Novel approaches for activation and expansion of genetically modified T cells in vivo

杀伤T淋巴细胞可以穿透肿瘤，它们的增殖和转移到癌症患者身上已经显示出一些令人鼓舞的结果，但这种形式的过继免疫治疗在大多数癌症患者中仍然无效。我们建议通过基因工程，使杀伤细胞能够识别和破坏癌细胞，从而提高杀伤细胞的肿瘤运输和抗肿瘤活性。我们之前的工作表明，杀伤T淋巴细胞可以在肿瘤识别受体的培养中进行基因工程改造。当转移到小鼠体内时，这些基因工程细胞可以释放导致肿瘤破坏的有毒和炎症蛋白。在这个提议中，我们希望通过设计具有(i)受体的小鼠杀伤T细胞来进一步在小鼠中测试这种方法，这些受体为杀伤和增殖提供更强的信号；（ii）受体靶向肿瘤细胞上的其他结构，包括肿瘤脉管系统，作为克服肿瘤逃逸的手段。此外，我们希望测试一种结合基因工程和疫苗接种策略的新方法，用于过继转移后扩增基因修饰细胞。这些研究将允许将最好的受体基因转移到人类白细胞中，并检查免疫缺陷小鼠的抗肿瘤效果。

Killer T lymphocytes can penetrate tumors and their propagation and transfer into cancer patients has demonstrated some encouraging results, but this form of adoptive immunotherapy remains ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. Our previous work has indicated that killer T lymphocytes can be genetically engineered in culture with tumor recognition receptors. When transferred into mice, these genetically engineered cells can release toxic and inflammatory proteins that cause tumor destruction. In this proposal we wish to further test this approach in mice by enginneering the mouse killer T cells with (i) receptors that provide stronger signals for killing and proliferation; and (ii) with receptors targeting other structures on tumor cells including the tumor vasculature as a means to overcome tumor escape. In addition, we wish to test a novel approach of combining both genetic engineering and vaccination strategies for expanding gene-modified cells after adoptive transfer. These studies will allow the best receptor genes to be transferred to human white blood cells and examined for anti-tumor effects in immune-deficient mice.