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.

项目摘要/摘要 造血细胞移植中的抗病毒药（PET）控制巨细胞病毒（CMV）病毒血症 接受者（HCT-R）是通过毒性升高平衡的治疗促进。较新的药物，例如Letermovir （Prevymis）毒性较低，功效提高。 FDA批准了Prevymis连续100天 （d）在高风险HCT-R中将CMV重新激活降低约2倍。抗病毒作用 18周后，没有生存益处降低。我们与NCI（MVA）的NCI共同开发 称为三种表达CMV免疫主导抗原的疫苗。我们发表了一项安全研究 表现出疫苗的强烈免疫原性（NCT1941056），该志愿者在已发表之前 CMV阳性（P）HCT-R成功的安慰剂对照和随机2期试验（NCT2506933） CMV阳性（CMV-P）或CMV阴性（CMV-N）HCT供体（HCT-D）。第二阶段试验符合其主要 疫苗组中CMV重新激活的终点降低了50％，并加速了保护性。 CMV免疫。可以改善三重结果；一种方法是接种免疫能力的HCT-D 正如我们正在进行的试点研究（NCT3560752）的令人印象深刻的初步结果所证明的那样 从接种匹配的相关供体（MRD）中，所有HCT-R（n = 12）均受到保护 需要宠物。我们假设三胞胎注射HCT-D将通过转移来启动保护性免疫 扩展的CMV保护T细胞是干细胞输注HCT-R的组成部分 Prevymis，从而消除了它的需求。在AIM 1中，我们提出了一项2期随机安慰剂控制试验（在 CMV-P HCT-R具有MRD（中间风险）的资格，未开处方MRD-HCT的中心 接受T细胞的HCT进行血液系统恶性肿瘤。 CMV-P HCT-R将随机分配以接收茎 HCT-D的细胞接受单个注射三重或安慰剂与试验试验相同的细胞。该审判将显示 单个HCT-D疫苗接种足以替代100D Prevymis，以防止在MRD-HCT-R中使用PET。 在180D试验期间，我们将评估PET使用情况，测量CMV特异性CD8/CD4 T细胞的目标 将频率，记忆表型和基因表达与防止重新激活相关联导致 病毒血症或疾病。为了将三倍型HCT-R扩展到使用后HCT环磷酰胺处理的单倍体HCT-R （PTCY）有CMV重新激活的高风险，在AIM 2中，我们提出了一项两阶段（第1B/2阶段）试验来选择 最佳的三环疫苗策略，可通过最小的CMV重新激活促进有效的免疫重建。 所有HCT-D将通过Triplex接种一次，所有HCT-R将在D28上使用3个三元注射来增强 56和100。初始的开放标签期1B段将使患者戒除prevymis，或给出 21d-100d的预防。疫苗接种方案的使用最少，但仍不会增加 与标准prevymis相比，将选择重新激活 与没有疫苗接种的护理标准Prevymis相比，疫苗接种降低或无药给药。