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

开发聚合合成生物材料 IP-001 通过热消融增强肝细胞癌的非全身免疫治疗

• 批准号: 10259123
• 负责人: Siu Kit Lam
• 金额: $ 40万
• 依托单位: IMMUNOPHOTONICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259123
• 关键词: Ablation; Aftercare; Alcoholic Liver Cirrhosis; Antigen-Presenting Cells; Antigens; Biocompatible Materials; Biological Markers; Biopolymers; Biotechnology; Blood; Blood Chemical Analysis; Breast Cancer Patient; CD8-Positive T-Lymphocytes; Cancer Etiology; Cells; Cessation of life; Chemistry; Cirrhosis; Clinical; Clinical Trials; Collaborations; Contralateral; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease remission; Dose; Excision; Feedback; Frequencies; Goals; Grant; Growth; Health; Hepatitis; Immune; Immune checkpoint inhibitor; Immune system; Immunity; Immunization; Immunotherapy; Implant; Injections; Interferon Type II; Intervention; Interventional radiology; Investigational Drugs; Investigational New Drug Application; Lead; Lesion; Liver; Liver Dysfunction; Malignant Neoplasms; Maximum Tolerated Dose; Metastatic Neoplasm to the Liver; Metastatic Neoplasm to the Lung; Methodology; Methods; Micrometastasis; Modeling; Monitor; Mus; Neoplasm Metastasis; Normal Range; Obesity; Oncology; Operative Surgical Procedures; Outcome; PD-1 inhibitors; Patients; Pharmaceutical Preparations; Phase; Phase I/II Clinical Trial; Polymers; Preclinical Testing; Primary carcinoma of the liver cells; Progression-Free Survivals; Rattus; Recurrence; Regional Disease; Reporting; Research Personnel; Research Project Grants; Safety; Serum; Small Business Innovation Research Grant; Soft tissue sarcoma; Solid; Survival Rate; Switzerland; T cell response; Thermal Ablation Therapy; Time; Toxic effect; Treatment Efficacy; Tumor Antigens; Tumor Immunity; United States; Universities; Validation; advanced breast cancer; analytical method; animal data; anti-PD-1; base; chemical property; comorbidity; efficacy testing; genetic analysis; immunoregulation; liver function; liver transplantation; long term memory; meetings; melanoma; microwave ablation; microwave electromagnetic radiation; mouse model; neutrophil; nonalcoholic steatohepatitis; novel; physical property; preclinical safety; predictive marker; research clinical testing; response; safety testing; scale up; standard of care; synergism; tumor; tumor growth

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.

摘要：Immunophotonics是一家生物技术公司，开发合成生物聚合物IP-001，以增强A 通过微波（MWA）热肿瘤消融的全身免疫疗法用于治疗肝细胞 癌（HCC）。此SBIR快速轨道的目的是将临床前的安全性和功效测试完成 根据与FDA会议的反馈，支持研究性新药（IND）申请。 意义：HCC是全球与癌症相关死亡的第四大原因，有42,030个新的 2019年在美国的病例。这一崛起部分是由于肝炎引起的肝硬化和非酒精性的增加所致 与肥胖和糖尿病有关的脂肪性肝炎（NASH）。目前，肝移植和手术 切除为长期缓解提供了最佳机会，但不到20％的患者符合条件。非- 具有区域疾病的手术候选人的生存率仅为10.8％。热肝烧蚀 MWA等疗法是BCLC阶段0，A和B期B子集的手术替代品的标准替代品 HCC患者。然而，消融仅针对局部肿瘤，以及对微膜片的全身性肿瘤作用 很少见，导致两年后复发率约为70％。需要更好的HCC疗法。 产品：IP-001用于热消融（MWA）后立即进行肿瘤内注射。它起作用1） 将消融释放并延长免疫系统的肿瘤抗原定位，2） 激活免疫细胞，例如抗原呈递细胞。这会导致更强的全身性T细胞反应 这可以减少局部复发，消除转移并引起长期记忆。研究人员驱动的试验 在晚期乳腺癌中，有良好的毒性特征和全身功效的早期迹象，有些 完整的响应者实现了长期缓解。该公司已收到临床试验申请（CTA） 瑞士的批准开始了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HCC患者中，IP-001的目标是在阶段0，A＆B中降低50％ 患者和无进展生存率延长了50％，在具有区域性的B＆C患者中的总体存活率 疾病。 IP-001可以通过将其转换为早期手段来彻底改变介入肿瘤学领域 免疫疗法广泛适用于其他固体癌症，而无需干扰护理标准。 方法和特定目的：在第一阶段，免疫原理将生成MWA+ IP-001的可行性数据 在Orthotic Rat HCC模型H-4-II-E（与路易斯维尔大学的Rob Martin博士合作）至1） 建立功效并生成数据，证明对癌症的全身免疫刺激增强 2）探索系统性免疫疗法的潜在协同作用，即小鼠HCC中的检查点抑制剂抗PD-1 型号HEPA1-6。在II期段中，免疫原子剂将进一步确定1）最大耐受剂量 IP-001的肝脏注射，2）常见合并症NASH/肝硬化对治疗功效的影响，3） 将开发CMC方法来扩展和分析药物。