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

摘要：免疫光子公司是一家生物技术公司，正在开发一种合成生物聚合物IP-001，以增强 微波(MWA)热肿瘤消融术治疗肝细胞癌 癌症(HCC)。SBIR Fast Track的目标是完成临床前安全性和有效性测试，以 根据与FDA会议的反馈，支持研究新药(IND)申请。 意义：肝细胞癌是全球第四大癌症相关死亡原因，新增42030例 2019年美国的病例。这一上升的部分原因是肝炎引起的肝硬变和非酒精性疾病的增加。 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 切除为长期缓解提供了最好的机会，但符合条件的患者不到20%。非- 患有地区性疾病的外科候选人的五年存活率只有10.8%。热肝消融术 像MWA这样的疗法是BCLC 0期、A期和B期的子集手术的标准护理替代方案 肝细胞癌患者。然而，消融仅针对局部肿瘤，对微转移具有全身性杀瘤作用。 罕见，导致两年后复发率约为70%。需要更好的肝癌治疗方法。 产品：IP-001用于热消融(MWA)后立即进行肿瘤内注射。它的作用是1) 对消融后释放的肿瘤抗原进行定位并延长其对免疫系统的可获得性 激活免疫细胞，如抗原提呈细胞。这会导致更强的系统性T细胞反应 这可以减少局部复发，消除转移，并激发长期记忆。由调查员主导的试验 在晚期乳腺癌中显示出良好的毒性特征和全身疗效的早期迹象，一些 实现长期缓解的完全应答者。该公司已收到临床试验申请(CTA) 瑞士批准开始黑色素瘤和软组织肉瘤的1/2期临床试验。 影响：在接受MWA消融的肝癌患者中，IP-001的目标是将0期、A期和B期的复发率降低50% 将B&C期局部化疗患者的无进展生存期和总生存期延长50% 疾病。IP-001可以使介入肿瘤学领域发生革命性变化，将其转变为早期的 免疫疗法广泛适用于其他实体癌症，而不会破坏护理标准。 方法和具体目标：在第一阶段，免疫光子学将产生MWA+IP-001的可行性数据 在原位大鼠肝癌模型H-4-II-E中(与路易斯维尔大学的Rob Martin博士合作)为1) 建立疗效并生成数据，证明增强了系统对癌症的免疫刺激， 2)探索与系统免疫治疗的潜在协同作用，即检查点抑制物抗PD-1在小鼠肝癌中的作用 HEPA1-6型。在第二阶段，免疫光子学公司将进一步确定1)最大耐受量 IP-001用于肝脏注射；2)常见的NASH/肝硬变共病对治疗效果的影响；3) 将开发CMC方法，用于扩大和分析药物产品。

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.