Immunology of human malignant melanoma initiating cells

人类恶性黑色素瘤起始细胞的免疫学

基本信息

批准号：
8239174
负责人：
Markus H. Frank
金额：
$ 40.11万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8239174
关键词：
Address Affect Affinity Applications Grants BRAF gene Biological Markers Biological Products Biopsy Specimen Blood Circulation Cells Cereals Clinical Combined Modality Therapy Development Disease Dissection Disseminated Malignant Neoplasm Drug Formulations Early Diagnosis Evolution Excision Goals Hematopoietic Human Immune Immune Targeting Immunity Immunocompromised Host Immunology Immunotherapeutic agent Immunotherapy In Vitro Indium Laboratories Ligands MS4A1 gene Malignant Neoplasms Mediating Mediator of activation protein Melanoma Cell Metastatic Melanoma Minority Modality Modeling Monoclonal Antibodies Multi-Drug Resistance Mus Mutate Nature Neoplasm Metastasis Operative Surgical Procedures Organ Outcome Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Population Regional Lymph Node Involvement Research Resistance Rice Skin Neoplasms Stem cells Survival Rate Therapeutic Treatment Protocols Tumor Immunity Tumor Tissue Virulence Virulent Visceral Xenograft Model Xenograft procedure antibody-dependent cell cytotoxicity cancer stem cell clinical application conventional therapy effective therapy in vivo melanoma novel novel strategies novel therapeutics outcome forecast pre-clinical receptor research clinical testing research study response self-renewal therapy resistant tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Malignant melanoma initiating cells (MMICs) are minority subpopulations in which clinical virulence resides as a consequence of unlimited self-renewal capacity, resulting in inexorable tumor progression and potential metastasis. Our laboratories have recently identified human MMICs and shown them to express the targetable biomarker and multidrug resistance transporter, ABCB5 (Nature, Jan 17, 2008). In this study, proof of principle of immune-mediated MMIC destruction and consequent inhibition of tumor growth was demonstrated. More recently, we have shown that MMICs employ mechanisms to thwart endogenous anti-tumor immunity via the B7-2 and PD1 pathways (Cancer Res, Jan 15, 2010). This proposal seeks to further advance these findings in a translationally-relevant manner with the goal of accelerating progress toward clinical application of anti- melanoma immune therapies specifically targeting MMICs. The specific aims of this proposal are: (1) Characterization of ABCB5+ MMIC response to immunotherapy in human patients and assessment/prediction of MMIC therapeutic response; (2) In vivo dissection of antitumor immunity pathway interactions with MMIC in a novel humanized xenotransplantation model, melanoma to hu-PBMC NOD-scid IL2r3null mice; and (3) Preclinical immunomodulatory/MMIC-targeted combination therapies. This initiative should enhance the rapid development and refinement of targeted immunotherapies directed against MMICs, and thus holds great promise for rapid evolution to clinical testing. PUBLIC HEALTH RELEVANCE: Malignant melanoma, a form of cancer that is increasing faster than any other cancer worldwide, becomes deadly once it spreads from a primary skin tumor (sometimes no larger than a grain of rice) to the body's vital organs. Until now, there is no effective therapy for metastatic melanoma, in large part because the most virulent melanoma cells, called cancer stem cells, are resistant to treatment. We have successfully identified these virulent melanoma stem cells, and have developed strategies to immunologically target and eliminate them, and this grant proposal advances this research to a point whereby patients with otherwise incurable disease may significantly benefit.

描述（由申请人提供）：恶性黑色素瘤起始细胞（MMIC）是少数亚群，由于无限的自我更新能力而存在临床毒力，导致肿瘤不可避免的进展和潜在的转移。我们的实验室最近鉴定了人类 MMIC，并证明它们能够表达靶向生物标志物和多药耐药性转运蛋白 ABCB5（《自然》杂志，2008 年 1 月 17 日）。在这项研究中，证明了免疫介导的 MMIC 破坏和随后的肿瘤生长抑制的原理。最近，我们发现 MMIC 采用机制通过 B7-2 和 PD1 途径阻止内源性抗肿瘤免疫（Cancer Res，2010 年 1 月 15 日）。该提案旨在以翻译相关的方式进一步推进这些发现，目标是加速专门针对 MMIC 的抗黑色素瘤免疫疗法的临床应用进展。该提案的具体目标是： (1) 人类患者中 ABCB5+ MMIC 对免疫治疗反应的表征以及 MMIC 治疗反应的评估/预测； (2) 在新型人源化异种移植模型中，将黑色素瘤移植到 hu-PBMC NOD-scid IL2r3null 小鼠中，体内解析抗肿瘤免疫途径与 MMIC 的相互作用； (3) 临床前免疫调节/MMIC 靶向联合疗法。这一举措将促进针对 MMIC 的靶向免疫疗法的快速开发和完善，从而为临床测试的快速发展带来巨大希望。公共健康相关性：恶性黑色素瘤是一种癌症，其增长速度比世界上任何其他癌症都快，一旦从原发性皮肤肿瘤（有时不大于一粒米）扩散到身体的重要器官，就会变得致命。到目前为止，转移性黑色素瘤还没有有效的治疗方法，很大程度上是因为毒性最强的黑色素瘤细胞（称为癌症干细胞）对治疗有抵抗力。我们已经成功地鉴定了这些有毒的黑色素瘤干细胞，并制定了免疫学靶向和消除它们的策略，这项拨款提案将这项研究推进到了一个阶段，使患有其他无法治愈疾病的患者可以显着受益。