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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：
10556326
负责人：
Nicholas Arpaia
金额：
$ 59.97万
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/10556326
关键词：
Adjuvant Adverse effects Antibodies Antigen-Presenting Cells Area Bacteria Body Temperature Body Weight CD47 gene CTLA4 gene Cancer Model Clinical Clinical Trials Clone Cells Colorectal Colorectal Cancer Colorectal Neoplasms Combination immunotherapy Cytolysis Distant Dose Dose Limiting Engineered Probiotics Engineering Escherichia coli Evaluation Excision 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 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 Promotion Vascularization Work antagonist anti-cancer anti-tumor immune response autoimmune toxicity cancer immunotherapy cancer therapy clinical practice colon cancer patients colorectal cancer metastasis comparative efficacy cytokine delivery vehicle exhaustion immune cell infiltrate 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.

项目概要/摘要近年来，随着单克隆抗体的使用，癌症免疫治疗领域出现了复兴。针对免疫检查点以激活抗癌免疫反应的抗体表现出无与伦比的优势临床成功。其中几种疗法现已获得 FDA 批准，并成为常规治疗的一部分多种恶性肿瘤的治疗方案。尽管免疫治疗方案取得了总体成功，但现有的目前的研究工作试图克服这些模式带来的复杂性：(1) 系统性递送检查点阻断单克隆抗体导致多种且不可预测的免疫相关不良事件（irAE），（2）内源性抗肿瘤库的增强反应通常依赖于前体的存在引发的抗肿瘤 T 细胞，在高度免疫抑制肿瘤或低突变肿瘤的情况下负担可能极其罕见，并且 (3) 尝试结合免疫疗法来额外增强 T 细胞反应表现出增加的靶向、脱肿瘤毒性。因此，为了规避毒性和免疫抑制，当代策略的重点是开发将有效的免疫刺激剂直接输送到肿瘤中的方法，局部启动抗肿瘤 T 细胞攻击具有相似抗原特征的播散性转移瘤。桥接根据这些观察结果，该提案的目标是设计选择性定植的益生菌菌株结直肠癌（CRC）和局部释放免疫检查点封锁。我们假设这种方法将产生更强大和多样化的抗肿瘤 T 细胞免疫，并促进定植的清除原发性和转移性结直肠癌病变以及系统性生长的结直肠癌衍生病灶。初级该提案的创新之处在于将益生菌设计为局部免疫治疗递送载体释放高剂量免疫检查点封锁。具体来说，所提出的系统相比之下有几个优点：目前的治疗策略包括：（1）肿瘤特异性免疫疗法和LPS佐剂的生产， (2) 细菌裂解，导致新型免疫治疗药物和 LPS 的有效释放，(3) 新型免疫治疗药物的局部递送全身给药具有毒性的免疫治疗药物，以及（4）选择性口服益生菌定植 CRC 转移灶。这项工作旨在改变当前的研究和临床实践范式，以克服通过提供一种独特的载体来局部提供免疫疗法，克服了目前免疫疗法的局限性刺激抗肿瘤免疫力，同时预防全身毒性并减轻 irAE。