Modulation of the tumor microenvironment with probiotic therapies

用益生菌疗法调节肿瘤微环境

基本信息

批准号：
10610407
负责人：
Nicholas Arpaia
金额：
$ 55.19万
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：
2020-04-03 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610407
关键词：
4T1 Adjuvant Adverse effects Anaerobic Bacteria Antibiotics Antibodies Antigen Presentation Antitumor Response Automobile Driving Bacteria Bar Codes Biodistribution Bone Tissue Breast Cancer Model Breast Cancer cell line CD47 gene CTLA4 gene Cells Cessation of life Circulation Clinical Trials Combined Modality Therapy Cytolysis Cytotoxic T-Lymphocytes Defect Disease Distant Metastasis Dose Engineered Probiotics Engineering Environment Escherichia coli Face Future Genetic Genetic Transcription Goals Growth Homing Immune Immune checkpoint inhibitor Immune system Immunity Immunologics Immunotherapeutic agent Immunotherapy In complete remission Inflammatory Injections Intelligence Interleukin-12 Intravenous Kinetics Knock-out Lesion Libraries Lipopolysaccharides Local Therapy Luciferases Lymphoma Malignant Neoplasms Measurement Mediating Medicine Metastatic Neoplasm to the Liver Metastatic breast cancer Modeling Molecular Monitor Mus Neoplasm Metastasis Neutrophil Infiltration Oral Oral Administration Organ Pathway interactions Patient-Focused Outcomes Patients Peptides Phagocytes Primary Lesion Primary Neoplasm Probiotics Production Property Reporting Soft tissue sarcoma Solid Neoplasm Source Specificity Stains Streptococcus T cell response T-Lymphocyte Therapeutic Toxic effect Translations Tropism Tumor Antigens Tumor Immunity Tumor-Infiltrating Lymphocytes Unresectable Woman Work antigen-specific T cells cancer immunotherapy cancer infiltrating T cells cancer therapy chemotherapy complement system cytokine delivery vehicle density design efficacy evaluation host-microbe interactions immunogenicity improved in vivo imaging system innovation intravenous administration knockout gene malignant breast neoplasm microbial mortality mouse model mutant nanobodies neoantigens novel pre-clinical preclinical development prevent probiotic therapy programmed cell death ligand 1 programs safety assessment side effect success synergism synthetic biology systemic toxicity targeted treatment transcription factor triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

Recent advances in cancer immunotherapy have provided promising treatment options for patients with triple-negative breast cancer (TNBC). Despite overall success in treating these malignancies, immunotherapeutic approaches face a number of unique challenges: (1) dose limitation due to off-target side effects, (2) additive toxicity of combination therapies, (3) and relatively low immunogenicity of breast cancer. To overcome these limitations, this proposal seeks to engineer probiotic strains of bacteria that selectively colonize breast cancer and locally release immunotherapeutics. The ultimate goal is to elicit more robust and diversified antitumor T cell immunity and promote the clearance of colonized primary and metastatic breast cancer lesions and systemically growing breast cancer-derived foci. The accompanying project will first focus on deciphering mechanisms that define the intratumoral tropism of the probiotic strain E. coli Nissle 1917 (EcN) by using antibody-mediated depletion approaches and targeted genetic knockouts to pinpoint host immunological pathways that regulate tumor-specific growth. Using synthetic biology approaches, EcN will then be engineered to stably express and release checkpoint inhibitor nanobodies targeting CD47, PD-L1, and CTLA-4 locally inside of tumors. Pro-inflammatory cytokines will additionally be expressed to promote antigen presentation and enhance cytotoxic T cell responses. The primary innovations of this proposal are in the combined approach of both developing a better understanding of probiotic colonization of tumors, along with engineering probiotics as an immunotherapeutic delivery vector. Specifically, this approach has several advantages over current therapeutic strategies, including: (1) identification of novel EcN host strains and mechanistic understanding of their tumor colonization for further improvements in engineered therapies, (2) tumor-specific production of immunotherapeutics, (3) bacteria lysis that leads to effective release of novel immunotherapeutics and lipopolysaccharides (LPS) adjuvant, and (4) local delivery of novel immunotherapeutic combinations that are toxic to deliver systemically. This work seeks to overcome current limitations of immunotherapies, by providing a targeted vehicle to locally deliver immunotherapies that stimulate antitumor immunity while preventing systemic toxicity and mitigating immune-related adverse effects.

癌症免疫疗法的最新进展为三个阴性患者提供了有希望的治疗选择乳腺癌（TNBC）。尽管总体上成功治疗这些恶性肿瘤，但免疫治疗方法面临许多独特的挑战：（1）由于靶向副作用而引起的剂量限制，（2）加性毒性联合疗法的（3）和乳腺癌的免疫原性相对较低。为了克服这些限制，该建议旨在设计细菌的益生菌菌株，这些细菌有选择地定居乳腺癌和本地释放免疫治疗药。最终目标是引起更健壮和多样化的抗肿瘤T细胞免疫力并促进定植原发性和转移性乳腺癌病变的清除，并全身增长乳腺癌衍生的焦点。随附的项目将首先关注定义的解密机制使用抗体介导的耗竭方法并针对遗传基因敲除，以查明调节肿瘤特异性的宿主免疫途径生长。使用合成生物学方法，将对ECN进行设计以稳定表达和释放检查点针对CD47，PD-L1和CTLA-4局部局部内部内部抑制剂纳米体。促炎性细胞因子还将表达以促进抗原表现并增强细胞毒性T细胞反应。该提案的主要创新是在建立更好理解的联合方法中肿瘤的益生菌定殖，以及工程益生菌作为免疫治疗递送载体。具体而言，这种方法比当前的治疗策略具有多个优点，包括：（1）识别新型ECN宿主菌株和对肿瘤定植的机理理解以进一步改善在工程疗法中，（2）免疫疗法的肿瘤特异性产生，（3）导致细菌裂解有效释放新型免疫疗法和脂多糖（LPS）佐剂，以及（4）局部递送新型免疫治疗组合有毒，有毒。这项工作旨在克服当前免疫疗法的局限性，通过提供靶向车辆来局部提供刺激的免疫疗法抗肿瘤免疫力，同时预防全身毒性并减轻与免疫相关的不良反应。