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

将来自免疫活性干细胞供体的疫苗诱导的免疫力转移作为抗病毒免疫疗法，以保护高危移植受者免受巨细胞病毒再激活

• 批准号: 10659635
• 负责人: Don J Diamond
• 金额: $ 68.81万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659635
• 关键词: Acceleration; Acute; Adoption; Adoptive Transfer; Adult; Antigens; Antiviral Agents; Blinded; CD4 Positive T Lymphocytes; CD8B1 gene; Chronic; Clinical Research; Collaborations; Cyclophosphamide; Cytomegalovirus; Data; Disease; Dose; Double-Blind Method; Eligibility Determination; Enrollment; Event; Frequencies; Gene Expression; Goals; Hematocrit procedure; Hematologic Neoplasms; Immune response; Immunity; Immunocompetence; Immunocompetent; Immunodominant Antigens; Immunotherapy; In complete remission; Incidence; Infusion procedures; Injections; Measurement; Measures; Medical center; Memory; Modified Vaccinia Virus Ankara; Names; Outcome; Patients; Performance; Phase; Phase II Clinical Trials; Phase Ib Clinical Trial; Phase Ib Trial; Phase Ib/II Trial; Phenotype; Pilot Projects; Placebo Control; Placebos; Population; Property; Prophylactic treatment; Publishing; Randomized; Recombinants; Regimen; Resistance; Risk; Safety; Side; Stem cell transplant; Steroids; T-Lymphocyte; Testing; Therapeutic; Time; Toxic effect; Transplant Recipients; Vaccinated; Vaccination; Vaccines; Viral; Viremia; arm; clinically significant; design; donor stem cell; healthy volunteer; hematopoietic cell transplantation; high risk; immune reconstitution; immunogenicity; improved; novel therapeutics; open label; phase 2 study; phase II trial; phase III trial; pilot trial; prevent; primary endpoint; randomized placebo controlled trial; randomized, clinical trials; reconstitution; safety study; secondary endpoint; standard of care; stem cells; underserved minority; vaccination strategy; vaccine immunogenicity; vaccine strategy; vaccine-induced immunity

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.

项目概要/摘要 造血细胞移植中抢先使用抗病毒药物（PET）控制巨细胞病毒（CMV）病毒血症 接受者（HCT-R）是一种治疗进步，但与毒性升高相平衡。较新的药物，例如莱特莫韦 (Prevymis) 具有较低的毒性和较高的功效。 FDA 连续 100 天批准 Prevymis (d) 预防措施可将高风险和低风险 HCT-R 中的 CMV 再激活减少约 2 倍。抗病毒作用 18周后逐渐减弱，没有生存获益。我们与 NCI 共同开发改良的安卡拉牛痘 (MVA) 名为 Triplex 的疫苗表达 CMV 免疫显性抗原。我们发表了一项健康安全研究 志愿者表现出疫苗的强免疫原性（NCT1941056），该疫苗先于发表的 CMV 阳性 (P) HCT-R 的成功安慰剂对照和随机 2 期试验 (NCT2506933) CMV 阳性 (CMV-P) 或 CMV 阴性 (CMV-N) HCT 供体 (HCT-D)。第二阶段试验达到了主要目标 加速重建保护性疫苗组中 CMV 再激活减少 50% 的终点 巨细胞病毒免疫。三重结果可以得到改善；一种方法是对具有免疫能力的 HCT-D 进行疫苗接种 正如我们正在进行的试点研究 (NCT3560752) 令人印象深刻的初步结果所证明的那样，该研究表明 所有接受来自已接种疫苗的匹配相关供体 (MRD) 的干细胞的 HCT-R (N=12) 均受到保护 需要PET。我们假设 HCT-D 的 Triplex 注射将通过转移 扩增的 CMV 保护性 T 细胞作为干细胞输注至 HCT-R 的组成部分，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 2 期随机安慰剂对照试验（在 不为 MRD-HCT 开 Prevymis 的中心），但有资格接受 MRD 的 CMV-P HCT-R（中等风险） 接受 T 细胞填充 HCT 治疗血液恶性肿瘤。 CMV-P HCT-R 将随机接受干细胞治疗 来自 HCT-D 的细胞接受与预试验相同的单次注射 Triplex 或安慰剂。此次试验将表明 一次 HCT-D 疫苗接种足以替代 100 天的 Prevymis，以防止 PET 在 MRD-HCT-R 中使用。 在 180 天的试用期内，我们将评估 PET 的使用情况，测量 CMV 特异性 CD8/CD4 T 细胞，目标是 将频率、记忆表型和基因表达与防止重新激活的保护联系起来 病毒血症或疾病。将 Triplex 的益处扩展到 HCT 后环磷酰胺治疗的半相合 HCT-R (PTCY) 处于 CMV 再激活高风险的人，在目标 2 中，我们建议进行两阶段（阶段 1b/2）试验来选择 最佳三联疫苗策略，可促进有效的免疫重建，同时将 CMV 重新激活降至最低。 所有 HCT-D 将接种一次 Triplex 疫苗，所有 HCT-R 将在第 28 天注射 3 次 Triplex 加强疫苗接种， 56 和 100。最初的开放标签 1b 期部分将让患者放弃 Prevymis，或者给予 21天至100天的预防。使用 Prevymis 最少但仍不增加的疫苗接种方案 与标准 Prevymis 相比重新激活的情况将被选择用于后续随机第 2 期部分 与不接种疫苗的标准护理 Prevymis 相比，减少或不接种 Prevymis 剂量的疫苗接种。