Promoting Tumor Immunity by Cross-linking B7-DC

描述（由申请人提供）：主动免疫疗法的主要目标是动员针对癌症的免疫应答。宿主免疫识别和破坏肿瘤细胞的能力已得到充分证实。然而，激活宿主抗肿瘤免疫应答的尝试仅部分成功。CD 8 + T细胞经常扩增，甚至浸润肿瘤床，但肿瘤逃避机制阻止了它们破坏生长中的癌症的能力。免疫调节抗体B7-DC XAb是从一名患有瓦尔登斯特罗姆巨球蛋白血症的马约诊所患者中分离出来的。这种抗体以不同于其他已知免疫激活剂的方式激活小鼠和人树突状细胞，快速将T调节细胞重编程为效应细胞，并增强可以识别和杀死肿瘤细胞的T细胞细胞毒性应答。用免疫调节剂治疗动物可防止黑色素瘤、肾细胞癌、淋巴瘤、白血病和乳腺癌的生长，证明了该试剂治疗多种癌症的潜在应用。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，易于发展自发性和侵袭性乳腺肿瘤的动物仍然没有癌症。提出使用小鼠模型的实验（1）确定被B7-DC XAb激活的树突状细胞授权为杀伤细胞的CTL前体的来源，（2）表征免疫调节剂B7-DC XAb控制DC激活和T细胞免疫动员的机制，和（3）评估B7-DC XAb治疗如何在已建立的乳腺癌和卵巢癌中发挥作用。这些研究与用于治疗人类癌症的免疫治疗策略的开发高度相关，因为正在研究的免疫增强剂是一种人抗体，其通过激活与最初在小鼠中定义的信号传导途径相似的信号传导途径来结合并刺激人树突状细胞。此外，通过B7-DC XAb处理活化的人树突状细胞显示出与在小鼠中观察到的功能特性相似的功能特性，包括增强的抗原摄取、细胞因子释放模式和增强的活化肿瘤特异性细胞毒性T细胞的能力。 公共卫生相关性：一种新的免疫调节抗体，称为B7-DC XAb，以不同于其他已知免疫激活剂的方式激活小鼠和人类免疫力，并迅速增强细胞反应，可以识别和杀死癌症。用免疫调节抗体治疗携带癌症的动物防止了黑色素瘤、肾细胞癌、淋巴瘤、白血病和乳腺癌的生长。使用动物模型和人类卵巢癌进行实验，以确定这种新治疗方法的工作原理，并确定如何最好地在密切模拟人类癌症自发发展的环境中使用它。

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. PUBLIC HEALTH RELEVANCE: A new immune modulatory antibody, called B7-DC XAb, activates both mouse and human immunity in a manner distinct from other known immune activators and rapidly potentiates cellular responses that can recognize and kill cancers. Treatment of cancer bearing animals with the immune modulating antibody prevented the outgrowth of melanoma, renal cell carcinoma, lymphoma, leukemia, and breast cancer. Experiments are proposed using animal models and human ovarian cancer to determine how this new treatment works and to define how best to use it in settings that closely mimic the spontaneous development of human cancers.