Immunology of human malignant melanoma initiating cells

人类恶性黑色素瘤起始细胞的免疫学

• 批准号: 9112874
• 负责人: Markus H. Frank
• 金额: $ 36.41万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112874
• 关键词: Address; Affect; Affinity; Applications Grants; BRAF gene; Biological Markers; Biological Products; Biopsy Specimen; Blood Circulation; Cells; Cereals; Clinical; Combined Modality Therapy; Cytotoxic T-Lymphocyte-Associated Protein 4; Development; Disease; Dissection; Disseminated Malignant Neoplasm; Early Diagnosis; Evolution; Excision; Formulation; 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; Patient-Focused Outcomes; 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; predicting response; receptor; research clinical testing; research study; response; self-renewal; targeted treatment; therapy resistant; treatment response; tumor; tumor growth; tumor progression

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.

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。

项目成果

Clinical Significance of Disseminated Pluripotent Tumor Cell Signature Expression in the Bone Marrow from Patients with Colorectal Cancer.

• DOI: 10.4172/1948-5956.1000490
• 发表时间: 2017
• 期刊: Journal of cancer science & therapy
• 作者: Gasser M;Kim M;Rehder R;Frank N;Frank M;Grimmig T;Moench R;Ribas C;Illert B;Germer CT;Rosenwald A;Waaga-Gasser AM
• 通讯作者: Waaga-Gasser AM