Enterovirus Vectors with Respiratory Tropism for Cancer Immunotherapy

描述（由申请人提供）：恶性胶质瘤的特征是早期局部浸润，健康CNS组织的微卫星浸润和肿瘤细胞在远处实质中的分散。这些特征显著阻碍了手术或放射治疗的成功，因为肿瘤不能在不对周围正常脑造成不可接受的损伤的情况下被完全治疗。 利用患者的免疫系统产生抗肿瘤反应有可能克服胶质瘤侵袭性所带来的治疗限制。免疫治疗方法直接靶向胶质瘤细胞，通过肿瘤独特的抗原特征，或间接通过攻击支持胶质瘤生长，侵袭或免疫逃避的机制。有效的癌症疫苗可能需要针对肿瘤本身和免疫耐受机制的联合反应。 我们基于柯萨奇病毒A21（CAV 21）（一种引起普通感冒的肠道病毒）产生了一种新的免疫平台。这包括（i）一种新技术，实现了用于递送外源抗原的病毒载体的永久遗传稳定性;（ii）CAV 21受体、人细胞间粘附分子-1（hICAM-1）转基因小鼠。我们在hICAM-1转基因小鼠中建立了普通感冒的啮齿动物模型，其在CAV 21感染后在呼吸道中表现出适度的病毒复制和轻度的气道炎症，与人类相似。CAV 21感染引起复杂的炎症反应，参与免疫系统的多个分支。 用我们的载体平台靶向血管内皮生长因子（VEGF）受体酪氨酸激酶的初步研究表明，在hICAM-1转基因小鼠的侵袭性同基因胶质瘤模型中具有强效的抗肿瘤作用。本研究的目的是检测CAV 21疫苗载体对VEGF受体1和2的抑制作用，并评价其免疫应答及其对肿瘤生长、转移和血管生成的影响。 公共卫生相关性：肿瘤的生长和侵袭与调节途径的激活相关，所述调节途径激活为肿瘤提供营养的血管的发芽。我们正在测试一种新型疫苗，这种疫苗是基于一种普通的引起感冒的病毒，针对这些途径。我们将在一种新的普通感冒动物模型中评估我们的免疫技术。

DESCRIPTION (provided by applicant): Malignant glioma is characterized by early local invasion, microsatellite infiltration of healthy CNS tissue and dispersion of tumor cells in distant parenchyma. These characteristics significantly hamper the success of surgical or radiation treatment, since the tumor cannot be treated in its entirety without unacceptable damage to surrounding normal brain. Harnessing the patients' immune system to generate anti-tumor responses has the potential to overcome treatment limits imposed by the invasive properties of glioma. Immunotherapy approaches target glioma cells directly, via antigenic signatures unique to tumor, or indirectly by attacking mechanisms supporting glioma growth, invasion or immune evasion. Efficacious cancer vaccines may require combined responses directed against the tumor itself and mechanisms of immune tolerance. We generated a new immunization platform based on Coxsackievirus A21 (CAV21), a common- cold causing enterovirus. This includes (i) a new technology achieving permanent genetic stability of viral vectors for the delivery of foreign antigens; (ii) mice transgenic for the CAV21 receptor, the human intercellular adhesion molecule-1 (hICAM-1). We established a rodent model for the common cold in hICAM-1 transgenic mice, which exhibit modest virus replication in the respiratory tract and mild airway inflammation upon CAV21 infection, similar to humans. CAV21 infection causes complex inflammatory reactions that engage multiple arms of the immune system. Preliminary studies of targeting the vascular endothelial growth factor (VEGF) receptor tyrosine kinases with our vector platform indicated potent anti-tumor effects in an aggressive syngeneic glioma model in hICAM-1 transgenic mice. The Aims of this project are to test CAV21 vaccine vectors against VEGF receptors 1 and 2 and evaluate the immunologic response and its effects on tumor growth, metastasis and angiogenesis. PUBLIC HEALTH RELEVANCE: Tumor growth and invasion correlates with activation of regulatory pathways that activate sprouting of blood vessels supplying the tumor with nutrients. We are testing a new type of vaccine based on a common cold- causing virus targeting these pathways. We will evaluate our immunization technology in a novel animal model for the common cold.