Engineering immunotherapeutic probiotics to mitigate irAE

工程免疫治疗益生菌以减轻 irAE

基本信息

批准号：
10302262
负责人：
Nicholas Arpaia
金额：
$ 58.41万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-21 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10302262
关键词：
Adjuvant Adverse effects Antibodies Antigen-Presenting Cells Area Autoimmune Bacteria Body Temperature Body Weight CD47 gene CTLA4 gene Cancer Model Clinical Clinical Trials Clone Cells Colorectal Colorectal Cancer Colorectal Neoplasms Combination immunotherapy Cytolysis Data Distant Dose Dose-Limiting Engineered Probiotics Engineering Escherichia coli Evaluation Exhibits Genetic Engineering Goals Growth Health Heart Rate Hepatic Immune Immune Targeting Immune checkpoint inhibitor Immune response Immunity Immunologic Adjuvants Immunophenotyping Immunosuppression Immunotherapeutic agent Immunotherapy Intravenous Kinetics Lead Lesion Liver Liver neoplasms Local Therapy Lung Malignant Neoplasms Measurement Metastatic Neoplasm to the Liver Methods Mind Modality Monitor Monoclonal Antibodies Monoclonal Antibody Therapy Mus Mutate Mutation Necrosis Neoplasm Metastasis Oral Oral Administration Patients Penetration Primary Neoplasm Probiotics Production Recombinants Regimen Renaissance Research Safety Solid Neoplasm Specificity Survival Rate System T cell response T-Lymphocyte Therapeutic Toxic effect Treatment Efficacy Treatment Protocols Tumor Antigens Tumor Immunity Tumor-infiltrating immune cells Vascularization Work antagonist anti-cancer anti-tumor immune response base cancer immunotherapy clinical practice colon cancer patients colorectal cancer metastasis comparative efficacy cytokine delivery vehicle exhaustion immune checkpoint immune checkpoint blockade immune-related adverse events immunoregulation in vivo imaging system innovation metastatic colorectal mouse model nanobodies neoantigens novel patient subsets prevent probiotic therapy programmed cell death ligand 1 response side effect success synthetic biology systemic toxicity tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT In recent years, the field of cancer immunotherapy has seen a renaissance – with the use of monoclonal antibodies that target immune checkpoints to activate anticancer immune responses demonstrating unparalleled clinical success. Several of these therapies have now gained FDA approval and are part of routine treatment regimens for several malignancies. Despite the overall success of immunotherapeutic regimens, existing modalities present complications that current research efforts seek to overcome: (1) systemic delivery of checkpoint blockade monoclonal antibodies lead to diverse and unpredictable immune-related adverse events (irAE), (2) boosting responses from the endogenous antitumor repertoire often relies on the existence of pre- primed antitumor T cells, which in the case of highly immunosuppressive tumors or those with low mutational burden may be extremely rare, and (3) attempts to combine immunotherapies to additively boost T cell responses demonstrate increased on-target, off-tumor toxicity. Thus, to circumvent toxicity and immunosuppression, contemporary strategies focus on developing methods to deliver potent immunostimulants directly into a tumor, locally priming antitumor T cells to attack disseminated metastases exhibiting a similar antigenic profile. Bridging these observations, the goals of this proposal are to engineer probiotic strains of bacteria that selectively colonize colorectal cancer (CRC) and locally release immune checkpoint blockade. We hypothesize that this approach will result in more robust and diversified antitumor T cell immunity and promote the clearance of colonized primary and metastatic colorectal cancer lesions and systemically growing CRC-derived foci. The primary innovations of this proposal are in engineering probiotics as an immunotherapeutic delivery vector to locally release high-dose immune checkpoint blockade. Specifically, the proposed system has several advantages over current therapeutic strategies, including: (1) tumor-specific production of immunotherapies and LPS adjuvant, (2) bacteria lysis, leading to effective release of novel immunotherapeutics and LPS, (3) local delivery of novel immunotherapeutics that are toxic to deliver systemically, and (4) oral delivery of probiotics that selectively colonize CRC metastases. This work seeks to shift current research and clinical practice paradigms to overcome current limitations of immunotherapies, by providing a unique vehicle to locally deliver immunotherapies that stimulate antitumor immunity while preventing systemic toxicity and mitigating irAE.

项目摘要/摘要近年来，癌症免疫疗法领域已经复兴 - 使用单克隆靶向免疫检查点以激活抗癌免疫反应的抗体表明无与伦比的抗体临床成功。这些疗法中的几种现在已获得FDA批准，并且是常规治疗的一部分几种恶性肿瘤方案。尽管免疫治疗方案的总体成功，但现有方式表现出当前研究工作试图克服的并发症：（1）系统交付 Checkpade glocade单克隆抗体导致潜水员和不可预测的免疫相关广告活动（irae），（2）内源性抗肿瘤库的增强反应通常取决于启动抗肿瘤T细胞，在高度免疫抑制肿瘤的情况下或突变低的肿瘤燃烧可能极为罕见，（3）试图结合免疫疗法以促进T细胞反应证明靶向上的肿瘤毒性增加。为了规避毒性和免疫抑制，当代策略专注于开发直接将有效免疫刺激剂传递到肿瘤的方法，局部启动抗肿瘤T细胞以攻击表现出类似抗原剖面的散布转移。桥接这些观察结果，该提案的目标是设计细菌的益生菌菌株，这些细菌有选择地定植结直肠癌（CRC）和局部释放免疫检查点封锁。我们假设这种方法将导致更健壮和多样化的抗肿瘤T细胞免疫，并促进定殖的清除率原发性和转移性结直肠癌病变以及全身增长的CRC衍生灶。主要该提案的创新是在工程益生菌中作为对本地的免疫治疗载体载体释放高剂量免疫检查点封锁。具体而言，拟议的系统具有多个优势当前的治疗策略，包括：（1）免疫疗法的肿瘤特异性产生和可调节的LPS的产生（2）细菌裂解，导致新型免疫疗法和LP的有效释放，（3）新型局部递送免疫治疗药有毒，有毒，（4）益生菌的口服递送定居CRC转移。这项工作旨在改变当前的研究和临床实践范式以克服通过提供独特的车辆来提供本地免疫疗法，目前的免疫疗法局限性刺激抗肿瘤免疫力，同时预防全身毒性并减轻IRAE。