Ultrasound-guided gene delivery in pancreatic cancer

描述（由申请人提供）：目前，转移性胰腺癌尚无有效的治疗方法。该提案旨在克服这一僵局，采用一种新的方法，采用癌症特异性的条件复制能力腺病毒表达的治疗性细胞因子，IFN-？或mda-7/IL-24（一种癌症终结者病毒（CTV））与超声（US）造影剂和US波的组合。这些研究是基于观察，IFN-？并且mda-7/IL-24显示出选择性抗胰腺癌活性、有效的“旁观者”抗肿瘤活性、抗血管生成活性。基于mda-7/IL-24的深刻的多功能、选择性抗癌活性，该基因已经在患有晚期癌症（不包括胰腺癌）的患者中通过重复瘤内注射表达mda-7/IL-24的非复制型腺病毒（Ad）（Ad.mda-7; INGN 241）在I期临床试验中进行了评估。这种治疗方法是安全的，并产生了显着的临床活性。基于Ad的治疗的限制包括快速降解和免疫系统清除，从而限制了全身应用。通过使用超声造影剂（微泡），我们将实现作用的特异性以及保护病毒载体免于失活。此外，气体填充的微球有效地降低了空化的能量阈值，允许诊断换能器在FDA规定的能量水平内操作以用于药物/基因递送。在超声处理区中，微泡经历空化，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。这已显示在实验动物中增加由微泡共同递送的大分子或纳米球的跨毛细血管通过。原则上，本方法应该允许有效的CTV递送，并且可以在原发性和远处转移性胰腺癌中引起治愈，这将在免疫缺陷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治疗胰腺癌，采用癌症特异性细胞因子，IFN-？或mda-7/IL-24，其通过条件复制型腺病毒、癌症终止病毒（CTV）与超声造影剂和超声波的组合递送。这种新的方法将允许CTV有效地全身递送到肿瘤，为开发局部和转移性胰腺癌的“治愈”提供了可能。成功实现本提案的目标将提供作为转移性胰腺癌的新的和潜在有效的疗法快速转化为临床。

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.