Precise Modulation of Immunometabolism to Boost Antibody Therapy in Oral Cancer

精确调节免疫代谢以促进口腔癌的抗体治疗

基本信息

批准号：
10511223
负责人：
Xin Ming
金额：
$ 23.25万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10511223
关键词：
Address Adenosine Antibodies Antibody Therapy Autoimmune Diseases Cancer Patient Cell surface Cells Cetuximab Chemistry Clinical Deamination Development Disease Drug resistance Effector Cell Enzymes Epidermal Growth Factor Receptor FDA approved Failure Goals Immune Immune system Immunity Immunomodulators Immunosuppression Immunotherapeutic agent Immunotherapy In Situ Inosine Ligands Link Malignant Neoplasms Mediating Medicine Metabolic Methods Mouth Neoplasms Mus Neoplasm Metastasis Normal tissue morphology Oral Stage Patients Play Public Health Radiation therapy Regimen Regulatory T-Lymphocyte Relapse Research Resistance Role Safety Sequential Treatment Signal Transduction Specificity Surface System Therapeutic Tissues Toxic effect Translating Tumor Antibodies Tumor Immunity adenosine deaminase anti-PD-L1 antibodies anti-cancer anticancer activity base cancer cell cancer immunotherapy cancer therapy effective therapy extracellular human disease immune activation immune function immunogenic immunoregulation in vivo malignant mouth neoplasm mouse model next generation precision medicine precision oncology programmed cell death ligand 1 programs single-cell RNA sequencing success targeted delivery therapy resistant tumor tumor microenvironment tumor-immune system interactions

项目摘要

” Abstract: The clinical benefit of anti-EGFR antibody, cetuximab, remains suboptimal among patients with oral cancer, and one underlying cause is the failure of this antibody to induce potent anticancer immunity due to immunosuppressive mechanisms within the tumor microenvironments. Elevated levels of adenosine is considered a major immunosuppressive mechanism in healthy tissues and tumors, and it may cause resistance to cetuximab by suppressing innate and adaptive antitumor immunity induced by the antibody. Adenosine deaminase (ADA) catalyzes the degradation of adenosine to inosine and is capable of reversing immunosuppressive effects of adenosine. However, systemic enzyme administration causes autoimmune disorders in normal tissues, where adenosine protects the host from excessive immune activation. We hypothesize that targeted delivery of ADA into oral tumors overcomes adenosine-mediated immunosuppression precisely in the tumors, enhancing the efficacy and safety of cetuximab therapy. Our preliminary studies have shown that targeted delivery of ADA led to localization of ADA on the cell surface EGFR+ oral cancer cells, and the surface-anchored ADA could deplete extracellular adenosine. In an orthotopic mouse model of oral cancer, the targeted delivery resulted in substantial increase in tumoral ADA level compared to non-targeted delivery. In tumor-bearing syngeneic mice, targeted ADA delivery led to reprograming of tumor microenvironments into an immunogenic landscape and resulted in immune-mediated tumor regression when combined with radiation therapy. In this proposal, we will explore immunostimulatory mechanisms of this targeted delivery approach (Aim 1) and will further optimize it by using a bi-targeting method (Aim 2). This project can be directly translated into a targeted cancer immunotherapy to treat patients with oral cancer. By addressing lack of cancer specificity, a main obstacle to the development of next-generation cancer treatments, we will contribute to the use of precision medicine for cancer immunotherapy.

” 抽象的：抗 EGFR 抗体西妥昔单抗在口腔癌患者中的临床益处仍然不理想，一个根本原因是由于肿瘤微环境中的免疫抑制机制，该抗体未能诱导有效的抗癌免疫。腺苷水平升高被认为是一种原因。腺苷是健康组织和肿瘤中的主要免疫抑制机制，可能通过抑制抗体诱导的先天性和适应性抗肿瘤免疫而引起对西妥昔单抗的耐药性。脱氨酶（ADA）催化腺苷降解为肌苷，并且能够逆转腺苷的免疫抑制作用，然而，全身酶给药会导致正常组织中的自身免疫性疾病，而腺苷可以保护宿主免受过度的免疫激活。我们的初步研究表明，口腔肿瘤中的腺苷介导的免疫抑制精确地克服了肿瘤，从而增强了西妥昔单抗治疗的有效性和安全性。 ADA 的递送导致 ADA 定位在 EGFR+ 口腔癌细胞的细胞表面，并且表面锚定的 ADA 可以消耗细胞外腺苷，在口腔癌原位小鼠模型中，与相比，靶向导致肿瘤 ADA 递送水平大幅增加。在荷瘤同基因小鼠中，靶向 ADA 递送导致肿瘤微环境重新编程为免疫原性景观，并与放射结合时导致免疫介导的肿瘤消退。在这个提案中，我们将探索这种靶向递送方法的免疫刺激机制（目标1），并通过使用双靶向方法进一步优化它（目标2），该项目可以直接转化为靶向癌症免疫疗法来治疗。通过解决癌症特异性缺乏这一开发下一代癌症治疗的主要障碍，我们将为癌症免疫治疗中精准医学的使用做出贡献。