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：此赠款应用程序继续我以前的工作，重点是整合干细胞生物学， 癌症干细胞和可以理解的免疫学：i）控制干细胞数量的机制，自我更新 和分化； ii）通过克隆促进癌症开始和进展的遗传/表观遗传学“事件” 干细胞的扩展和竞争； iii）通过 巨噬细胞吞噬作用以及癌细胞如何逃避这些细胞，iv）发展先天系统[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，并使用资金开发了第一种识别和 分离出血液形成干细胞[HSC]。我们在自体的临床试验中应用了这一发现 从动员的外周血[MPB]向转移性乳腺癌移植，无癌的HSC 高剂量化疗后的患者导致33％18 - 20年的生存率，而MPB的患者为7％。 然后，我们映射了从干细胞到所有成熟血细胞的分化步骤，在髓样的背景下 白血病生成研究了遗传改变如何修饰受影响的干细胞。我们隔离了白血病茎 细胞[LSC]可以再生髓质白血病，发现这些细胞不是表型HSC 但是下游MPP祖细胞。尽管同一患者中的许多HSC患有癌症 突变，它们不是白血病！需要其他突变或“事件”，每种促进克隆 普雷克血症HSC的扩张和竞争超过了正常的HSC。这个顺序进程的模型 在HSC“克隆”中一次进行一个事件，直到LSC出现在所有髓样白血病和 Preleukemias。将LSC与HSC进行比较，我们发现CD47的表达，“不要吃我”信号 对于包括白血病在内的所有癌症，巨噬细胞清除型细胞是一个较晚的事件。我们进行了阻止 CD47的抗体，发现这些抗体导致肿瘤细胞吞噬作用和癌症消退，并且经常治愈 在人类白血病和实体瘤的异种移植模型中。抗CD47抗体与所有其他抗体协同 迄今为止测试的癌症抗体。当前的建议扩展了这些研究，以测试是否积累 突变也发生在中枢神经系统干细胞（CNS SC）克隆中，导致脑癌 干细胞[CSC]。这些预科剂和癌症中细胞的基因表达谱应确定新的 治疗靶标。重要的是，当CD47被阻塞时，正常C47+细胞不会食用，因为它们缺乏 Pro-Phagococytic“ Eat Me Signal”，Calreticulin，这是所有癌症。我们将研究癌细胞如何标记 使用钙洛噬细胞消除钙网蛋白，并扩展我们的巨噬细胞吞噬作用研究 了解巨噬细胞如何摆脱旧，受损和垂死的细胞，以及致病性干细胞如何避免 通过CD47或其他“不要吃我”的信号食用。在这些研究中，我们将检查其他干细胞 出现问题时会导致癌症和其他疾病的系统。