CMVPepVax to Protect HCT Recipients from Cytomegalovirus Infection

CMVPepVax 可保护 HCT 受者免受巨细胞病毒感染

基本信息

批准号：
8920520
负责人：
Don J Diamond
金额：
$ 71.1万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-03 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8920520
关键词：
Address Adjuvant Adult Adverse effects Agonist Antiviral Agents Biological Assay Blinded Boxing CD8B1 gene Cells Clinical Clinical Trials Collection Color Cytomegalovirus Cytomegalovirus Infections Data Disease Dose Double-blind trial Effectiveness Enrollment Ensure Epitopes Evaluation Event Frequencies Functional disorder Genome Goals HLA-A2 Antigen Health Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Herpesviridae Immune Immune response Immunity Immunocompetence Immunologics Immunosuppression Incidence Injection of therapeutic agent Investigation Kidney Life Link Malignant Neoplasms Measurable Measurement Measures Memory Minnesota Monitor Morbidity - disease rate Natural Killer Cells Neutropenia Opportunistic Infections Outcome Participant Patient risk Patients Peptides Phase Phase II Clinical Trials Phenotype Placebo Control Placebos Population Production Property Randomized Recovery Refractory Research Design Risk Safety Siblings Stem cell transplant Stem cells T-Lymphocyte T-bet protein Testing Tetanus Therapeutic Time Toxic effect Transplant Recipients Umbilical Cord Blood Universities Vaccinated Vaccination Vaccines Viral Viremia Virus Diseases anergy arm base chemotherapy chronic graft versus host disease clinically significant cohort cost cytokine cytotoxic cytotoxicity design graft vs host disease healthy volunteer high risk immunogenicity improved leukemia mortality novel phase 2 study pilot trial prevent randomized trial response safety study standard of care success transcription factor trial design

Address Adjuvant Adult Adverse effects Agonist Antiviral Agents Biological Assay Blinded Boxing CD8B1 gene Cells Clinical Clinical Trials Collection Color Cytomegalovirus Cytomegalovirus Infections Data Disease Dose Double-blind trial Effectiveness Enrollment Ensure Epitopes Evaluation Event Frequencies Functional disorder Genome Goals HLA-A2 Antigen Health Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Herpesviridae Immune Immune response Immunity Immunocompetence Immunologics Immunosuppression Incidence Injection of therapeutic agent Investigation Kidney Life Link Malignant Neoplasms Measurable Measurement Measures Memory Minnesota Monitor Morbidity - disease rate Natural Killer Cells Neutropenia Opportunistic Infections Outcome Participant Patient risk Patients Peptides Phase Phase II Clinical Trials Phenotype Placebo Control Placebos Population Production Property Randomized Recovery Refractory Research Design Risk Safety Siblings Stem cell transplant Stem cells T-Lymphocyte T-bet protein Testing Tetanus Therapeutic Time Toxic effect Transplant Recipients Umbilical Cord Blood Universities Vaccinated Vaccination Vaccines Viral Viremia Virus Diseases anergy arm base chemotherapy chronic graft versus host disease clinically significant cohort cost cytokine cytotoxic cytotoxicity design graft vs host disease healthy volunteer high risk immunogenicity improved leukemia mortality novel phase 2 study pilot trial prevent randomized trial response safety study standard of care success transcription factor trial design

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项目摘要

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.

描述（由申请人提供）：造血干细胞移植（HCT）负责化学疗法难治性白血病和其他恶性肿瘤的令人印象深刻的治愈率。然而，包括巨细胞病毒（CMV）在内的机会主义感染，通过提高HCT的全面治疗潜力，通过提高HCT的全面治疗潜力，从而降低了HCT的全面治疗潜力。限制CMV病毒血症的抗病毒药物精确的发病成本，包括肾功能障碍，中性粒细胞减少和免疫抑制。用刺激多种免疫机制的疫苗代替有毒抗病毒药可以改善HCT结果。该疫苗由HLA混杂的Tetanus t辅助表位组成，该表位与CMV的HLA-A2限制的CTL表位共同附加到CMV的HLA-A2限制的CTL表位，当与单个链的寡头氧基辅助剂和TLRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRRENEIS中刺激了强烈的免疫反应，并刺激了强烈的免疫反应。（辉瑞）。在健康成年人的完成1B期试验之后，我们在匹配的相关（MRD）和无关（URD）供体HCT-R中启动了一项随机的2臂初步1B试验（PILOT）。 HCT-R中试验的临时分析支持疫苗概念，因为初步数据显示CMV特异性的免疫力更高，CMV重新激活的速率较低，而疫苗与观察部门的慢性GVHD相比。在此应用中，我们将通过进行2种随机，盲目和安慰剂对照的2期试验来推进这种疫苗概念（CMVPEPVAX），以防止与明尼苏达大学共同与HCT-R共同激活CMV。在特定目标（SA）1中，我们将进行试验1 用于测试MRD-HCT中CMV重新激活和疾病降低的主要终点。 CMV阳性HCT-R将随机分为疫苗（VA）和安慰剂（PA）臂，并给予2次相距4周的注射，而供体将同时且共同随机进行随机，以在干细胞收集前2-5周接收一次疫苗接种。供体疫苗接种对改善HCT-R结果的影响将是次要终点，从而使多达67％的捐助者能够下降，但仍具有对HCT-R的影响力。免疫学20端点将通过使用HLA多聚体和具有T-box转录因子T-BET和EOMES的功能研究来量化CMV特异性T细胞的频率测量。重要的是，这项研究将测试我们的新观察结果，即NK细胞通过激活特定的NKG2C+持久（内存）响应来对HCT后CMV重新激活响应，该反应可以使用CMVPEPVAX模仿，这将对该领域产生重大的一般影响。在SA2中，试验2将测试CMVPEPVAX在较高风险乌尔德和脐带血（UCB）受体中的保护功能。该试验将采用与试验1相同的格式，除非没有捐助者参与来解决广泛的URD环境或较少匹配的UCB移植物，均导致与MRD相比，CMV重新激活和疾病的风险更高。目的是通过进行2阶段研究来利用我们的CMVPepvax的第一阶段成功，该研究不仅可以为HCT-R建立患有CMV感染并发症风险的HCT-R的治疗益处，而且还定义了该保护的免疫学基础。