NIH Myeloid Malignancy Program

NIH 骨髓恶性肿瘤计划

• 批准号: 10487131
• 负责人: Steven Pavletic
• 金额: $ 21.59万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10487131
• 关键词: Acute Myelocytic Leukemia; Adult; Aftercare; Aging; Agreement; Allergic; Allogenic; Anemia; Antibodies; Biogenesis; Biological Markers; Biology; Bite; Blood Platelet Disorders; Bone Marrow; CCR; CD8-Positive T-Lymphocytes; CDK9 Protein Kinase; CSF1R gene; Cell Compartmentation; Cells; Chemoresistance; Child; Childhood Leukemia; Clinic; Clinical; Clinical Research; Clinical Trials; Clonal Hematopoietic Stem Cell; Collection; Consultations; Continuous Infusion; Cooperative Research and Development Agreement; Correlative Study; DNA; DNA Sequence Alteration; Data Collection; Defect; Development; Diagnosis; Disease; Disease Pathway; Disease Progression; Dose; Dysmyelopoietic Syndromes; Dysplasia; Elderly; Enrollment; Environment; Failure; Familial Platelet Disorder; Family; Genomics; Germ-Line Mutation; Half-Life; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Hereditary Disease; Human; IL3RA gene; IL8RB gene; Immune; Immune Targeting; Immune system; Immunologics; Immunotherapy; In complete remission; Individual; Ineffective Hematopoiesis; Inflammatory; Interleukin-15; Interleukin-8; International; Laboratory Research; Lead; Link; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Marrow; Measurable; Mission; Modeling; Mutation; Myeloid Cells; Myelopoiesis; Myeloproliferative disease; National Cancer Institute; Natural History; Natural Killer Cells; Partial Remission; Pathogenesis; Pathology; Patient Monitoring; Patients; Penetrance; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phenotype; Population; Post-Transcriptional Regulation; Pre-Clinical Model; Predictive Factor; Predisposition; Progressive Disease; Proteins; Proteomics; RNA Splicing; RUNX1 gene; Recombinants; Recurrence; Recurrent disease; Refractory; Regulation; Relapse; Research Personnel; Residual Tumors; Respiratory Signs and Symptoms; Ribosomes; Role; Sampling; Science; Secondary Myelodysplastic Syndrome; Sequential Treatment; Shapes; Solid Neoplasm; Somatic Mutation; Spliceosomes; Stromal Cells; Surface; T-Lymphocyte; Therapeutic; Translating; Translations; Transplantation; United States National Institutes of Health; Vision; acute myeloid leukemia cell; comorbidity; curative treatments; cytokine; cytopenia; cytotoxicity; disorder later incidence prevention; engineered T cells; faculty research; gastrointestinal symptom; genotoxicity; graft vs leukemia effect; granulocyte; hematopoietic tissue; high risk; improved; in vivo; in vivo Model; inhibitor/antagonist; interest; kinase inhibitor; leukemia; leukemia relapse; leukemic stem cell; lifetime risk; macrophage; neoantigens; next generation sequencing; novel; novel therapeutics; organizational structure; outcome prediction; overexpression; partial response; peripheral blood; prevent; programs; relapse risk; small molecule; standard of care; stem cells; success; therapeutic target; translational study; tumor-immune system interactions; young adult

