Immunobiology of Allogeneic Hematopoietic Cell Transplantation

同种异体造血细胞移植的免疫生物学

• 批准号: 10442486
• 负责人: Marcel R M van den Brink
• 金额: $ 252.21万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-09-30 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10442486
• 关键词: Acute; Adoptive Cell Transfers; Affect; Allogenic; Allografting; Antibiotics; Antineoplastic Agents; Antiviral Response; Antiviral resistance; CD19 gene; Cells; Characteristics; Clinical; Clinical Trials; Collaborations; Communities; Cytomegalovirus; Development; Disease; Drug Delivery Systems; EBV specific T-cells; Epigenetic Process; Epstein-Barr Virus-Related Malignant Neoplasm; Functional disorder; Genetic Engineering; Genotype; Germ-Free; Home; Homologous Transplantation; Human Herpesvirus 4; Immune checkpoint inhibitor; Immunobiology; Individual; Infection; Lower Respiratory Tract Infection; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Morbidity - disease rate; Mus; Natural Killer Cells; Non-Malignant; Patients; Pharmaceutical Preparations; Prodrugs; Prophylactic treatment; Regimen; Relapse; Research; Research Personnel; Resistance; Role; Running; Severity of illness; Shapes; Site; Survival Rate; System; T cell response; T cell therapy; T-Lymphocyte; Technology; Testing; Time; Toxic effect; Translations; Transplantation; Transplantation Tolerance; Viral; Viral Drug Resistance; base; chimeric antigen receptor T cells; chronic graft versus host disease; clinical biomarkers; comorbidity; conditioning; cost effective; fecal microbiota; fecal transplantation; genomic profiles; graft vs host disease; gut microbiome; gut microbiota; hematopoietic cell transplantation; immune reconstitution; improved; leukemia; man; member; microbiota; mortality; novel therapeutic intervention; patient tolerability; post-transplant; pre-clinical; preservation; prevent; response; success; synthetic enzyme; tumor; tumor specificity

Abstract Allogeneic Hematopoietic Cell Transplantation (allo-HCT) is an established therapy with curative intent for a variety of malignant and non-malignant disorders. Although overall survival rates are steadily improving (3), allo-HCT patients continue to incur significant morbidity and mortality from infections, GVHD and relapse. The overall objective of this P01 is to study both in mouse and man the mechanisms underlying these complications and develop novel therapeutic strategies to be tested in clinical trials in allo-HCT patients. The major themes of this P01 are: intestinal microbiota, antiviral resistance (especially to CMV), GVHD, antiviral NK and T responses, and adoptive T cell therapy. Our overall hypotheses are: 1)Specific members of the intestinal microbiota contribute to antiviral resistance, 2) The intestinal microbiota has a significant role in the development of GVHD, is a potent modulator of GVHD severity, and can be targeted to prevent or treat GVHD, 3) HLA-mediated efficiency of T-cell response shapes the NK repertoire and perturbations in anti-viral NK response will potentially affect the T-cell response, 4) Synthetic tumor-specific T cells can home to the tumor site and synthesize and release anti-neoplastic drugs locally with less toxicity and less tumor-resistance, 5) Third party EBV-specific cytotoxic T lymphocytes (EBV- CTL) can be used as “off the shelf” adoptive cell therapy for EBV+ and – malignancies in allo-HCT patients, and 6) Overall success of allo-HCT can be improved through clinical trials focused on TCRalpha/beta depletion of the allograft, third party EBV CD19 CAR T cells, and preservation of the intestinal microbiota through antibiotic stewardship and fecal microbiota transplantation. Our overarching Specific Aims are: 1) To correlate fecal microbiota composition with CMV reactivation or lower respiratory tract infection after allo-HCT and develop microbiota communities that can confer antiviral resistance in germ-free and antibiotic-treated mice, 2) To assess the role of the intestinal microbiota in the pathophysiology of acute and chronic GVHD and its use as a clinical biomarker, 3) To demonstrate that HLA genotype and activated NK cells can impact the T cell response to HCMV, as well as the T cell response to HCMV can shape the NK cell repertoire, 4) To generate and test Synthetic Enzyme Activating Killer (SEAKER) cells with prodrug/drug and killer switch systems and tumor-specificity through CAR and TCR mimic technology in preclinical and clinical settings, 5) To augment adoptive cell therapy with third party EBV-CTL for EBV+ and – malignancies with epigenetic modifiers, CD19-CARs or checkpoint inhibitors, and 6) To initiate investigator-initiated clinical trials based on strategies developed in the individual Projects. This project is highly interactive with investigators at a single center, who have an extensive track record of collaborations and translation of their research into clinical trials in allo-HCT patients.

抽象的 同种异体造血细胞移植（Allo-HCT）是一种已建立的疗法，具有治愈性的目的 多种恶性和非恶性疾病。尽管总体生存率正在悄悄提高（3），但 Allo-HCT患者继续引起感染，GVHD和缓解的显着发病率和死亡率。这 该P01的总体目标是在小鼠和人类中研究这些机制 并发症并制定新的治疗策略，将在Allo-HCT患者的临床试验中进行测试。 该P01的主要主题是：肠道菌群，抗病毒抗性（尤其是CMV），GVHD，抗病毒NK 和T反应以及自适应T细胞疗法。 我们的总体假设是：1）肠道菌群的特定成员有助于抗病毒抗性，2） 肠道菌群在GVHD的发展中具有重要作用，是GVHD的潜在调节剂 严重性，可以针对预防或治疗GVHD，3）HLA介导的T细胞响应形状的效率 抗病毒NK反应中的NK曲目和扰动可能会影响T细胞反应，4） 合成肿瘤特异性T细胞可以回家肿瘤部位，并合成并释放抗塑性药物 局部毒性较小，耐肿瘤的耐药性较小，5）第三方EBV特异性细胞毒性T淋巴细胞（EBV- CTL）可以用作Allo-HCT患者的EBV+和 - Malignancys的“搁置”自适应细胞疗法， 6）可以通过针对Tcralpha/beta部署的临床试验来提高Allo-HCT的整体成功 同种异体移植物，第三方EBV CD19 CAR T细胞，并通过 抗生素管理和粪便菌群移植。 我们的总体具体目的是：1）将粪便菌群组成与CMV重新激活相关或较低 Allo-HCT之后的呼吸道感染，并发展了可以赋予抗病毒的微生物群落 无菌和抗生素处理的小鼠的耐药性，2）评估肠道菌群在 急性和慢性GVHD的病理生理及其用作临床生物标志物，3）证明HLA 基因型和活化的NK细胞会影响T细胞对HCMV的反应，以及T细胞对 HCMV可以塑造NK细胞库，4）生成和测试合成酶激活杀手（Seaker） 具有前药/药物和杀手开关系统的细胞以及通过汽车和TCR模拟的肿瘤特异性 临床前和临床环境中的技术，5）使用第三方EBV-CTL增强自适应细胞疗法 EBV+和 - 带有表观遗传修饰剂，CD19卡或检查点抑制剂的Malignancys，以及6） 研究者发动的临床试验基于各个项目中制定的策略。这个项目是 与单个中心的调查员高度互动，他们在合作和合作方面有广泛的记录 将其研究转化为Allo-HCT患者的临床试验。