A new immune checkpoint pathway in human bladder cancer

人类膀胱癌的新免疫检查点通路

基本信息

批准号：
10811317
负责人：
Xingxing Zang
金额：
$ 2.38万
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/10811317
关键词：
Acceleration Address Antigen-Presenting Cells Basic Science Biology Blocking Antibodies CD276 gene CD28 gene CD8-Positive T-Lymphocytes CD80 gene CTLA4 blockade CTLA4 gene Cancer Model Cancer Patient Clinical Clinical Management Clinical Research Cytoplasmic Tail Data Development Disease Endogenous Retroviruses FDA approved Family Family member Future Generations Goals Grant Health Human Human Biology Immune Immune checkpoint inhibitor Immunoglobulin Domain Immunoglobulins Immunologist Immunotherapy Killer Cells Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Membrane Minority Mission Molecular Monkeys Mus Natural Killer Cells Oncologist Outcome PD-1/PD-L1 PDL1 inhibitors Parents Pathway interactions Patients Public Health Publishing Rattus Recurrence Reporting Research Research Personnel Research Support Research Training Sampling Signal Transduction Survival Rate T-Lymphocyte Testing Therapeutic Translating Translational Research Treatment Efficacy Tumor Immunity Tumor-infiltrating immune cells United States United States National Institutes of Health Urologist VTCN1 gene Work cancer cell cancer therapy design doctoral student effective therapy immune cell checkpoints immune checkpoint immune checkpoint blockade inhibitor innovation insight member minority student multidisciplinary new therapeutic target novel overexpression programmed cell death ligand 1 programmed cell death protein 1 programs receptor response therapeutic target tool

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.

人类膀胱癌的新免疫检查点通路该提案是对 PAR-19-183（膀胱癌生物学）的回应。膀胱癌是美国最常见的恶性肿瘤之一。过去30年膀胱癌的生存率基本没有变化年。最近，PD-1/PD-L1抑制剂被FDA批准用于治疗治疗转移性膀胱癌患者，但仅对一小部分患者有效约 15-25% 的患者。因此，迫切需要开发新的和治疗膀胱癌的有效方法。开发新型检查点抑制剂，尤其是针对 PD1/PD-L1 和 CTLA-4 途径之外的抑制剂一个有前途的策略，可能对临床产生重大影响人类膀胱癌的治疗。我们这个提案的中心假设是 KIR3DL3-HHLA2 是一种以前未被认识的免疫抑制途径以及人类膀胱癌的新治疗靶点。在我们的指导下发表的临床和基础研究以及我们强有力的初步数据，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 中表达的机制； 2）剖析 KIR3DL3-HHLA2 通路的共抑制功能和信号传导；和 3）针对人类膀胱癌开发新的免疫疗法 KIR3DL3-HHLA2 途径。该提案包括一个综合网络多学科协作研究人员（免疫学家、泌尿科医生、肿瘤学家和生物信息学家）加速转化研究和最大限度地提高未来的临床效益。该项目的成果将揭示新的人类膀胱癌的基础生物学，并将指导合理的治疗开发治疗人类膀胱的新免疫疗法癌症。