T Cell Based Carriers for In Vivo Gene Therapy of Cancer

描述（由申请人提供）：癌症基因治疗的成功最终将取决于将基因特异性地递送到体内肿瘤细胞。然而，由于低滴度、免疫失活、非特异性粘附和循环中病毒颗粒的损失，病毒原液的全身给药迄今尚未实现转移性疾病的治疗靶向。因此，如果载体可以被携带到肿瘤生长的局部部位，并响应外部施加的信号（如药物）或肿瘤本身的生物学特性提供的环境线索而释放，这将是有价值的。几种细胞类型可以用作载体的肿瘤归巢细胞载体，包括肿瘤抗原特异性T细胞。我们最近已经表明，全身递送表面靶向的T细胞，经改造以在T细胞识别特定肿瘤抗原后产生转录肿瘤靶向的逆转录病毒载体，在转移性疾病模型中产生高度显著的治疗效果。然而，我们的T细胞研究在缺乏功能性免疫系统的小鼠中使用缺乏细胞溶解效应子功能的人T细胞。我们现在建议扩展用于癌症基因治疗的T细胞载体的概念。如图18和19中所总结的，我们将1：证明抗原特异性的鼠细胞毒性T细胞可以在体外转化为逆转录病毒生产细胞，它们可以在体内过继转移到携带肿瘤的宿主，并且它们可以在完全完整的免疫系统存在下运输并特异性地运输抗原阳性肿瘤：2：表征通过将细胞毒性逆转录病毒的肿瘤局部产生与T细胞的天然效应器功能相结合而产生的治疗增强（靶细胞杀伤和细胞因子释放）在恶性黑素瘤的免疫活性鼠模型中的过继性T细胞疗法方案中的作用：和3;研究在肿瘤部位产生基于抗原特异性T细胞的逆转录病毒载体以增强进一步剂量过继转移T细胞的募集和内源性抗肿瘤免疫效应物的募集/激活的潜力。在临床上，这些实验应迅速导致改善的患者试验过继性T细胞治疗癌症，他们将开发基于细胞的载体的潜力，在体内基因传递到转移性疾病。

DESCRIPTION (provided by applicant): The success of gene therapy for cancer will eventually depend on delivering genes specifically to tumor cells in vivo. However, systemic administration of viral stocks has not so far achieved therapeutic targeting of metastatic disease, due to low titres, immune inactivation, non-specific adhesion and loss of viral paticles in the circulation. It would, therefore, be valuable if vectors could be carried to local sites of tumor growth and be released in response to externally applied signals (such as drugs) or environmental cues supplied by the biological properties of the tumor itself. Several cell types could serve as tumor homing cell carriers of vectors, including tumor antigen specific T cells. We have recently shown that systemic delivery of surface targeted T cells, engineered to produce a transcriptionally tumor targeted retroviral vector upon recognition by the T cell of a specific tumor antigen, generated highly significant therapeutic effects in a model of metastatic disease. However, our T cell studies used human T cells lacking cytolytic effector functions, in mice lacking a functional immune system. We now propose to expand the concept of T cell carriers for the gene therapy of cancer. As summarized in Figures 18 and 19 we will 1: Demonstrate that antigen specific, murine cytotoxic T cells can be converted into retroviral producer cells in vitro, that they can be adoptively transferred in vivo to tumor bearing hosts and that they can traffick to and specifically transduce antigen positive tumors in the presence of a fully intact immune system: 2: Characterise the therapeutic enhancement produced by combining tumor localized production of cytotoxic retrovirus with the T cells' natural effector functions (target cell killing and cytokine release) in a protocol of adoptive T cell therapy in an immunocompetent murine model of malignant melanoma: and 3; Investigate the potential of antigen specific T cell based retroviral vector production at the tumor site to enhance the recruitment of further doses of adoptively transferred T cells and the recruitment/activation of endogenous anti tumor immune effectors. Clinically, these experiments should rapidly lead to improved patient trials for adoptive T cell therapy of cancer and they will develop the potential of cell-based carriers for in vivo gene delivery to metastatic disease.