Promoting Tumor Immunity by Cross-linking B7-DC

描述(申请人提供)：主动免疫治疗的一个主要目标是动员对癌症的免疫反应。宿主免疫识别和摧毁肿瘤细胞的能力已经确立。然而，激活宿主抗肿瘤免疫反应的尝试只取得了部分成功。CD8+T细胞经常被扩增，甚至渗入肿瘤床，但肿瘤逃避机制阻止了它们摧毁不断增长的癌症的能力。免疫调节抗体B7-DC Xab是从梅奥诊所1例Waldenstrom巨球蛋白血症患者中分离出来的。这种抗体以一种不同于其他已知免疫激活剂的方式激活小鼠和人类树突状细胞，迅速将T调节细胞重新编程为效应器，并增强T细胞细胞毒反应，从而识别和杀死肿瘤细胞。用免疫调节剂治疗动物可以防止黑色素瘤、肾癌、淋巴瘤、白血病和乳腺癌的生长，展示了这种试剂在治疗各种癌症方面的潜在应用。值得注意的是，当B7-DC Xab与部分有效的疫苗一起给予动物时，容易发生自发性和侵袭性乳腺癌的动物仍然没有癌症。建议使用小鼠模型进行实验(1)确定被B7-DC Xab激活的树突状细胞许可为杀伤细胞的CTL前体的来源，(2)表征免疫调节剂B7-DC Xab激活和动员T细胞免疫的机制，以及(3)评估B7-DC Xab在已建立的乳腺癌和卵巢癌中的治疗作用。这些研究与开发治疗人类癌症的免疫治疗策略高度相关，因为正在研究的免疫增强剂是一种人类抗体，它通过激活与小鼠最初定义的信号通路相似的信号通路来结合和刺激人类树突状细胞。此外，经B7-DC Xab处理激活的人树突状细胞显示出与小鼠相似的功能特性，包括增强抗原摄取、细胞因子释放模式以及增强激活肿瘤特异性细胞毒性T细胞的能力。

DESCRIPTION (provided by applicant): A principal goal of active immunotherapy is to mobilize the immune response against cancer. The ability of host immunity to recognize and destroy tumor cells is well established. However, attempts to activate host anti-tumor immune responses have been only partially successful. Frequently CD8+ T cells are expanded and even infiltrate tumor beds, but tumor evasion mechanisms block their ability to destroy growing cancers. The immune modulatory antibody, B7-DC XAb, was isolated from a Mayo Clinic patient with Waldenstrom's macroglobulinemia. This antibody activates both mouse and human dendritic cells in a manner distinct from other known immune activators, rapidly reprogramming T regulatory cells into effectors and potentiating T cell cytotoxic responses that can recognize and kill tumor cells. Treatment of animals with the immune modulator prevented the outgrowth of melanoma, renal cell carcinoma, lymphoma, leukemia, and breast cancer, demonstrating the potential application of this reagent to the treatment of a wide variety of cancers. Remarkably, when B7-DC XAb was given to animals in conjunction with a partially effective vaccine, animals prone to the development of spontaneous and aggressive breast tumors remained cancer free. Experiments using mouse models are proposed (1) to determine the origin of CTL precursors that are licensed as killer cells by B7-DC XAb-activated dendritic cells, (2) to characterize the mechanisms governing DC activation and mobilization of T cell immunity by the immune modulator B7-DC XAb, and (3) to evaluate how B7-DC XAb treatment functions in established breast and ovarian carcinoma. These studies are highly relevant to the development of an immunotherapy strategy for the treatment of human cancers because the immune potentiator being studied is a human antibody that binds to and stimulates human dendritic cells by activating similar signaling pathways to those originally defined in the mouse. Furthermore, human dendritic cells activated by B7-DC XAb-treatment display similar functional properties to those seen in the mouse, including enhanced antigen uptake, the patterns in cytokine release, and an enhanced ability to activate tumor specific cytotoxic T cells.