Combinatorial targeting of melanoma initiating cells

描述（由申请人提供）：本提案的目的是测试一种新的概念，即恶性黑色素瘤的有效治疗是以靶向恶性黑色素瘤起始细胞（MMIC）和肿瘤相关周细胞的组合免疫疗法为代表，与连续低剂量环磷酰胺联合，即节拍化疗。这一战略源于以下证据：i）癌症干细胞（CSC）必须被靶向用于作为有效抗癌治疗的疗法，因为CSC理论假定肿瘤中只有小细胞群是自我更新的、致瘤的和耐药物和放射的，ii）迫切需要开发恶性黑素瘤的有效疗法，因为它的发病率持续增加并且没有有效的疗法可用，和iii）靶向MMIC和肿瘤微环境中的肿瘤相关周细胞的基于T细胞和抗体的免疫疗法的组合预期抵消肿瘤细胞利用的多种逃避机制以避免免疫识别。为我们的策略选择的靶标是硫酸软骨素蛋白聚糖4（CSPG 4），其将被基于T和抗体的免疫疗法靶向。利用存活手术-复发-转移模型，该提议的具体目的是检验以下假设：基于T细胞和抗体的组合免疫疗法与节拍化疗组合有效抑制在移植的原发性肿瘤手术切除后从细胞系和病变分离的人MMIC在免疫缺陷小鼠中的复发和转移扩散。概述的研究将受益于多个相关研究领域的现有专业知识和独特试剂的可用性，预计将为CSC和恶性黑色素瘤免疫治疗领域做出新的和潜在的重要贡献。

DESCRIPTION (provided by applicant): The goal of this proposal is to test the novel concept that an effective treatment for malignant melanoma is represented by a combinatorial immunotherapy, which targets malignant melanoma initiating cells (MMIC) and tumor-associated pericytes, in combination with continuous low dose cyclophosphamide, i.e. metronomic chemotherapy. This strategy stems from the following lines of evidence: i) cancer stem cells (CSC) have to be targeted for a therapy to be an effective anticancer treatment, since the CSC theory postulates that only a small cell population in tumors is self-renewing, tumorigenic and drug- and radio-resistant, ii) there is an urgent need to develop an effective therapy of malignant melanoma, since its incidence continues to increase and no effective therapy is available, and iii) a combination of T cell- and antibody-based immunotherapy that targets MMIC and tumor-associated pericytes in the tumor microenvironment is expected to counteract the multiple escape mechanisms utilized by tumor cells to avoid immune recognition. The target selected for our strategy is chondroitin sulfate proteoglycan 4 (CSPG4) which will be targeted with T- and antibody-based immunotherapy. Utilizing a survival surgery- recurrence-metastasis model, the specific aims of this proposal are to test the hypothesis that combinatorial T cell- and antibody- based immunotherapy in combination with metronomic chemotherapy is effective in inhibiting recurrence and metastatic spreading in immunodeficient mice of human MMIC isolated from cell lines and from lesions, following surgical removal of the grafted primary tumor. The outlined studies, which will benefit from the available expertise in multiple relevant research areas and the availability of unique reagents, are expected to yield novel and potentially important contributions to the fields of CSC and immunotherapy of malignant melanoma.