Transarterial Immunomodulatory Embolization: A novel approach to cancer therapy

 描述(申请人提供)：不能手术的癌症，如大多数肝细胞癌，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果。虽然以肿瘤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反应方面显示了一些效果，但由于肿瘤内存在的抑制机制，这些反应往往是无效的。通过免疫抑制进行治疗干预已被证明可以改善癌症的免疫治疗；然而，在全身给药过程中，经常会出现严重的副作用，如自身免疫。我们假设，通过经皮介入提供的生物工程免疫刺激库，局部和持续地将免疫调节剂靶向肿瘤微环境，将逆转肿瘤内的免疫抑制，并导致肿瘤进展和/或消退的停止。为了验证这一假说，这项提议的总体目标是使用一种我们称为经动脉免疫调节栓塞术(TIE)的新技术，实现局部和持续地将促凋亡药物和免疫刺激药物输送到肿瘤内的炎性细胞。与经动脉化疗栓塞术(TACE)类似，TIE是一种图像引导的微创外科手术，有可能用于治疗肝脏内无法手术的恶性病变。与TACE不同的是，通过微粒进行不适当的栓塞会减少对正常肝组织的血液供应，而TACE可以很容易地逆转，由于使用以热可逆的柠檬酸盐为基础的聚合物作为输送和栓塞剂，该过程可以重复。逆转栓塞术的能力意味着更多的患者将有资格接受这种手术。其具体目的是：1)制备和表征一种热可逆的不透射线的栓塞剂，该栓塞剂可以通过释放氧化还原敏感的纳米载体有效地包裹并缓慢传递炎性免疫刺激剂，以及2)评估针对特定目标1开发的TiE系统是否能够激活兔肝癌模型中驻留的肿瘤免疫细胞并抑制肿瘤生长。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，并为新的工具奠定基础，这些工具可能通过经皮介入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.