Theme 1: Pre-clinical models to study MDS biology and therapy Investigators at the NCI CCR have developed an in vivo model for MDS, which has been used by numerous investigators to study MDS biology, including the role of the immune system and an inflammatory microenvironment in the development and progression of MDS. Moreover, this model was used to provide proof of concept for the development of luspatercept, the only new drug to receive FDA approval for the treatment of MDS in the past decade. An NCI inter-divisional agreement has been formed between the DCTD and CCR to study the in vivo efficacy of novel DNA hypomethylating agents (HMA) using this model, and a CRADA with Tolero Pharmaceuticals to use this model to study the CDK9 kinase inhibitor alvocidib has been signed recently (PI Peter Aplan). Additional ongoing or planned studies are focused on the MDS/AML microenvironment, and determining how AML cells can influence or "shape" the microenvironment, which in turn influences the number and function of co-existing normal hematopoietic stem and progenitor cells (HSPC). Furthermore, there is a growing understanding of the importance of myeloid and stromal cells in the regulation of the bone marrow niche environment during normal development/aging and pathology. Approaches that rebalance this dysregulated microenvironment may, in combination with other therapies, prevent disease progression or limit relapse. For example, a recent clinical trial of pexidartinib, a CSF1R inhibitor in recurrent, refractory leukemias and solid tumors suggests that approaches that target the immune suppressive microenvironment may be effective in the setting of MDS/AML and other dysregulated bone marrow microenvironments (PI Rosandra Kaplan). Theme 2: Post-transcriptional regulation in MDS/AML Changes in post-transcriptional regulation are a hallmark of myeloid diseases. For example, 60% of MDS patients have somatic mutations in the core spliceosomal machinery, and spliceosome mutations are enriched in relapsed-refractory AML. Similarly, germline mutations in the translation and ribosome biogenesis machinery selectively result in anemia and other defects in myelopoiesis. We hypothesize that characterization of post-transcriptional regulation (splicing, translation) in immunological sub-populations, correlated with underlying DNA mutations, will reveal new pathways of disease progression and treatment. For example, we will identify how splicing factor mutations modify the immune microenvironment and how spurious translation might generate neo-antigens, both of which contribute to success/failure of immunotherapy (PI Dan Larson). Theme 3: Germline predispositions to myeloid malignancy RUNX1 Familial Platelet Disorder: Autosomal dominant germline RUNX1 mutations are associated with qualitative and quantitative platelet disorders and a 20-50% lifetime risk of hematologic malignancy. Currently, there is a poor understanding of the variability in penetrance of cancer development across different families and even among individuals within the same family. In addition, the disease manifestations outside of the hematopoietic tissues have not been studied systematically. We started a comprehensive natural history study on patients with germline RUNX1 mutations last year, which has quickly become the largest such study in the world with enrollment of 50 patients and 48 family