Modulation of the tumor microenvironment with probiotic therapies

用益生菌疗法调节肿瘤微环境

• 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
• 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

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.

癌症免疫治疗的最新进展为三阴性患者提供了有希望的治疗选择 乳腺癌（TNBC）。尽管在治疗这些恶性肿瘤方面取得了总体成功， 面临着许多独特的挑战：（1）由于脱靶副作用导致的剂量限制，（2）添加剂毒性 联合治疗，（3）乳腺癌的免疫原性相对较低。为了克服这些局限性， 该提案寻求设计益生菌菌株，选择性地定植于乳腺癌， 释放免疫治疗剂。最终目标是诱导更强大和多样化的抗肿瘤T细胞免疫 并促进清除定植的原发性和转移性乳腺癌病灶， 乳腺癌源性病灶。伴随的项目将首先集中在破译机制，定义了 益生菌菌株E.大肠杆菌Nissle 1917（EcN）的抗体介导的消减方法 并有针对性地敲除基因，以确定调节肿瘤特异性 增长使用合成生物学方法，EcN将被工程化以稳定表达和释放检查点 靶向肿瘤内部局部的CD 47、PD-L1和CTLA-4的抑制剂纳米抗体。促炎细胞因子 将另外表达以促进抗原呈递并增强细胞毒性T细胞应答。 本提案的主要创新之处在于， 肿瘤的益生菌定植，沿着工程益生菌作为免疫递送载体。 具体而言，这种方法与当前的治疗策略相比具有几个优点，包括：（1）识别 新型EcN宿主菌株及其肿瘤定植机制的了解，以进一步改善 在工程化治疗中，（2）免疫治疗剂的肿瘤特异性产生，（3）导致 有效释放新型免疫治疗剂和脂多糖（LPS）佐剂，和（4）局部递送 对全身递送有毒的新免疫增强剂组合。这项工作旨在克服目前 免疫疗法的局限性，通过提供靶向载体来局部递送免疫疗法， 抗肿瘤免疫，同时防止全身毒性和减轻免疫相关的副作用。