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A New Immune Checkpoint Pathway in Human Bladder Cancer

人类膀胱癌的新免疫检查点途径

基本信息

批准号：
10583686
负责人：
Xingxing Zang
金额：
$ 54.55万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
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：
2022-12-01 至 2027-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10583686
关键词：
Acceleration Basic Science Biology Bladder CD276 gene CD28 gene CD8-Positive T-Lymphocytes CD80 gene CTLA4 gene Cells Clinical Clinical Management Clinical Research Computational Biology Coupled Cytoplasmic Tail Data Development Disease Endogenous Retroviruses FDA approved Family Family member Future Human Human Biology ITIM Immune Immune checkpoint inhibitor Immunoglobulin Domain Immunoglobulins Immunologist Immunosuppression Immunotherapy Killer Cells Knowledge Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Medical Oncology Membrane Mission Modeling Molecular Monkeys Monoclonal Antibodies Mus Natural Killer Cells Oncologist Outcome PD-1/PD-L1 PDL1 inhibitors Pathway interactions Patients Phylogenetic Analysis Public Health Publishing Qualifying Rattus Reagent Recurrence Research Research Personnel Resources Signal Transduction Survival Rate System Testing Translating Translational Research Treatment Efficacy Trees United States United States National Institutes of Health Urologist Urology VTCN1 gene Work anti-PD-L1 antibodies cancer type checkpoint inhibition combinatorial effective therapy experience humanized mouse immune checkpoint inhibitor innovation insight member mouse model multidisciplinary new therapeutic target novel overexpression programmed cell death ligand 1 programmed cell death protein 1 programs receptor response therapeutic target

项目摘要

A new immune checkpoint pathway in human bladder cancer This proposal is in response to the PAR-19-183 (Biology of Bladder Cancer). Bladder cancer is one of the most common malignancies in the United States. The survival rate of bladder cancer has been largely unchanged for the last 30 years. Very recently PD-1/PD-L1 inhibitors were approved by FDA for the treatment of patients with metastatic bladder cancer, but worked in only a subset of ~15-25% of patients. Thus, there is a pressing need to develop new and effective treatment for bladder cancer. Developing novel checkpoint inhibitors, especially inhibitors that target outside the PD1/PD-L1 and CTLA-4 pathways, is a promising strategy and may potentially have high impact in clinical management of human bladder cancer. Our central hypothesis of this proposal is that KIR3DL3-HHLA2 is a previously unrecognized immunosuppressive pathway as well as a novel therapeutic target in human bladder cancer. Guided by our published clinical and basic research and our strong preliminary data, we will pursue following specific aims: 1) Investigate the cellular and molecular mechanisms of HHLA2 expression in human bladder cancer and APCs; 2) Dissect co-inhibitory function and signaling of the KIR3DL3-HHLA2 pathway; and 3) Develop new immunotherapies against human bladder cancer by targeting the KIR3DL3-HHLA2 pathway. This proposal comprises an integrated network of multi-disciplinary collaborative investigators (immunologists, urologists, oncologists, and bioinformaticians) to accelerate translational research and maximize future clinical benefits. The outcomes of this project will reveal new fundamental biology of human bladder cancer and will guide the rational development of new immunotherapies for the treatment of human bladder cancer.

膀胱癌中一种新的免疫检查点途径这项建议是对PAR-19-183(膀胱癌生物学)的响应。膀胱癌是美国最常见的恶性肿瘤之一。膀胱癌的存活率在过去30年中基本没有变化。好几年了。最近，PD-1/PD-L1抑制剂被FDA批准用于转移性膀胱癌患者的治疗，但只在一个子集中有效约15%-25%的患者。因此，迫切需要开发新的和有效治疗膀胱癌。开发新的检查点抑制剂，尤其是靶向PD1/PD-L1和CTLA-4通路外的抑制剂，是一种很有前途的策略，可能会在临床上产生很大的影响人类膀胱癌的管理。我们对这一提议的中心假设是 KIR3DL3-HHLA2是一种先前未知的免疫抑制途径以及人类膀胱癌的新治疗靶点。由我们的指导已发表的临床和基础研究以及我们强大的初步数据，我们将追求以下具体目标：1)研究细胞和分子 HHLA2在人膀胱癌和APC中的表达机制剖析KIR3DL3-HHLA2通路的共同抑制功能和信号转导； 3)开发针对人膀胱癌的新的免疫疗法 KIR3DL3-HHLA2途径。这项建议包括一个综合网络，多学科协作调查人员(免疫学家、泌尿科医生、肿瘤学家和生物信息学家)来加速翻译研究和最大限度地提高未来的临床效益。这个项目的成果将揭示出新的并将指导人类膀胱癌的基础生物学研究治疗人膀胱疾病的新型免疫疗法的研究进展癌症。