Local Tumoral Delivered Immune Checkpoint Blockades Immunotherapy and Radioembolization Combination Therapy

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PROJECT SUMMARY Systemic mono- or combination- immune checkpoint blockade (ICB) immunotherapy has been an established therapeutic paradigm. However, a risk of serious autoimmune side effect has been evidenced with non-specific cytotoxic T cell expansion. Substantial research has investigated into how best to harness the antitumor potential of combination immunotherapies and how to direct immunotherapies at the tumor. Hepatocellular carcinoma (HCC) is the 5th most common malignancy in the world and the 4th leading cause of cancer death in the US. Resection and transplantation are the sole potentially curative treatments for HCC, but only 10-15% of patients are candidates. Recent clinical trials demonstrate the potential of ICB antibodies against programmed cell death 1 (PD-1) or its ligand PD-L1 for the treatment of HCC. However, the strong immune suppressive microenvironment and low expression of immune checkpoint molecules within the HCC tumor lead to a resistance to immunotherapy in HCC; thus, the efficacy of ICB immunotherapy may not be sufficient to elicit durable clinical benefits. 90Y-radioembolization (90Y-RE) can precisely deliver high doses of radiation to HCC, protecting healthy tissues and avoiding side effects. 90Y-RE should be an ideal complement to ICB immunotherapy given that 90Y-RE induces immunogenic cell death. Recently clinical trials have been initiated to evaluate systemic ICB immunotherapy in combination with 90Y-RE in the hope of enhancing overall therapeutic effects. However, one limitation that accounts for the compromised efficacy of combined ICB immunotherapy is off-target binding of the ICBs to normal tissues upon systemic administration. Ideally these ICBs should be delivered selectively to the tumor lesion to avoid systemic non-specific activation of the immune system. We propose catheter-directed intra-arterial (IA) infusion of anti-PD-L1 (aPD-L1) loaded Au supra-nanostructures (AuSN) in a combination with 90Y-RE. Catheter directed local infusion of aPD-L1 with high surface area and reactive oxygen species responsive degradable AuSN will augment the localization of immunotherapy to the targeted HCC permitting radiation-enhanced activation of the immune system for superior therapeutic outcomes. Our proposed tumoral IA infused anti-PD-L1 loaded AuSN will permit efficient and targeted delivery of immunostimulatory aPD-L1 to allow an increase in the dosage and improved safety profile. The local ICB delivery of AuSN carriers will offer the potential to significantly increase the local immune- stimulating efficacy of 90Y-RE. Our CT visible AuSN and cross-sectional CT and MR image guidance should also permit us to monitor/track/quantify the delivery of aPD-L1-AuSN to the targeted tumor tissues. It should allow early prediction of elicited responses to prompt timely adjustments to individual treatment regimens. Through a collaborative project, we seek to develop a powerful new approach for tumor directed local combinational aPD-L1 immunotherapy and 90Y-RE for the treatment of HCC.