controls from 25 families. We perform comprehensive genomic studies and extensive phenotyping. We have identified previously unrecognized allergic, immunologic, gastrointestinal, and pulmonary symptoms in many of our patients, with consultation of clinical and research faculty from 6 ICs. The RUNX1 natural history study is shaping up to be an international hub for patient referrals, a central collection of data and patient samples, and a focal point for collaborative clinical and translational studies to understand the disease mechanism, to identify biomarkers for disease progression, and to improve patient monitoring, management, and treatment (PIs Lea Cunningham, Paul Liu). Theme 4: Role of the immune system in control of MDS/AML CD123: Treating relapsed/refractory AML/MDS is a challenge and there is a major unmet need for new therapies to target the chemo-resistant cells responsible for relapse. CD123 (IL3R) is expressed on most AML/MDS cells and is enriched within the leukemic stem cell (LSC) compartment. We have engineered T cells (CD123-ENG) to constitutively secrete a bispecific small molecule (CD123xCD3) which directs T cell cytotoxicity to cells with surface expression of CD123.26 Unlike trials of CD123-BiTEs requiring several weeks of continuous infusion due to their short half-life,27 CD123-ENG T cells are given as a single dose, long-lived therapy which enables continuous in vivo secretion of the CD123xCD3 bispecific engager molecule. We propose a first-in-class phase I clinical trial of CD123-ENG for patients with AML/high-risk MDS with correlative studies including next generation sequencing to track the ability of ENG-T cells to eradicate very low levels of measurable residual disease, a key factor predicting outcome in these patients28 (PI Kate Stringaris). Interleukin-15 (IL-15): Immune escape from the donor T- and NK-cell-driven graft-versus-leukemia (GVL) effect is a major driver of disease relapse after hematopoietic stem cell transplantation (HSCT). NK cell expansion after HSCT has been associated with a lower 2-year leukemia relapse risk.29 IL-15 is a potent immunostimulatory cytokine, that expands CD8+ T-cell and NK-cell populations. A recombinant form of human IL-15 (rhIL-15) was formulated at the National Cancer Institute (NCI) by Dr. Thomas Waldmann and is currently being studied in several phase I/II studies in the solid neoplasms and lymphoma (NCT03759184, NCT02689453, NCT01021059). IL-15, studied in treatment of relapsed hematologic malignancies post-HSCT, was well tolerated and as monotherapy lead to a complete and partial response. While treating relapse after transplant with IL-15 appears safe and promising, prevention of relapse is of greater interest, representing an important unmet need with no current standard of care. A phase I clinical trial will be exploring if post-HSCT rhIL-15 administration can safely augment the GVL effect in MDS/AML patients at high risk of relapse (PI Noa Holtzman). Interleukin-8 (IL-8): Cytokine profile analysis in the peripheral blood and bone marrow of MDS patients identified a strong correlation between upregulated IL-8 levels and the MDS phenotype,33 even after treatment with hypomethylating agents (HMA).34 Further, both IL-8 and