Exploiting novel uses of gene-modified drug-resistant hematopoietic cells

描述（由申请人提供）：目前晚期或转移性癌症患者的治疗选择有限，在许多情况下无效。虽然手术、放射治疗和各种化疗方案的组合可能是有效的，但疾病复发仍然是主要并发症。诱导抗肿瘤免疫是一种新兴的治疗许多类型的癌症，特别是那些化疗是适度有效的。尽管有希望，但由于几个原因，预测单独的抗肿瘤免疫活性细胞不会完全根除人类中的肿瘤生长。此外，将这种治疗与化疗相结合是有问题的，因为细胞毒性化疗方案可能严重影响基于细胞的治疗。为了克服这些限制，我们开发了几种基于基因转移的方法，用于赋予细胞毒性免疫活性细胞耐药性。使用模型基因治疗系统，我们表明通过组合造血耐药基因治疗和HSC衍生的免疫活性细胞的体内扩增实现了动物存活率的显著改善，其中100%接种肉瘤肿瘤细胞系的小鼠实现了长期治愈。我们建议进一步开发基因修饰的HSC的这种新用途，通过测试以下假设：保护免疫活性细胞免受化疗的毒性作用将允许联合使用化疗和免疫调节剂，并且联合使用将比单一药物更有效。因此，该提案的最终目标是1）详细了解基因工程免疫活性细胞的后果，以及2）将这种基因治疗治疗方式的有用性扩展到临床相关的动物模型。 公共卫生相关性：神经母细胞瘤是一种预后极差的儿童疾病。这项提案的目标是开发新的策略，结合联合收割机耐药基因治疗和免疫治疗。如果成功的话，也有可能将这种新的治疗策略推广到其他癌症。

DESCRIPTION (provided by applicant): Current treatment options for patients with late stage or metastatic cancer are limited and, in many cases, ineffective. Although combinations of surgery, radiation therapy, and various chemotherapy regimens can be effective, disease relapse remains a major complication. Induction of anti-tumor immunity is an emerging treatment for many types of cancers, especially those where chemotherapy is modestly effective. Although promising, for several reasons, it is predicted that anti-tumor immunocompetent cells alone will not completely eradicate tumor growth in humans. In addition, combining this treatment with chemotherapy is problematic because cytotoxic chemotherapy regimens can severely affect cell-based therapies. To overcome these limitations, we developed several gene-transfer-based methods for conferring drug resistance to cytotoxic immunocompetent cells. Using a model gene therapy system, we showed that significant improvement in animal survival is achieved by combining hematopoietic drug- resistance gene therapy and in vivo expansion of HSC-derived immunocompetent cells, where 100% of mice inoculated with a sarcoma tumor cell line achieve long-term cure. We propose to further develop this novel use of gene-modified HSCs by testing the hypothesis that protection of immunocompetent cells from the toxic effects of chemotherapy will allow for the combined use of chemotherapy and immune modulating agents, and the combined use will be more effective than the single agents. The ultimate goal of this proposal, therefore, is to 1) develop a detailed understanding of the consequences of genetically engineering immunocompetent cells, and 2) expand the usefulness of this gene therapy treatment modality to a clinically relevant animal model. Public Health Relevance: Neuroblastoma is a childhood disease with very poor prognosis. The goal of this proposal is to develop novel strategies that combine drug-resistance gene therapy and immunotherapy. If successful, it may also be possible to generalize this new treatment strategy to other cancers.