Ultrasound-guided gene delivery in pancreatic cancer

描述（由申请人提供）：目前，转移性胰腺癌没有有效的治疗方法。本研究旨在通过采用一种新的方法来克服这一僵局，该方法采用一种表达治疗性细胞因子IFN-？或mda-7/IL-24（一种癌症终止病毒（CTV）），联合超声造影剂和超声波。这些研究是基于IFN-？mda-7/IL-24表现出选择性抗胰腺癌活性、强效“旁观者”抗肿瘤活性、抗血管生成活性。基于mda-7/IL-24深刻的多功能，选择性抗癌活性，该基因已在晚期癌症患者（不包括胰腺癌）的I期临床试验中进行了评估，通过重复肿瘤内注射表达mda-7/IL-24的非复制腺病毒（Ad.mda-7; ingn241）。这种治疗方法是安全的，并产生了显著的临床活性。基于ad的疗法的局限性包括免疫系统的快速降解和清除，从而限制了全身应用。通过使用美国造影剂（微泡），我们将获得特异性的作用，并保护病毒载体免于失活。此外，充满气体的微球有效地降低了空化的能量阈值，允许诊断传感器在FDA规定的能量水平内工作，用于药物/基因传递。在超声区，微气泡发生空化，破坏气泡并释放其内容物，产生增加细胞渗透性的小冲击波。在实验动物中，这已被证明可以增加由微泡共同递送的大分子或纳米球的经毛细血管通道。原则上，目前的方法应该允许有效的CTV递送，并可能在原发性和远处转移性胰腺癌中引起治愈，这将在免疫功能不全的动物模型中进行测试。这些研究的成功完成将为未来的临床试验铺平道路。公共卫生相关性：本研究旨在开发一种有效的胰腺癌治疗方法，利用癌症特异性凋亡诱导细胞因子IFN-？或mda-7/IL-24，由一种有条件复制的腺病毒，一种癌症终止病毒（CTV），结合超声造影剂和超声波传递。这种新方法将允许将CTV有效地全身输送到肿瘤中，为开发局部和转移性胰腺癌的“治愈”提供了潜力。成功实现本提案的目标将提供快速转化到临床作为一个新的和潜在的有效治疗转移性胰腺癌。

DESCRIPTION (provided by applicant): At present, no effective therapy is available for metastatic pancreatic cancer. This proposal seeks to overcome this impasse by employing a novel approach employing a cancer-specific conditionally replication competent adenovirus that expresses a therapeutic cytokine, IFN-? or mda-7/IL-24 (a cancer terminator virus (CTV)), in combination with an ultrasound (US) contrast agent and US waves. These studies are based on the observations that IFN-? and mda-7/IL-24 displays selective anti-pancreatic cancer activity, potent 'bystander' anti-tumor activity, anti-angiogenic activity. Based on profound multifunctional, selective anti-cancer activities of mda-7/IL-24, this gene has been evaluated in a Phase I clinical trial in patients with advanced cancers, not including pancreatic cancer, by repeat intratumoral injections with a non-replicating adenovirus (Ad) expressing mda-7/IL-24 (Ad.mda-7; INGN 241). This therapeutic approach was safe and resulted in significant clinical activity. Restrictions of Ad-based therapies include rapid degradation and clearance by the immune system, thus limiting systemic applications. By using US contrast agents (microbubbles) we will achieve both specificity of action as well as protection of the viral vectors from inactivation. Additionally, the gas filled microspheres effectively lower the energy threshold for cavitation allowing diagnostic transducers operating within the energy levels mandated by the FDA to be used for drug/gene delivery. In the sonification zone the microbubbles undergo cavitation, destroying the bubbles and releasing their contents, creating small shockwaves that increase cell permeability. This has been shown to increase transcapillary passage of macromolecules or nanospheres co-delivered by the microbubbles in experimental animals. In principle, the present approach should allow efficient CTV delivery and may evoke a cure in both primary and distant mestastatic pancreatic cancer, which will be tested in immune incompetent animal models. Successful accomplishment of these studies will pave the way for future clinical trials. PUBLIC HEALTH RELEVANCE: The present study seeks to develop an effective therapy for pancreatic cancer that employs cancer-specific apoptosis-inducing cytokines, IFN-? or mda-7/IL-24, delivered by a conditionally replication competent adenovirus, a cancer terminator virus (CTV), in combination with ultrasound contrast agents and ultrasound waves. This novel approach will permit efficient systemic delivery of the CTV to tumors, offering the potential to develop a 'cure' for both localized and metastatic pancreatic cancer. Successful achievement of the objectives of the present proposal will provide for rapid translation into the clinic as a new and potentially effective therapy for metastatic pancreatic cancer.