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.
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. 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 an immunostimulantory drug to intratumoral inflammatory cell populations using a novel technique we refer to as transarterial immunomodulatory embolization (TIE).
