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: 10322906
• 负责人: Michael Rettig
• 金额: $ 24.79万
• 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/10322906
• 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/antagonist; 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，包括同种异体造血干细胞 移植（alloHSCT），用于治疗恶性血液病。HSCT是许多人唯一的治愈性疗法。 恶性血液病和一些非恶性疾病如血红蛋白病、自身免疫性 疾病和遗传性代谢紊乱。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，控制移植物 抗宿主病（GvHD），以及治疗HSCT之前和之后的疾病复发。博士 在过去的25年里，DiPersio一直致力于通过一种从板凳到床边的方法来克服HSCT的这些障碍。 再回到研究方法。我很幸运地花了整整20年的研究生研究 与迪佩西奥医生一起工作在这段时间里，我为迪佩西奥博士的37篇同行评审论文做出了贡献。 手稿，为五个项目进行临床前研究，导致首次在人体临床试验，完成 21项不同临床试验的相关研究，涉及550多名患者，并协助培训12名 博士后/研究员和9名技术员。DiPersio博士未来几年的研究计划将使用我们的 在临床前建模，癌症基因组学以及早期临床试验的设计和执行方面的优势， (1)开发HSPC动员和GvHD治疗的新方法;（2）定义遗传和表观遗传 导致alloHSCT后AML复发的变化;和（3）进行测试双特异性抗体的临床试验 或嵌合抗原受体T细胞（CART）疗法以在HSCT之前或之后治疗血液恶性肿瘤。 成功的HSCT需要输注足够数量的能够归巢到骨骼的HSPC 骨髓和再生造血及时。我们开发了新型聚乙二醇 （PEG）缀合的整合素极晚期抗原4（VLA-4）的小分子抑制剂，并证明 当与普乐沙福（一种CXCR 4）联合使用时，它们协同动员小鼠和非人灵长类动物中的HSPC 抑制剂.在研究项目1中，我正在测试我们的聚乙二醇化VLA-4的长效版本的功效 抑制剂，以（1）当与BL-8040（一种长效CXCR 4抑制剂）组合时动员鼠HSPC，和（2） 当单独给药或与baricitinib（JAK 1/JAK 2抑制剂）联合给药时，治疗alloHSCT后的GvHD。研究 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 alloHSCT后部分通过免疫原性mHA的下调或缺失介导。由于30%-50%的后- alloHSCT AML复发表现出MHCII类下调，我正在研究MHCII的机制 在AML中下调，并开发方法重新诱导MHCII在这些免疫学上被掩盖的 肿瘤的在研究项目3中，我正在完成相关研究，以评估 Flotetuzumab，一种CD 123 ′ CD 3双特异性抗体，用于化疗后复发的AML患者，或 alloHSCT和测试是否可以通过施用长效人IL-7（NT-I7）来增强CART疗法。