Combinatorial targeting of melanoma initiating cells

描述（由申请人提供）：本提案的目的是测试恶性黑色素瘤有效治疗的新概念，即组合免疫治疗代表恶性黑色素瘤的有效治疗，其靶向恶性黑色素瘤起始细胞（MMIC）和肿瘤相关周细胞，结合连续低剂量环磷酰胺，即节拍化疗。这一策略源于以下证据：1)癌症干细胞（cancer stem cells， CSC）必须成为有效抗癌治疗的靶点，因为CSC理论认为肿瘤中只有一小部分细胞群具有自我更新、致瘤性、耐药和耐辐射能力；2)恶性黑色素瘤的发病率持续增加，且没有有效的治疗方法，因此迫切需要开发一种有效的治疗方法。iii)针对肿瘤微环境中的MMIC和肿瘤相关周细胞的基于T细胞和抗体的免疫治疗组合有望抵消肿瘤细胞为避免免疫识别而利用的多种逃避机制。我们的策略选择的目标是硫酸软骨素蛋白多糖4 (CSPG4)，它将以T和抗体为基础的免疫治疗为目标。利用生存手术-复发-转移模型，本提案的具体目的是验证基于T细胞和抗体的联合免疫治疗与节律化疗联合的假设，在移植原发肿瘤手术切除后，从细胞系和病变分离的免疫缺陷小鼠中，有效抑制复发和转移性扩散。这些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，预计将对CSC和恶性黑色素瘤的免疫治疗领域产生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.