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: 10247050
• 负责人: IRVING L. WEISSMAN
• 金额: $ 101.65万
• 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/10247050
• 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; antibody test; 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，专注于整合干细胞生物学， 癌症干细胞和免疫学理解：i）机制控制干细胞数量，自我更新， ii）通过克隆和分化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）通过免疫细胞化学方法去除癌前细胞的程序性细胞清除机制， 巨噬细胞吞噬作用以及癌细胞如何逃避这些，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，我获得了NCI OIG，并利用这笔资金开发了第一种识别和 分离造血干细胞[HSC]。我们将这一发现应用于一项临床试验， 从动员的外周血[MPB]中纯化的无癌HSC移植到转移性乳腺癌 接受大剂量化疗的患者，18-20年生存率为33%，而MPB为7%。 然后，我们绘制了从干细胞到所有成熟血细胞的分化步骤，并在骨髓细胞的背景下， 白血病，研究了遗传改变如何修改受影响的干细胞。我们分离了白血病干细胞 细胞[LSC]可以再生髓性白血病，并发现这些细胞不是表型HSC 而是下游MPP祖细胞。虽然同一患者中的许多HSC具有癌启动的细胞周期， 突变，他们不是白血病！需要额外的突变或“事件”，每个促进克隆 白血病前HSC相对于正常HSC的扩增和竞争。这种连续发展的模式 在HSC“克隆”中一次发生一个事件，直到LSC出现，这对所有骨髓性白血病都适用， 白血病前期比较LSC和HSC，我们发现CD 47的表达，一个“不要吃我”的信号， 巨噬细胞清道夫细胞是所有癌症包括白血病的晚期事件。我们做了拦网 他们发现，这些抗体导致肿瘤细胞吞噬作用和癌症消退， 在人类白血病和实体瘤的异种移植模型中。抗CD 47抗体与所有其他抗CD 47抗体协同作用。 迄今为止检测的癌症抗体。目前的建议扩大了这些研究，以测试积累是否 的突变也发生在中枢神经系统干细胞（CNS SC）克隆，导致脑癌 干细胞[CSC]。这些癌前病变和癌症细胞的基因表达谱应该能识别新的 治疗目标重要的是，当CD 47被阻断时，正常的C47+细胞不会被吃掉，因为它们缺乏一种免疫抑制剂。 促吞噬细胞的“吃掉我的信号”，钙网蛋白，这是对所有癌症。我们将研究癌细胞如何被标记 与钙网蛋白的巨噬细胞消除，并扩大我们的巨噬细胞吞噬作用的研究，试图 了解巨噬细胞如何摆脱旧的，受损的，垂死的细胞，以及致病干细胞如何避免 通过CD 47或其他“不要吃我”信号被吃掉。在这些研究中，我们将检查额外的干细胞 当系统出错时会导致癌症和其他疾病。