Preserving CTLA-4 immune checkpoint for safer and more effective cancer immunotherapy

保留 CTLA-4 免疫检查点以实现更安全、更有效的癌症免疫治疗

基本信息

批准号：
10669173
负责人：
Lishan Su
金额：
$ 51.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-07 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669173
关键词：
Ablation Address Adverse effects Adverse event Affect Alternative Splicing Antibodies Autoimmune Autoimmune Diseases Autoimmunity Binding CTLA4 gene CTLA4-Ig Cancer Patient Cell surface Clinic Clinical Combined Modality Therapy Data Engineering Exhibits Experimental Models Foundations Genetic Human Immune Targeting Immune checkpoint inhibitor Immunologics Immunooncology Immunotherapy Knock-in Link Malignant Neoplasms Malignant neoplasm of lung Marketing Mediating Membrane Modeling Molecular Monoclonal Antibodies Mus PD-1/PD-L1 Pathogenesis Patients Pre-Clinical Model Prevention Proteins Publishing Quality of life Recycling Regulatory T-Lymphocyte Research Research Personnel Role Severities Testing Therapeutic Therapeutic Effect Toxic effect Treatment Efficacy Tumor Immunity Work anti-CTLA4 anti-CTLA4 antibodies anti-PD-1 cancer immunotherapeutics cancer immunotherapy cancer therapy compliance behavior effective therapy immune checkpoint in vivo interest ipilimumab melanoma mouse model mutant novel preservation prevent programmed cell death protein 1 prophylactic therapy adverse effect tumor microenvironment

项目摘要

Summary Combination therapy with anti-CTLA-4 and anti-PD-1 mAbs has emerged as the most potent and durable cancer immunotherapy. However, the autoimmune adverse effect associated with the combination therapy is considerably more severe, with 50-90% of melanoma patients developing grade 3 and 4 immunotherapy-related adverse effect. A major challenge in cancer immunotherapy is how to reduce adverse effects of the combination therapy without affecting therapeutic efficacy. This is in part related to the fact that the mechanism by which combination therapy exacerbate irAE is not well understood. To address this issue, we have developed a novel model in which combination therapy with anti-mouse PD-1 in conjunction with either Ipilimumab or Tremelizumab recapitulates the severe irAE observed in clinic. Importantly, different anti- human CTLA4 antibodies differ dramatically in irAE in this preclinical model. We have carried out extensive preliminary studies to elucidate the molecular basis of irAE-prone vs non-prone antibodies and have shown the antibody-mediated degradation of membrane-associated CTLA-4 as a major feature of irAE-prone antibodies. Meanwhile, it has long been established that soluble CTLA-4 (sCTLA4) molecule is protective against autoimmune diseases in the mice. We have obtained data that showed strong correlation between the levels of sCTLA4 and irAE in the clinic. We further established a striking correlation between high binding to soluble CTLA4 protein and the severity of irAE in human CTLA4KI mice. Based on these unexpected observations and the strong therapeutic effect of CTLA4-Fc (Abatacept, marketed as Orencia) for autoimmune diseases including irAE, we hypothesize that both cell surface and sCTLA-4 confers protection against irAE and that sCTLA4 that evades clearance by irAE-inducing anti-CTLA-4 antibodies is a potential therapeutic for prevention and treatment of irAE. Our proposal challenges the prevailing paradigm that autoimmunity and cancer immunity are based on the same mechanism and thus intrinsically linked. More importantly, our work will have a transforming impact in immune-oncology research, as it may offer prophylactic and treatment for irAEs associated with the most effective immunotherapy in use in the clinic.

概括抗 CTLA-4 和抗 PD-1 mAb 的联合治疗已成为最有效和最有效的治疗方法。持久的癌症免疫疗法。然而，与联合用药相关的自身免疫不良反应治疗要严重得多，50-90% 的黑色素瘤患者发展为 3 级和 4 级免疫治疗相关的不良反应。癌症免疫治疗的一个主要挑战是如何减少不良反应联合治疗的效果不影响治疗效果。这部分与以下事实有关：联合治疗加剧 irAE 的机制尚不清楚。为了解决这个问题，我们开发了一种新模型，其中抗小鼠 PD-1 联合治疗 Ipilimumab 或 Tremelizumab 概括了临床中观察到的严重 irAE。重要的是，不同的抗在此临床前模型中，人 CTLA4 抗体在 irAE 方面存在显着差异。我们开展了广泛的初步研究阐明了易产生 irAE 抗体与不易产生 irAE 抗体的分子基础，并表明抗体介导的膜相关 CTLA-4 降解是易产生 irAE 的抗体的主要特征。同时，人们早已确定可溶性 CTLA-4 (sCTLA4) 分子可以预防小鼠自身免疫性疾病。我们获得的数据显示各级别之间存在很强的相关性 sCTLA4 和 irAE 在临床中的应用。我们进一步建立了高结合与可溶性之间的显着相关性 CTLA4 蛋白和人类 CTLA4KI 小鼠中 irAE 的严重程度。基于这些意想不到的观察和 CTLA4-Fc（Abatacept，商品名 Orencia）对自身免疫性疾病的强大治疗作用包括 irAE，我们假设细胞表面和 sCTLA-4 都具有针对 irAE 的保护作用，并且 sCTLA4 可以逃避 irAE 诱导的抗 CTLA-4 抗体的清除，是一种潜在的治疗方法 irAE 的预防和治疗。我们的提案挑战了自身免疫和癌症免疫所基于的普遍范式相同的机制，因此具有内在的联系。更重要的是，我们的工作将产生变革性的影响在免疫肿瘤学研究中，因为它可以为与大多数相关的 irAE 提供预防和治疗临床上使用有效的免疫疗法。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment.

CTLA-4 抗体-药物偶联物揭示了与调节性 T 细胞损伤相关的 B 淋巴细胞的自体破坏。

DOI：
发表时间：
2023-08-29
期刊：
影响因子：
0
作者：
Muthana, Musleh M;Du, Xuexiang;Liu, Mingyue;Wang, Xu;Wu, Wei;Ai, Chunxia;Su, Lishan;Zheng, Pan;Liu, Yang
通讯作者：
Liu, Yang

CTLA-4 antibody-drug conjugate reveals autologous destruction of B-lymphocytes associated with regulatory T cell impairment.

CTLA-4 抗体-药物偶联物揭示了与调节性 T 细胞损伤相关的 B 淋巴细胞的自体破坏。

DOI：
发表时间：
2023-12-21
期刊：
影响因子：
7.7
作者：
Muthana, Musleh M;Du, Xuexiang;Liu, Mingyue;Wang, Xu;Wu, Wei;Ai, Chunxia;Su, Lishan;Zheng, Pan;Liu, Yang
通讯作者：
Liu, Yang