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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.

总结

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：
10.1101/2023.03.01.530608
发表时间：
2023
期刊：
bioRxiv : the preprint server for biology
影响因子：
0
作者：
Muthana,MuslehM;Du,Xuexiang;Liu,Mingyue;Wang,Xu;Wu,Wei;Ai,Chunxia;Su,Lishan;Zheng,Pan;Liu,Yang
通讯作者：
Liu,Yang