCT2506933) of CMV-positive (P) HCT-R with either CMV-Positive (CMV-P) or CMV-Negative (CMV-N) HCT donors (HCT-D). The Phase 2 trial met its primary endpoint of reduced CMV reactivation in the vaccine arm by 50% with accelerated reconstitution of protective CMV immunity. Triplex outcomes can be improved; one approach is to vaccinate the immunocompetent HCT-D as demonstrated by our impressive preliminary results from an ongoing pilot study (NCT3560752) which showed that all HCT-R (N=12) receiving stem cells from vaccinated matched related donors (MRD) were protected from requiring PET. We hypothesize that Triplex injection of HCT-D will initiate protective immunity by transfer of expanded CMV-protective T cells as a component of the stem cell infusion to the HCT-R, preceding dosing with Prevymis, thereby eliminating its need. In Aim 1, we propose a Phase 2 randomized placebo-control trial (in centers not prescribing Prevymis for MRD-HCT) with eligibility of CMV-P HCT-R with MRD (intermediate risk) undergoing T-cell replete HCT for hematologic malignancy. CMV-P HCT-R will be randomized to receive stem cells from HCT-D receiving a single injection of Triplex or placebo identical to the pilot trial. This trial will show that a single HCT-D vaccination is sufficient to replace 100d of Prevymis to prevent PET usage in MRD-HCT-R. In the 180d trial period we will assess PET usage, measure CMV-specific CD8/CD4 T cells with the goal of associating frequency, memory phenotype, and gene expression with protection against reactivation leading to viremia or disease. To extend Triplex benefit to haploidentical HCT-R treated with post-HCT cyclophosphamide (PTCY) who are at high risk for CMV reactivation, in Aim 2 we propose a two-stage (Phase 1b/2) trial to choose an optimal Triplex vaccine strategy that promotes effective immune reconstitution with minimal CMV reactivation. All HCT-D will be vaccinated once with Triplex, and all HCT-R will be boosted with 3 Triplex injections on d28, 56, and 100. The initial open-label Phase 1b segment will either have patients abstain from Prevymis, or given 21d-100d of prophylaxis. The vaccination regimen with the least usage of Prevymis that still results in no increase in reactivation compared to standard Prevymis will be selected for follow-on randomized Phase 2 segment of vaccination with reduced or no Prevymis dosing compared to standard of care Prevymis with no vaccination.