Combating melanoma with an attenuated bacterial therapeutic

用减毒细菌疗法对抗黑色素瘤

• 批准号: 10659841
• 负责人: THOMAS A FICHT
• 金额: $ 62.15万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659841
• 关键词: Adoptive Cell Transfers; Animals; Attenuated; Brucella melitensis; Cell-Mediated Cytolysis; Cells; Clinical; Combined Modality Therapy; Data; Development; Effectiveness; Engineering; Evaluation; Goals; Goat; Granzyme; Immune; Immunocompetent; Immunotherapy; Inflammatory; Knowledge; Laboratories; Macaca mulatta; Macrophage; Major Histocompatibility Complex; Mediating; Memory; Microbe; Modeling; Molecular; Mus; Natural Immunity; Outcome; PD-1/PD-L1; PD-L1 blockade; Pathogenesis; Phenotype; Production; Proteins; Publishing; Regulation; Research; Resistance; Role; Safety; Sheep; Signal Transduction; System; T cell therapy; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Tryptophan; Tumor Antigens; Tumor Immunity; Tumor Suppression; Tumor Tissue; Vaccines; Work; adaptive immunity; antigen-specific T cells; cancer immunotherapy; cancer therapy; cytokine; cytotoxic; humanized mouse; hydroxyindole; immune checkpoint blockade; immune modulating agents; immunomodulatory strategy; immunoregulation; improved; innovation; melanoma; microbial; microbiota; mutant; neoplasm immunotherapy; neoplastic cell; nonhuman primate; novel; novel therapeutic intervention; permissiveness; recruit; therapeutic candidate; tissue culture; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor-immune system interactions; vaccine discovery

PROJECT SUMMARY/ABSTRACT Immunotherapy has led to impressive advances in the treatment of melanoma; yet, its clinical outcomes remain limited by various pathophysiological factors, such as the suppressive tumor microenvironment (TME), and the key molecular determinants of antitumor immunity remain elusive. Discovering novel and effective immunomodulatory targets and the mechanisms involved would lead to innovative strategies for enhancing the effectiveness of current cancer immunotherapy. Such discoveries are urgently needed. Previous work from this research team showed that attenuated Brucella melitensis mutants (i.e., BmΔvjbR) substantially improved the suppressive TME, and the use of BmΔvjbR significantly enhanced adoptive cell transfer (ACT)-based immunotherapy. Intriguingly, treatment with BmΔvjbR resulted in the accumulation of this safe, attenuated mutant in tumor tissues, polarized M1 macrophages (Mφ), and promoted T cell activation and the production of proinflammatory cytokines; moreover, combining BmΔvjbR treatment with an ACT of tumor antigen (Ag)-specific T cells significantly enhanced the accumulation of M1 Mφ and T cell persistence in tumor tissues. In addition, metabolite signals from the microbiota instruct T cell fate and function; tryptophan (Trp) metabolites (e.g., hydroxyindoles, HI) promote T cell activity. Recent preliminary studies show that compared with BmΔvjbR, a BmΔvjbR-HI strain that produces HI dramatically improved production of tumor-killing cytokines (e.g., TNFa, IFNg and Granzyme B), accumulated in melanoma tissues, and suppressed tumor growth. It also dramatically improved animal survival. Based on these exciting preliminary data, this research team hypothesizes that engineered BmΔvjbR-HI will greatly improve the TME, and that targeting BmΔvjbR-HI can enhance the efficacy of immunotherapy for melanoma. The overall goals of this multiple-PI project are to understand the role and mechanism of BmΔvjbR-HI in modulating TME and immunotherapy resistance, and to establish this microbe as a novel immunomodulatory target. This project will pursue the following three highly related and interactive specific aims: (1) Determine the role and mechanism of BmΔvjbR-HI in modulating innate immunity; (2) Determine the role and mechanism of BmΔvjbR-HI in regulating adaptive immunity; and (3) Identify the impact of BmΔvjbR-HI on melanoma immunotherapy. This proposal combines the strength of cancer immunology in the Song laboratory with the expertise of microbial pathogenesis in the de Figueiredo laboratory and the knowledge of vaccine discovery in the Ficht laboratory. The research team has already established a humanized mouse (NOD-scid IL2rgnull) tumor model in the laboratory as well as murine syngeneic systems for the proposed studies. Therefore, they are poised to accomplish the above aims. Successful completion of this project would not only reveal engineered BmΔvjbR-HI as a novel immunomodulatory agent to improve TME and elucidate its mechanism of action, but also, provide new therapeutic strategies to significantly enhance current cancer immunotherapy.

项目摘要/摘要 免疫疗法在治疗黑色素瘤方面取得了令人印象深刻的进展;然而，其临床结果仍然存在 受各种病理生理因素的限制，如抑制性肿瘤微环境（TME）和肿瘤微环境（TME）。 抗肿瘤免疫的关键分子决定因素仍然难以捉摸。发现新颖有效 免疫调节靶点和所涉及的机制将导致创新的战略， 目前癌症免疫治疗的有效性。这些发现是迫切需要的。以前的工作从这个 研究小组显示减毒羊种布鲁氏菌突变体（即，BmΔvjbR）显著改善了 抑制性TME和BmΔvjbR的使用显著增强了基于过继细胞转移（ACT）的 免疫疗法有趣的是，BmΔvjbR治疗导致这种安全的、减毒的 肿瘤组织中的突变体，极化M1巨噬细胞（Mφ），并促进T细胞活化和产生 促炎细胞因子;此外，将BmΔvjbR治疗与肿瘤抗原（Ag）特异性ACT结合， T细胞显著增强肿瘤组织中M1 Mφ的积聚和T细胞持久性。此外，本发明还提供了一种方法， 来自微生物群的代谢物信号指示T细胞命运和功能;色氨酸（Trp）代谢物（例如， 羟基吲哚，HI）促进T细胞活性。最近的初步研究表明，与BmΔvjbR相比， 产生HI的BmΔvjbR-HI菌株显著提高了肿瘤杀伤细胞因子（例如，TNF α， IFNg和粒酶B）在黑素瘤组织中积累，并抑制肿瘤生长。它还极大地 提高动物生存率。基于这些令人兴奋的初步数据，该研究小组假设， 工程化的BmΔvjbR-HI将大大改善TME，靶向BmΔvjbR-HI可以提高疗效 免疫治疗黑色素瘤这个多PI项目的总体目标是了解角色， BmΔvjbR-HI调节TME和免疫治疗耐药性的机制，并确定该微生物为 一种新的免疫调节靶点。本项目将追求以下三个高度相关和互动 具体目的：（1）明确BmΔvjbR-HI在天然免疫调节中的作用及机制;（2） 确定BmΔvjbR-HI在调节获得性免疫中的作用和机制;（3）确定BmΔvjbR-HI对获得性免疫的影响 BmΔvjbR-HI在黑色素瘤免疫治疗中的作用。这项建议结合了癌症免疫学的力量， Song实验室在de Figueiredo实验室和 Ficht实验室发现疫苗的知识。研究团队已经建立了人性化的 小鼠（NOD-scid IL 2 rgnull）肿瘤模型以及小鼠同基因系统的建议 问题研究因此，他们准备实现上述目标。该项目的成功完成将 不仅揭示了工程化的BmΔvjbR-HI作为一种新型的免疫调节剂，以改善TME，并阐明其 作用机制，而且还提供了新的治疗策略，以显着提高目前的癌症 免疫疗法。