Stem Cell Biology, Cancer Stem Cell Biology, and Cancer Immunotherapy

干细胞生物学、癌症干细胞生物学和癌症免疫治疗

• 批准号: 10458105
• 负责人: IRVING L. WEISSMAN
• 金额: $ 99.83万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10458105
• 关键词: Affect; Anti-CD47; Antibodies; Applications Grants; Autologous Transplantation; Award; Blocking Antibodies; Blood; Blood Cells; Breast Cancer Patient; CD47 gene; Cell Count; Cell surface; Cells; Clinical Trials; Clonal Expansion; Clone Cells; Disease; Eating; Epigenetic Process; Event; Excision; Funding; Gene Expression; Genetic; Genetic study; Goals; High Dose Chemotherapy; Immune system; Immunologic Surveillance; Immunology; Label; Lead; Malignant Neoplasms; Malignant neoplasm of brain; Maps; Metastatic breast cancer; Metastatic to; Methods; Modeling; Mutation; Myelogenous; Myeloid Leukemia; Natural regeneration; Neuraxis; Normal tissue morphology; Pathogenicity; Patients; Phagocytes; Phagocytosis; Preleukemia; Premalignant Cell; Signal Transduction; Solid Neoplasm; System; Testing; Time; Tissues; Woman; Work; Xenograft Model; anti-cancer; base; calreticulin; cancer cell; cancer immunotherapy; cancer initiation; cancer regression; cancer stem cell; cancer therapy; human model; leukemia; leukemic stem cell; leukemogenesis; macrophage; neoplastic cell; new therapeutic target; peripheral blood; premalignant; progenitor; self-renewal; stem cell biology; stem cells; tissue stem cells; tumor; tumor progression

Summary: This grant application continues my previous work, focusing on integrating stem cell biology, cancer stem cells and immunology to understand: i) mechanisms controlling stem cell numbers, self-renewal and differentiation; ii) the genetic/epigenetic `events' that drive cancer initiation and progression through clonal expansion and competition of stem cells; iii) mechanisms of programmed cell removal of precancerous cells by macrophage phagocytosis and how cancer cells evade those, and iv) developing innate system [mainly macrophage-based] cancer immunotherapies. I was awarded an NCI OIG 28 years ago and used the funding to develop the first method to identify and isolate blood forming stem cells [HSC]. We applied this discovery in a clinical trial where autologous transplantation of purified, cancer-free HSC from mobilized peripheral blood [MPB] to metastatic breast cancer patients following high dose chemotherapy, resulted in 33% 18-20 year survival compared to 7% with MPB. We then mapped the differentiation steps from stem cells to all mature blood cells and in the context of myeloid leukemogenesis, studied how genetic alterations modify the affected stem cells. We isolated leukemic stem cells[LSC] that could regenerate myelogenous leukemia and found that these cells were not phenotypic HSC but downstream MPP progenitors. Although many HSC in the same patients had the cancer-initiating mutations, they were not leukemic! Additional mutations or `events' were required, each promoting clonal expansion and competition of the preleukemic HSC over normal HSC. This model of sequential progression of events accruing one at a time in HSC `clones' until the LSC emerges holds true for all myeloid leukemias and preleukemias. Comparing LSC to HSC we discovered that the expression of CD47, a `don't eat me' signal for macrophage scavenger cells, was a late event for all cancers including leukemias. We made blocking antibodies to CD47, and found that these led to tumor cell phagocytosis and cancer regression and often cures in xenograft models of human leukemias and solid tumors. Anti-CD47 antibody synergizes with all other anti- cancer antibodies tested to date. The current proposal expands on these studies to test whether accumulation of mutations also occurs in a central nervous system stem cell(CNS SC) clone that gives rise to a brain cancer stem cell [CSC]. The gene expression profiles of cells from these precancers and cancers should identify new therapeutic targets. Importantly, normal C47+ cells aren't eaten when CD47 is blocked, because they lack a pro-phagocytic `eat me signal', calreticulin, that is on all cancers. We will study how cancer cells are labeled with calreticulin for elimination by macrophages, and extend our macrophage phagocytosis studies to try to understand how macrophages get rid of old, damaged, and dying cells, and how pathogenic stem cells avoid being eaten via CD47 or other `don't eat me' signals. In these studies we will examine additional stem cell systems that when gone awry lead to cancer and other diseases.

摘要：这项资助申请延续了我之前的工作，重点是整合干细胞生物学， 癌症干细胞和免疫学，了解：i) 控制干细胞数量、自我更新的机制 和差异化； ii) 通过克隆驱动癌症发生和进展的遗传/表观遗传“事件” 干细胞的扩增和竞争； iii) 程序性细胞去除癌前细胞的机制 巨噬细胞吞噬作用以及癌细胞如何逃避这些作用，以及 iv) 发育先天系统[主要是 基于巨噬细胞的]癌症免疫疗法。 28 年前，我被授予 NCI OIG，并利用这笔资金开发了第一种方法来识别和 分离造血干细胞[HSC]。我们将这一发现应用到了一项临床试验中，其中自体 将来自动员外周血 [MPB] 的纯化、无癌 HSC 移植到转移性乳腺癌 接受高剂量化疗的患者 18-20 年生存率为 33%，而 MPB 为 7%。 然后，我们在骨髓细胞的背景下绘制了从干细胞到所有成熟血细胞的分化步骤 白血病发生，研究遗传改变如何改变受影响的干细胞。我们分离出白血病干 可以再生骨髓性白血病的细胞[LSC]，并发现这些细胞不是表型HSC 但下游 MPP 祖细胞。尽管同一患者的许多 HSC 都具有癌症起始基因 突变，他们不是白血病！需要额外的突变或“事件”，每一个都促进克隆 白血病前期 HSC 相对于正常 HSC 的扩张和竞争。这种顺序进展模型 HSC“克隆”中一次发生一个事件，直到 LSC 出现为止，这对于所有髓细胞性白血病都是如此 白血病前期。比较 LSC 和 HSC，我们发现 CD47 的表达，这是一种“别吃我”的信号 巨噬细胞清道夫细胞，是包括白血病在内的所有癌症的晚期事件。我们做了封锁 CD47 抗体，发现这些抗体会导致肿瘤细胞吞噬作用和癌症消退，并且通常可以治愈 在人类白血病和实体瘤的异种移植模型中。抗 CD47 抗体与所有其他抗 CD47 抗体具有协同作用 迄今为止已测试的癌症抗体。当前的提案扩展了这些研究，以测试累积是否 中枢神经系统干细胞 (CNS SC) 克隆中也会发生突变，从而导致脑癌 干细胞[CSC]。来自这些癌前病变和癌症的细胞的基因表达谱应该能够识别出新的 治疗目标。重要的是，当 CD47 被阻断时，正常的 C47+ 细胞不会被吃掉，因为它们缺乏 促吞噬细胞的“吃我信号”，即钙网蛋白，适用于所有癌症。我们将研究癌细胞是如何被标记的 与钙网蛋白一起通过巨噬细胞消除，并扩展我们的巨噬细胞吞噬作用研究以尝试 了解巨噬细胞如何清除老化、受损和垂死的细胞，以及致病干细胞如何避免 通过 CD47 或其他“别吃我”信号被吃掉。在这些研究中，我们将检查额外的干细胞 当系统出现问题时，会导致癌症和其他疾病。