CXCR2 are overexpressed in purified MDS/AML stem cells and granulocyte-macrophage progenitor cells.35 A comprehensive proteomics profiling study identified IL-8 as the central molecule in the network of more than 150 dysregulated proteins in the bone marrow of patients with AML, suggesting that IL-8 is a promising therapeutic target. Recently, CCR intramural investigators identified a direct link between a mutation in the splicing factor U2AF1 and post-transcriptional regulation of IL-8.9 We propose a phase 1/2 clinical trial of sequential treatment with HMA and humanized anti-IL-8 antibody in patients with MDS (PIs Pavletic, Larson, Ostojic).

主题 1：研究 MDS 生物学和治疗的临床前模型 NCI CCR 的研究人员开发了 MDS 体内模型，许多研究人员已使用该模型来研究 MDS 生物学，包括免疫系统和炎症微环境的作用MDS 的发生和进展。此外，该模型还为luspatercept的开发提供了概念验证，luspatercept是过去十年中唯一获得FDA批准用于治疗MDS的新药。 DCTD 和 CCR 之间已达成 NCI 部门间协议，以使用该模型研究新型 DNA 低甲基化剂 (HMA) 的体内功效，并且与 Tolero Pharmaceuticals 达成 CRADA，以使用该模型研究 CDK9 激酶抑制剂 alvocidib最近已签约（PI Peter Aplan）。其他正在进行或计划中的研究重点关注 MDS/AML 微环境，并确定 AML 细胞如何影响或“塑造”微环境，进而影响共存的正常造血干细胞和祖细胞 (HSPC) 的数量和功能。此外，人们越来越认识到骨髓细胞和基质细胞在正常发育/衰老和病理过程中调节骨髓生态位环境的重要性。重新平衡这种失调的微环境的方法可以与其他疗法相结合，防止疾病进展或限制复发。例如，pexidartinib（一种 CSF1R 抑制剂）最近在复发性难治性白血病和实体瘤中进行的一项临床试验表明，针对免疫抑制微环境的方法可能对 MDS/AML 和其他失调的骨髓微环境有效（PI Rosandra Kaplan） ）。主题 2：MDS/AML 中的转录后调控 转录后调控的变化是骨髓疾病的一个标志。例如，60% 的 MDS 患者在核心剪接体机制中存在体细胞突变，而剪接体突变在复发难治性 AML 中丰富。同样，翻译和核糖体生物发生机制中的种系突变选择性地导致贫血和骨髓生成的其他缺陷。我们假设免疫亚群中转录后调控（剪接、翻译）​​的特征与潜在的 DNA 突变相关，将揭示疾病进展和治疗的新途径。例如，我们将确定剪接因子突变如何改变免疫微环境以及虚假翻译如何产生新抗原，这两者都有助于免疫疗法的成功/失败（PI Dan Larson）。主题 3：种系易患骨髓恶性肿瘤 RUNX1 家族性血小板疾病：常染色体显性种系 RUNX1 突变与血小板定性和定量疾病以及 20-50% 的终生血液恶性肿瘤风险相关。目前，人们对不同家庭甚至同一家庭内的个体之间癌症发展外显率的变异性了解甚少。此外，造血组织以外的疾病表现尚未得到系统研究。去年，我们开始了一项针对种系 RUNX1 突变患者的全面自然史研究，该研究很快成为世界上规模最大的此类研究，招募了来自 25 个家庭的 50 名患者和 48 名家庭对照。我们进行全面的基因组研究和广泛的表型分析。经过 6 个 IC 的临床和研究人员的咨询，我们在许多患者中发现了以前未被识别的过敏、免疫、胃肠道和肺部症状。 RUNX1 自然史研究正在成为一个国际患者转诊中心、数据和患者样本的集中收集中心，以及合作临床和转化研究的焦点，以了解疾病机制、识别疾病进展的生物标志物，以及改善患者监测、管理和治疗（PI Lea Cunningham、Paul Liu）。主题 4：免疫系统在控制 MDS/AML CD123 中的作用：治疗复发/难治性 AML/MDS 是一项挑战，针对导致复发的化疗耐药细胞的新疗法的需求尚未得到满足。 CD123 (IL3R) 在大多数 AML/MDS 细胞上表达，并在白血病干细胞 (LSC) 区室中富集。我们对 T 细胞 (CD123-ENG) 进行了改造，使其持续分泌一种双特异性小分子 (CD123xCD3)，该分子将 T 细胞的细胞毒性引导至表面表达 CD123 的细胞。26 与 CD123-BiTE 的试验不同，由于其时间短，需要数周的连续输注半衰期27 CD123-ENG T 细胞作为单剂量、长寿命的治疗给予，能够在体内持续分泌CD123xCD3 双特异性接合分子。我们提议针对 AML/高危 MDS 患者开展一项首创的 CD123-ENG I 期临床试验，并进行相关研究，包括下一代测序，以追踪 ENG-T 细胞根除极低水平可测量残留疾病的能力，预测这些患者结果的关键因素28 (PI Kate Stringaris)。白介素 15 (IL-15)：供体 T 细胞和 NK 细胞驱动的移植物抗白血病 (GVL) 效应的免疫逃逸是造血干细胞移植 (HSCT) 后疾病复发的主要驱动因素。 HSCT 后 NK 细胞扩增与较低的 2 年白血病复发风险相关。29 IL-15 是一种有效的免疫刺激细胞因子，可扩增 CD8+ T 细胞和 NK 细胞群。 Thomas Waldmann 博士在国家癌症研究所 (NCI) 配制了人 IL-15 (rhIL-15) 的重组形式，目前正在实体瘤和淋巴瘤的多项 I/II 期研究中进行研究（NCT03759184、NCT02689453） ，NCT01021059）。 IL-15 在治疗 HSCT 后复发性血液恶性肿瘤方面进行了研究，其耐受性良好，并且作为单一疗法可产生完全和部分缓解。虽然用 IL-15 治疗移植后复发似乎是安全且有希望的，但预防复发更令人感兴趣，这代表着在目前没有护理标准的情况下一个重要的未满足的需求。 I 期临床试验将探索 HSCT 后给予 rhIL-15 是否可以安全地增强高复发风险 MDS/AML 患者的 GVL 效应（PI Noa Holtzman）。白介素 8 (IL-8)：MDS 患者外周血和骨髓中的细胞因子谱分析发现，IL-8 水平上调与 MDS 表型之间存在很强的相关性，33 即使在使用低甲基化药物 (HMA) 治疗后也是如此。 34 进一步，IL-8 和 CXCR2 在纯化的 MDS/AML 干细胞和粒细胞-巨噬细胞祖细胞中过度表达。 35 一项全面的蛋白质组学分析研究确定IL-8 作为 AML 患者骨髓中 150 多种失调蛋白网络的中心分子，表明 IL-8 是一个有前途的治疗靶点。最近，CCR 壁内研究人员发现剪接因子 U2AF1 突变与 IL-8.9 转录后调节之间存在直接联系。我们建议开展一项 1/2 期临床试验，对患者进行 HMA 和人源化抗 IL-8 抗体序贯治疗与 MDS（PIs Pavletic、Larson、Ostojic）。