Transarterial Immunomodulatory Embolization: A novel approach to cancer therapy

 描述（由申请人提供）：不可手术的癌症，如大多数肝细胞癌病例，仍然是一个重大的临床挑战;因此，需要新的治疗方法来改善患者的结局。尽管癌症疫苗接种形式的免疫疗法在产生预防、控制和逆转肿瘤生长所需的抗原特异性细胞应答方面显示出一定的功效，但由于肿瘤内存在的抑制机制，这些应答通常是无效的。通过免疫抑制的治疗性干预已被证明可以改善癌症免疫治疗;然而，严重的副作用，如自身免疫，通常发生在全身给药期间。我们假设，通过经皮介入递送的生物工程免疫刺激贮库，将免疫调节剂局部和持续靶向肿瘤微环境，将逆转肿瘤内免疫抑制，并导致肿瘤进展和/或消退停止。为了验证这一假设，本提案的总体目标是使用我们称为经动脉免疫调节栓塞（TIE）的新技术实现促凋亡药物和免疫刺激药物向肿瘤内炎症细胞群的局部和持续递送。与经动脉化疗栓塞（TACE）类似，TIE是一种图像引导的微创外科手术，可能用于治疗肝脏中无法手术的恶性病变。与TACE不同，其中通过微粒进行的不适当栓塞会减少正常肝组织的血液供应，TIE可以很容易地逆转，并且由于使用热可逆性柠檬酸盐基聚合物作为递送和栓塞载体，可以重复该过程。逆转栓塞的能力意味着更多的患者将有资格接受该手术。具体目标是：1）制造和表征热可逆的不透射线的栓塞剂，其可以通过释放氧化还原敏感性纳米载体来有效地捕获和缓慢递送炎性免疫刺激剂，以及2）评估在特定目的1中开发的TIE系统是否将激活驻留的肿瘤免疫细胞并抑制兔肝癌模型中的肿瘤生长。拟议的实验将使我们能够开发和评估一种治疗肿瘤的创新方法，并为新工具奠定基础，这些新工具可能用于通过经皮干预局部靶向肿瘤微环境来帮助阐明免疫调节机制。

 DESCRIPTION (provided by applicant): Inoperable cancers, such as most cases of hepatocellular carcinoma, remain a significant clinical challenge; therefore, novel therapies are required to improve the patient's outcome. Although immunotherapy in the form of cancer vaccination has shown some efficacy in generating the antigen-specific cellular responses required to prevent, control and reverse tumor growth, these responses are often ineffective due to the suppressive mechanisms present within the tumor. Therapeutic intervention through immune suppression has been shown to improve cancer immunotherapy; however, severe side effects, such as autoimmunity, often occur during systemic administration. We hypothesize that localized and persistent targeting of immunomodulators to the tumor microenvironment via a bioengineered immunostimulatory depot delivered by percutaneous intervention will reverse intratumoral immune suppression and lead to a halt in tumor progression and/or regression. To test this hypothesis, the overall goal of this proposal is to achieve localized and sustained delivery of a pro-apoptotic drug and an immunostimulatory drug to intratumoral inflammatory cell populations using a novel technique we refer to as Transarterial Immunomodulatory Embolization (TIE). Similar to transarterial chemoembolization (TACE), TIE is an image-guided, minimally-invasive surgical procedure that could potentially be used to treat malignant inoperable lesions in the liver. Unlike TACE, where improper embolization via microparticles can reduce blood supply to normal liver tissue, TIE can be easily reversed and the procedure repeated due to the use of a thermoreversible citrate-based polymer as the delivery and embolization vehicle. The ability to reverse the embolization means that many more patients would be eligible for the procedure. The specific aims are to: 1) Fabricate and characterize a thermoreversible radiopaque embolic agent that can efficiently entrap and slowly deliver inflammatory immunostimulants via release of redox-sensitive nanocarriers, and 2) Assess whether the TIE system developed in Specific Aim 1 will activate resident tumor immune cells and inhibit tumor growth in a rabbit liver cancer model. The proposed experiments will allow us to develop and evaluate an innovative approach to treat tumors and lay the foundation for novel tools that could potentially be used to help elucidate mechanisms of immunomodulation by locally targeting the tumor microenvironment via percutaneous intervention.