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：
10643886
负责人：
Xin Ming
金额：
$ 19.38万
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/10643886
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 Immunity adenosine deaminase anti-PD-L1 antibodies anti-cancer anticancer activity 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.

透明抽象的：抗EGFR抗体Cetuximab的临床益处在口腔癌患者中仍然是最佳的，而潜在的原因是该抗体未能在肿瘤微环境中诱导潜在的抗癌免疫异常。腺苷的水平升高被认为是健康组织和肿瘤中主要的免疫抑制机制，它可能通过抑制由抗体诱导的先天和适应性抗肿瘤免疫组织化学而对西替昔单抗的抗性。腺苷死亡酶（ADA）催化腺苷降解为肌苷，能够逆转腺苷的免疫抑制作用。然而，全身性酶给药会引起正常组织中的自身免疫性疾病，在这种组织中，腺苷可保护宿主免受过多的免疫激活。我们假设将ADA的靶向递送到口腔肿瘤中，以克服腺苷介导的免疫抑制精确地在肿瘤中，增强了西妥昔单抗治疗的有效性和安全性。我们的初步研究表明，ADA的靶向递送导致ADA在细胞表面EGFR+口腔癌细胞上定位，并且表面锚定的ADA可以完全扩大细胞外腺苷。在原位小鼠口腔癌模型中，与非靶向递送相比，靶向递送导致肿瘤ADA水平的大幅增加。在含有肿瘤的同性小鼠中，有针对性的ADA递送导致肿瘤微环境重编程为免疫原性景观，并在与放射治疗结合使用时导致免疫介导的肿瘤回归。在此提案中，我们将探讨这种有针对性的输送方法的免疫刺激机制（AIM 1），并通过使用双向目标方法进一步优化它（AIM 2）。该项目可以直接转化为有针对性的癌症免疫疗法，以治疗口腔癌患者。通过解决缺乏癌症特异性，这是下一代癌症治疗的发展的主要障碍，我们将有助于将精密医学用于癌症免疫疗法。