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.

项目总结/摘要 在造血细胞移植中预先使用抗病毒药物（PET）控制巨细胞病毒（CMV）病毒血症 受体（HCT-R）是通过升高的毒性平衡的治疗进展。较新的药物，如莱特莫韦 （Prevymis）具有较低的毒性和增加的功效。FDA批准Prevymis连续100天 (d)在高危和低危HCT-R中，预防性治疗可使CMV再活化降低约2倍。抗病毒效果 18周后下降，没有生存益处。我们与NCI共同开发了一种改良的安卡拉牛痘（MVA） 表达CMV免疫显性抗原的名为Triplex的疫苗。我们发表了一项安全性研究， 志愿者显示出疫苗（NCT 1941056）的强免疫原性，该疫苗早于已发表的 CMV阳性（P）HCT-R的成功安慰剂对照和随机化II期试验（NCT 2506933）， CMV阳性（CMV-P）或CMV阴性（CMV-N）HCT供体（HCT-D）。II期试验符合其主要 疫苗组中CMV再激活减少50%，加速保护性免疫重建的终点 巨细胞病毒免疫。三重结果可以得到改善;一种方法是接种免疫活性的HCT-D 正如我们正在进行的试点研究（NCT 3560752）令人印象深刻的初步结果所证明的那样， 所有接受来自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的三重注射将通过转移HCT-D来启动保护性免疫。 扩增的CMV保护性T细胞作为干细胞输注至HCT-R的组分，在给予 Prevymis，从而消除其需要。在目标1中，我们提出了一项2期随机安慰剂对照试验（在 未处方Prevymis用于MRD-HCT的临床试验机构），符合CMV-P HCT-R伴MRD（中等风险）的资格 接受T细胞充满的HCT治疗恶性血液病CMV-P HCT-R将随机接受股骨柄 来自HCT-D的细胞接受与初步试验相同的Triplex或安慰剂的单次注射。这次审判将证明 单次HCT-D疫苗接种足以替代100天Prevymis，以防止MRD-HCT-R中PET的使用。 在180天的试验期内，我们将评估PET的使用，测量CMV特异性CD 8/CD 4 T细胞， 将频率、记忆表型和基因表达与防止再激活相关联， 病毒血症或疾病。将三联获益扩展至HCT后环磷酰胺治疗的单倍体相合HCT-R （PTCY）CMV再激活风险高的患者，在目标2中，我们提出了一项两阶段（1b/2期）试验， 最佳的三重疫苗策略，促进有效的免疫重建与最小的CMV再激活。 所有HCT-D将接种一次三联疫苗，所有HCT-R将在第28天加强接种3次三联疫苗， 56和100。最初的开放标签1b期部分将使患者放弃Prevymis，或给予 预防期21 ~ 100 d。使用最少Prevymis的疫苗接种方案仍然没有导致增加 与标准Prevymis相比，重新激活的Prevymis将被选择用于后续随机2期部分 与不接种Prevymis的标准护理相比，减少或不接种Prevymis的标准护理。