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）是一种既定疗法，旨在治愈造血细胞 尽管总体生存率正在稳步提高 (3)， allo-HCT 患者因感染、GVHD 和复发而继续出现显着的发病率和死亡率。 该 P01 的总体目标是研究小鼠和人类的这些机制 并发症并开发新的治疗策略，以在异基因 HCT 患者的临床试验中进行测试。 P01的主要主题是：肠道微生物群、抗病毒耐药性（尤其是CMV）、GVHD、抗病毒NK T 反应和过继性 T 细胞疗法。 我们的总体假设是：1）肠道微生物群的特定成员有助于抗病毒耐药性，2） 肠道微生物群在 GVHD 的发生中具有重要作用，是 GVHD 的有效调节剂 严重程度，并且可以有针对性地预防或治疗 GVHD，3) HLA 介导的 T 细胞反应形状效率 NK 库和抗病毒 NK 反应的扰动可能会影响 T 细胞反应，4) 合成的肿瘤特异性T细胞可以归巢到肿瘤部位并合成和释放抗肿瘤药物 局部毒性较小，抗肿瘤能力较差，5）第三方EBV特异性细胞毒性T淋巴细胞（EBV- CTL）可用作异基因 HCT 患者的 EBV+ 和 – 恶性肿瘤的“现成”过继细胞疗法， 6) 通过专注于 TCRα/β 耗竭的临床试验可以提高异基因 HCT 的总体成功率 同种异体移植物、第三方 EBV CD19 CAR T 细胞，以及通过以下方式保存肠道微生物群 抗生素管理和粪便微生物群移植。 我们的总体具体目标是：1) 将粪便微生物群组成与 CMV 重新激活或更低水平联系起来 allo-HCT 后呼吸道感染，并形成可赋予抗病毒作用的微生物群落 无菌和抗生素治疗小鼠的耐药性，2) 评估肠道微生物群在 急性和慢性 GVHD 的病理生理学及其作为临床生物标志物的用途，3) 证明 HLA 基因型和活化的 NK 细胞可以影响 T 细胞对 HCMV 的反应，以及 T 细胞对 HCMV 可以塑造 NK 细胞库，4) 生成并测试合成酶激活杀伤剂 (SEAKER) 具有前药/药物和杀手开关系统的细胞以及通过 CAR 和 TCR 模拟实现肿瘤特异性 临床前和临床环境中的技术，5) 使用第三方 EBV-CTL 增强过继细胞疗法 EBV+ 和 – 使用表观遗传修饰剂、CD19-CAR 或检查点抑制剂的恶性肿瘤，以及 6) 启动 研究者根据各个项目中制定的策略启动临床试验。 与单一中心的研究人员高度互动，他们拥有广泛的合作记录和 将他们的研究转化为异基因 HCT 患者的临床试验。