Targeted Anchoring Ecto-enzyme on Cancer Cell Surface to Enhance Antibody Therapy in Breast Cancer

靶向锚定癌细胞表面的胞外酶以增强乳腺癌的抗体治疗

基本信息

批准号：
10353727
负责人：
Xin Ming
金额：
$ 21.74万
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：
2021
资助国家：
美国
起止时间：
2021-12-10 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10353727
关键词：
Address Adenosine Antibodies Antibody Therapy Breast Cancer Cell Cell Lineage Cell surface Cells Chemistry Clinical Cytometry Deamination Development Disease ERBB2 gene Effector Cell Enzymes FDA approved Goals Immune Immunity Immunomodulators Immunosuppression Immunotherapeutic agent Immunotherapy In Situ Inosine Link Malignant Neoplasms Mediating Medicine Methods Mus Neoplasm Metastasis Normal tissue morphology Patients Public Health Regimen Regulatory T-Lymphocyte Research Resistance Safety Sequential Treatment Specificity Surface Therapeutic Toxic effect Translating Trastuzumab Tumor Antibodies Tumor Immunity Tyrosine Kinase Inhibitor Ubiquitination adenosine deaminase anti-cancer anticancer activity base cancer cell cancer immunotherapy extracellular human disease immune activation immune function immunoregulation in vivo lapatinib malignant breast neoplasm next generation precision oncology prevent success targeted delivery therapy resistant tumor tumor microenvironment tumor-immune system interactions

项目摘要

Abstract: Although the anti-HER2 antibody, trastuzumab, has been the mainstay of therapy for HER2+ breast cancer (BC), its clinical benefit remains heterogeneous among HER2+ patients and metastatic HER2+ BC remains generally incurable. The final success of HER2 antibody therapy relies on the induction of anticancer immunity, but this is limited by immunosuppressive mechanisms posed by the tumor microenvironment (TME), resulting in treatment resistance, metastasis, and ultimately lethal BC. Elevated adenosine level is considered a major immunosuppressive mechanism in the TME, causing resistance to trastuzumab by suppressing innate and adaptive antitumor immunity induced by the antibody. Adenosine deaminase (ADA) catalyzes the deamination of adenosine and is capable of reversing immunosuppressive activities of adenosine. However, systemic ADA administration causes toxicity in normal tissues, where adenosine protects the host from excessive immune activation. We hypothesize that targeted anchoring of ADA on HER2+ BC cell surface reprograms immunometabolism in the TME, enhancing the efficacy and safety of HER2-directed immunotherapy. We have developed a highly cancer specific targeting approach to deliver ADA to the surface of HER2+ BC cells. Targeted ADA delivery with an anti-HER2 antibody led to localization of ADA on the cell surface of HER2+ BC cells, and the surface-anchored ADA was capable of depleting adenosine. In tumor-bearing syngeneic mice, HER2-targeted delivery resulted in 5.6-fold increase in tumoral ADA level compared to free ADA administration. Targeted ADA delivery led to TME reprograming into an immunostimulatory landscape and resulted in immune-mediated tumor regression. In the proposed studies, we will elucidate the mechanisms of TME reprograming by surface ADA anchoring (Aim 1) and will develop an approach to enhance surface ADA anchoring by combination with a tyrosine kinase inhibitor (Aim 2). This project can be directly translated into a targeted cancer immunotherapy to treat patients with HER2+ BC. By addressing lack of disease specificity, a main obstacle to the development of next-generation immunotherapeutic regimens, we will contribute to the use of precision medicine for cancer immunotherapy.

抽象的：尽管抗HER2抗体Trastuzumab一直是HER2+乳腺癌（BC）治疗的支柱，但其临床益处在HER2+患者和转移性HER2+ BC中仍然是异质的。 HER2抗体疗法的最终成功取决于抗癌免疫的诱导，但这受到肿瘤微环境（TME）产生的免疫抑制机制的限制，导致治疗耐药性，转移性，最终导致杀伤力。升高的腺苷水平被认为是TME中的主要免疫抑制机制，通过抑制抗体诱导的先天和适应性抗肿瘤免疫来抗性曲妥珠单抗。腺苷脱氨酶（ADA）催化腺苷的脱氨酸，并能够逆转腺苷的免疫抑制活性。然而，全身性ADA给药会在正常组织中引起毒性，在正常组织中，腺苷可保护宿主免疫过度激活。我们假设ADA在HER2+ BC细胞表面上的靶向锚定在TME中的免疫代谢，从而增强了HER2定向免疫疗法的功效和安全性。我们已经开发了一种高度癌症特异性的靶向方法，可以将ADA传递到HER2+ BC细胞的表面。具有抗HER2抗体的靶向ADA递送导致ADA在HER2+ BC细胞的细胞表面定位，而表面锚定的ADA能够耗尽腺苷。与自由给药相比，在含有肿瘤的同性小鼠中，靶向HER2靶向的递送使肿瘤ADA水平增加了5.6倍。靶向的ADA递送导致TME重编程为免疫刺激景观，并导致免疫介导的肿瘤消退。在拟议的研究中，我们将通过表面ADA锚定（AIM 1）阐明TME重编程的机理（AIM 1），并将开发一种通过与酪氨酸激酶抑制剂联合使用的方法来增强表面ADA锚定（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HER2+ BC患者。通过解决缺乏疾病特异性，这是下一代免疫治疗方案发展的主要障碍，我们将有助于将精密医学用于癌症免疫疗法。