Targeted Nanomedicines with Synergistic Chemotherapeutics to Enhance Immunotherapy of Metastatic Colorectal Cancer

靶向纳米药物与协同化疗增强转移性结直肠癌的免疫治疗

基本信息

批准号：
10208813
负责人：
Wenbin Lin
金额：
$ 36.98万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208813
关键词：
Address Affect Antibodies Antigens Antitumor Response Azoxymethane Biodistribution Biological Markers CAR T cell therapy CD8-Positive T-Lymphocytes CTLA4 gene Cancer Etiology Cancer Vaccines Cecum Cell Death Cells Cessation of life Chemicals Cleaved cell Clinical Trials Collaborations Colon Carcinoma Colorectal Cancer DNA DNA Sequence Alteration Dependence Deposition Diagnosis Disseminated Malignant Neoplasm Distant Distant Metastasis Drug Kinetics Epidermal Growth Factor Receptor FDA approved Human Immune Immune system Immunotherapy Implant In Vitro Infiltration Inflammatory Response Injections MC38 Microsatellite Instability Microsatellite Repeats Mismatch Repair Modeling Mus Neoplasm Metastasis Operative Surgical Procedures Organ PD-1 blockade PUVA Photochemotherapy Patients Permeability Phage Display Polymers Progression-Free Survivals Proteins Radiation Rodent Signal Transduction Solid Stable Disease Survival Rate Therapeutic Time Treatment Efficacy Tumor Antigens Tumor-infiltrating immune cells anti-PD-L1 anti-PD-L1 antibodies anti-PD1 antibodies anti-cancer anti-tumor immune response antibody immunotherapy base beta catenin biomaterial compatibility cancer cell cancer type clinical translation colon cancer patients cytotoxic effective therapy exhaustion immune activation immune checkpoint immune checkpoint blockade immunogenic immunogenic cell death improved in vivo metastatic colorectal migration mouse model nanocarrier nanomedicine nanoparticle nanoscale nanotherapeutic novel novel strategies novel therapeutics overexpression oxaliplatin particle preclinical study response tumor tumor growth

项目摘要

Project Summary Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Over half of CRC patients have regional or distant metastasis at the time of diagnosis, and those with metastases to other organs have a 5-year survival rate of only ~12%. Checkpoint blockade immunotherapy stimulates the host immune system to generate an antitumor immune response, and has showed impressive results treating patients with mismatch repair (MMR) deficient CRC. However, up to 95% of patients with metastatic CRC (mCRC) have MMR- proficient, microsatellite-stable disease, who do not benefit from current immunotherapy. We propose to develop nanoscale coordination polymer-based targeted nanomedicines containing oxaliplatin and dihydroartemesinin (DHA), two immunogenic chemotherapeutics, for treating mCRC. EGFR-targeted nanomedicines can exert direct cytotoxic effects on CRC cells, and simultaneously induce and potentiate an antitumor immune effect. We propose the following Specific Aims in order to develop a novel combined chemotherapeutic nanomedicine and checkpoint blockade immunotherapy for the effective treatment of mCRC. Aim 1: Evaluate the mechanisms of OxPt/DHA nanoparticle anticancer efficacy on CRC cells. Aim 2: Actively target OxPt/DHA nanoparticles to CRC with an anti-EGFR Fab. Aim 3: Evaluate the anticancer efficacy of OxPt/DHA and EGFR-OxPt/DHA nanoparticles in orthotopic mouse models of CRC. Aim 4: Elucidate the immune mechanisms of antitumor response in mice treated with OxPt/DHA or EGFR-OxPt/DHA nanoparticles in combination with PD-L1 antibody. Through these aims, we seek to establish a new paradigm for the treatment of mCRC by increasing the response rate and therapeutic efficacy of immunotherapy for mCRC. Given that checkpoint blockade immunotherapies have been approved by FDA to treat multiple types of cancers, our strategy of utilizing chemotherapeutic nanomedicine as an immune system booster to potentiate checkpoint blockade can have broad impact on treating other metastatic cancers.

项目概要结直肠癌 (CRC) 是美国癌症相关死亡的第二大原因。超过一半的结直肠癌患者在诊断时已出现区域或远处转移，并且那些转移到其他器官的患者的 5 年生存率仅为 12% 左右。检查站封锁免疫疗法刺激宿主免疫系统产生抗肿瘤免疫反应，并在治疗错配修复 (MMR) 患者方面显示出令人印象深刻的结果 CRC 缺陷。然而，高达 95% 的转移性 CRC (mCRC) 患者患有 MMR- 熟练的、微卫星稳定的疾病，无法从当前的免疫疗法中受益。我们提议开发基于纳米级配位聚合物的靶向纳米药物奥沙利铂和双氢青蒿素（DHA），两种免疫原性化疗药物，用于治疗转移性结直肠癌。 EGFR靶向纳米药物可以对CRC细胞产生直接的细胞毒作用，并且同时诱导和增强抗肿瘤免疫作用。我们提出以下建议具体目标是开发一种新型的联合化疗纳米药物和检查点阻断免疫疗法可有效治疗转移性结直肠癌。目标 1：评估 OxPt/DHA 纳米粒子对 CRC 细胞的抗癌功效机制。目标 2：使用抗 EGFR Fab 主动将 OxPt/DHA 纳米粒子靶向 CRC。目标 3：评估 OxPt/DHA 和 EGFR-OxPt/DHA 纳米粒子的抗癌功效 CRC原位小鼠模型。目标 4：阐明接受 OxPt/DHA 治疗的小鼠抗肿瘤反应的免疫机制或 EGFR-OxPt/DHA 纳米颗粒与 PD-L1 抗体组合。通过这些目标，我们寻求通过以下方式建立转移性结直肠癌治疗的新范例：提高 mCRC 免疫疗法的反应率和治疗效果。鉴于检查点阻断免疫疗法已获得 FDA 批准用于治疗多种类型的癌症，我们利用化疗纳米药物作为免疫系统增强剂的策略加强检查点封锁可能对治疗其他转移性癌症产生广泛影响。