Development of polymeric synthetic biomaterial IP-001 to potentiate asystemic immunotherapy of hepatocellular carcinoma via thermal ablation

翻译后摘要：免疫光子学是一家生物技术公司开发的合成生物聚合物，IP-001， 微波热消融肿瘤全身免疫治疗肝癌 癌（HCC）。SBIR快速通道的目标是完成临床前安全性和有效性测试， 根据与FDA会议的反馈，支持研究性新药（IND）申请。 意义：HCC是全球癌症相关死亡的第四大常见原因， 2019年在美国的案例。这种上升部分是由于肝炎引起的肝硬化和非酒精性肝硬化的增加。 与肥胖和糖尿病相关的脂肪性肝炎（NASH）。目前，肝移植和外科手术 切除术为长期缓解提供了最佳机会，但只有不到20%的患者符合条件。非 有局部疾病的外科候选人只有10.8%的五年生存率。热肝脏消融 MWA等疗法是BCLC 0期、A期和B期子集手术的标准护理替代方案 HCC患者。然而，消融仅针对局部肿瘤，并且对微转移具有全身杀瘤作用。 罕见，导致两年后复发率约为70%。需要更好的HCC治疗方法。 产品：IP-001预期在热消融（MWA）后立即进行瘤内注射。它的作用是1） 定位通过消融释放的肿瘤抗原并延长其对免疫系统的可用性，以及2） 激活免疫细胞如抗原呈递细胞。这导致更强的全身性T细胞反应 可以减少局部复发，消除转移，并引发长期记忆。研究者驱动的试验 在晚期乳腺癌中显示出有利的毒性特征和全身疗效的早期迹象， 达到长期缓解的完全应答者。公司已收到临床试验申请（CTA） 在瑞士批准开始一项针对黑色素瘤和软组织肉瘤的1/2期临床试验。 影响：在接受MWA消融术的HCC患者中，IP-001旨在将0、A和B期的复发率降低50% 在B & C期患者中， 疾病IP-001可以彻底改变介入肿瘤学领域，将其转变为早期治疗的手段。 免疫疗法广泛适用于其他实体癌，而不破坏护理标准。 方法和具体目标：在第一阶段，免疫光子学将生成MWA+ IP-001的可行性数据 原位大鼠HCC模型H-4-II-E（与路易斯维尔大学的Rob Martin博士合作）至1） 建立功效并产生数据，证明针对癌症的增强的全身免疫刺激， 2)探索与全身免疫治疗的潜在协同作用，即小鼠HCC中的检查点抑制剂抗PD-1 型号Hepa 1 -6。在第二阶段，免疫光子学将进一步确定1）最大耐受剂量 IP-001用于肝脏注射，2）常见合并症NASH/肝硬化对治疗疗效的影响，以及3） 将开发CMC方法，用于放大和分析制剂。

Abstract: Immunophotonics is a biotech company developing a synthetic biopolymer, IP-001, to potentiate a systemic immunotherapy via microwave (MWA) thermal tumor ablation for treatment of Hepatocellular carcinoma (HCC). The goal of this SBIR Fast Track is to complete preclinical safety and efficacy testing to support an investigational new drug (IND) application based on the feedback from a meeting with the FDA. Significance: HCC is the fourth most common cause of cancer-related death worldwide, with 42,030 new cases in the U.S. in 2019. This rise is partly due to an increase in hepatitis-induced cirrhosis and non-alcoholic steatohepatitis (NASH) associated with obesity and diabetes. Currently, hepatic transplant and surgical resection provide the best opportunity for long term remission, but less than 20% of patients are eligible. Non- surgical candidates with regional disease only have a 10.8% five-year survival rate. Thermal liver ablative therapies like MWA are a standard of care alternative to surgeries for BCLC stage 0, A and a subset of stage B HCC patients. However, ablation targets only local tumors, and systemic tumoricidal effects on micro-metastasis are rare, leading to recurrence rate of around 70% after two years. Better therapies for HCC are needed. Product: IP-001 is intended for intratumoral injection immediately after thermal ablation (MWA). It acts by 1) localizing tumor antigens liberated by ablation and prolonging their availability to the immune system and 2) activating immune cells such as antigen-presenting cells. This results in a stronger systemic T cell response that can reduce local recurrence, eliminate metastases, and elicit long-term memory. Investigator-driven trials in advanced breast cancer show a favorable toxicity profile and early signs of systemic efficacy, with some complete responders achieving long-term remission. The company has received clinical trial application (CTA) approval in Switzerland to begin a Phase 1/2 clinical trial in melanoma and soft tissue sarcoma. Impact: In HCC patients who receive MWA ablation, IP-001 aims to lower recurrence by 50% in stage 0, A & B patients and prolong progression-free survival by 50% and overall survival in stage B & C patients with regional disease. IP-001 could revolutionize the field of interventional oncology by transforming it into a means of early immunotherapy that is broadly applicable to other solid cancers without disruption to the standard of care. Approach and Specific Aims: In the Phase I, Immunophotonics will generate feasibility data of MWA+ IP-001 in orthotopic rat HCC model H-4-II-E (in collaboration with Dr. Rob Martin at the University of Louisville) to 1) establish efficacy and generate data demonstrating heightened systemic immune stimulation against cancer, 2) explore potential synergism with systemic immunotherapy, i.e. checkpoint inhibitor anti-PD-1 in mouse HCC model Hepa1-6. In the Phase II segment, Immunophotonics will further determine 1) maximum tolerated dose of IP-001 for liver injection, 2) impacts of common comorbidity NASH/cirrhosis on treatment efficacy, and 3) will develop CMC methods for scaling up and analysis of the drug product.