BM NICHE DISRUPTION AND IMMUNOTHERAPY IN HEMATOLOGICAL MALIGNANCIES

血液系统恶性肿瘤中的 BM 生态位破坏和免疫治疗

• 批准号: 10493285
• 负责人: Michael Rettig
• 金额: $ 24.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10493285
• 关键词: AMD3100; Allogenic; Autoimmune Diseases; Back; Bispecific Antibodies; Bone Marrow; CAR T cell therapy; CD3 Antigens; CXCR4 gene; Cancer Research Project; Clinical Trials; Correlative Study; Disease; Down-Regulation; Epigenetic Process; Exhibits; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hemoglobinopathies; Hereditary Disease; Homing; Human; IL3RA gene; IL7 gene; Immunologics; Immunotherapy; Infusion procedures; Integrin alpha4beta1; Integrins; JAK1 gene; JAK2 gene; Laboratories; MHC Class II Genes; Manuscripts; Mediating; Metabolic Diseases; Methods; Minor Histocompatibility Antigens; Mus; Mutation; Natural regeneration; Non-Malignant; Patients; Peer Review; Polyethylene Glycols; Post Graduate Year; Postdoctoral Fellow; Pre-Clinical Model; Recurrence; Relapse; Research; Scientist; Testing; Time; Training; Transplantation; base; bench to bedside; cancer genomics; career; chemotherapy; curative treatments; design; early phase clinical trial; efficacy evaluation; efficacy testing; first-in-human; graft vs host disease; immunogenic; inhibitor; man; nonhuman primate; novel; preclinical study; programs; small molecule inhibitor; success; tumor

The DiPersio Unit strives to optimize immunotherapy, including allogeneic hematopoietic stem cell transplantation (alloHSCT), for treating hematological malignancies. HSCT is the only curative therapy for many hematological malignancies and some non-malignant diseases such as hemoglobinopathies, autoimmune diseases, and inherited disorders of metabolism. Key obstacles to the success of HSCT include collecting sufficient numbers of hematopoietic stem/progenitor cells (HSPCs) to proceed to transplant, control of graft- versus-host disease (GvHD), and treating disease recurrence both before and especially after HSCT. Dr. DiPersio has focused over the last 25 years on overcoming these obstacles to HSCT through a bench-to-bedside and back again research approach. I have been fortunate to spend my entire 20-year post-graduate research career working with Dr. DiPersio. During this time, I contributed to 37 of Dr. DiPersio’s peer-reviewed manuscripts, performed pre-clinical studies for five projects that led to first-in-human clinical trials, completed correlative studies for 21 different clinical trials involving over 550 patients, and assisted in the training of 12 post-docs/fellows and nine technicians. Dr. DiPersio’s research program over the next several years will use our strengths in preclinical modeling, cancer genomics and the design and execution of early phase clinical trials to (1) develop novel methods for HSPC mobilization and GvHD treatment; (2) define the genetic and epigenetic changes that contribute to AML relapse after alloHSCT; and (3) perform clinical trials testing bispecific antibody or chimeric antigen receptor T cell (CART) therapies to treat hematological malignancies before or after HSCT. Successful HSCT requires the infusion of an adequate number of HSPCs that are capable of homing to the bone marrow and regenerating hematopoiesis in a timely fashion. We have developed novel polyethylene glycol (PEG)-conjugated small molecule inhibitors of the integrin very late antigen 4 (VLA-4) and demonstrated that they synergistically mobilize HSPCs in mice and non-human primates when combined with plerixafor, a CXCR4 inhibitor. In research program 1, I am testing the efficacy of long-acting versions of our PEGylated VLA-4 inhibitors to (1) mobilize murine HSPCs when combined with BL-8040, a long-acting CXCR4 inhibitor and (2) treat GvHD after alloHSCT when given alone or in combination with baricitinib, a JAK1/JAK2 inhibitor. In research program 2, I am defining minor histocompatibility antigens (mHAs) in mice and man and examining if relapse after alloHSCT is mediated in part via downregulation or loss of immunogenic mHAs. Since 30%-50% of post- alloHSCT AML relapses exhibit MHC Class II downregulation, I am examining the mechanisms of MHCII downregulation in AML and developing approaches to re-induce MHCII on these immunologically cloaked tumors. In research program 3, I am completing correlative studies for trials evaluating the efficacy of Flotetuzumab, a CD123´CD3 bispecific antibody, in patients with AML who relapse after chemotherapy or alloHSCT and testing if CART therapy can be enhanced via administration of long-acting human IL-7 (NT-I7).

DiPersio单位致力于优化免疫治疗，包括异基因造血干细胞 移植(Allo HSCT)，用于治疗血液系统恶性肿瘤。造血干细胞移植是许多疾病的唯一治疗方法。 恶性血液病和一些非恶性疾病，如血红蛋白病、自身免疫 疾病和遗传性新陈代谢障碍。HSCT成功的关键障碍包括收集 足够数量的造血干/祖细胞(HSPC)进行移植，移植的控制- 抗宿主病(GvHD)，以及治疗移植前和移植后的疾病复发。Dr。 在过去的25年里，DiPersio一直致力于通过从板凳到床边的方式克服HSCT的这些障碍 再次回到研究方法上来。我有幸花了整整20年的研究生研究时间 与迪佩西奥博士共事的职业生涯。在此期间，我参与了迪佩西奥博士的37次同行评议 手稿，为导致首次人类临床试验的五个项目进行临床前研究，完成 对涉及550多名患者的21项不同临床试验进行了相关性研究，并协助培训了12名 博士后/研究员和9名技术人员。DiPersio博士的研究计划在未来几年将使用我们的 在临床前建模、癌症基因组学以及设计和执行早期临床试验方面的优势 (1)开发HSPC动员和GvHD治疗的新方法；(2)定义遗传学和表观遗传学 同种异基因造血干细胞移植后导致AML复发的变化；以及(3)进行临床试验检测双特异性抗体 或嵌合抗原受体T细胞(CART)治疗HSCT前后的恶性血液病。 成功的HSCT需要输注足够数量的能够归巢到骨骼的HSPC 及时更新骨髓和再生造血功能。我们已经开发出新型聚乙二醇组分 (PEG)偶联的整合素非常晚期抗原4(VLA-4)的小分子抑制物，并证明 当它们与CXCR4-plerixafor结合时，它们在小鼠和非人类灵长类动物中协同动员HSPC 抑制剂。在研究计划1中，我正在测试我们的聚乙二醇化VLA-4长效版本的疗效 抑制剂：(1)与长效CXCR4抑制剂BL-8040联合使用时，可动员小鼠HSPC； 单独给药或与JAK1/JAK2抑制剂巴利替尼联合使用时，治疗异基因造血干细胞移植后的GvHD。在研究中 程序2，我正在定义小鼠和人的次要组织相容性抗原(MHA)，并检查是否复发 在异基因HSCT后，部分通过下调或丢失免疫原性mHa来介导。因为30%-50%的职位- AllallHSCT AML复发显示MHC II类下调，我正在研究MHCII的机制 急性髓系白血病的下调以及在免疫伪装的情况下重新诱导MHCII的方法 肿瘤。在研究计划3中，我正在完成相关研究，以评估 CD123‘CD3双特异性抗体Floteuzumab在化疗后复发的AML患者中的应用 AllallHSCT和测试CART治疗是否可以通过注射长效人IL-7(NT-I7)来增强。