Project 3: Modeling and overcoming resistance to melanoma immunotherapy

项目 3：建模并克服黑色素瘤免疫疗法的耐药性

基本信息

批准号：
10693132
负责人：
ANTONI RIBAS
金额：
$ 50.76万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
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：
2020-09-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693132
关键词：
Activated Natural Killer Cell Adoptive Transfer Agonist Animals Antibodies Antigen Presentation Award Bioinformatics Biology Biometry Biopsy CRISPR/Cas technology Cell Line Cells Chemosensitization Clinical Trials Collaborations Combined Modality Therapy Data Epigenetic Process Exclusion Gene Expression Genetic Goals Human Immune Immunotherapy In Vitro Interferon Activation Interferon Receptor Interferon Type II Interferons JAK1 gene JAK2 gene Knock-out Knowledge Laboratories Laboratory Research Learning Malignant Neoplasms Mediating Melanoma Cell Minority Modeling Molecular Molecular Biology Mus Mutation Natural Killer Cells Nivolumab Pathologic Pathology Pathway interactions Patient Care Patients Phosphotransferases Positioning Attribute Process Reagent Reporting Research Research Personnel Resistance Resistance Process Role Sampling T-Lymphocyte Testing Tissues Toll-like receptors cancer cell cancer immunotherapy genetic resistance improved in vivo Model inhibitor loss of function loss of function mutation melanoma mouse model non-genetic participant enrollment pharmacologic prevent programs rational design resistance mechanism response standard of care statistics targeted treatment therapy resistant tumor

项目摘要

PROJECT 3 ABSTRACT We have started to make progress in defining mechanisms that lead to primary and acquired resistance to anti- PD-1/L1 therapy at the molecular level. In this Project, we propose to characterize their biology, discover how to overcome resistance based on mechanistic understanding, and study how this knowledge can improve patient care. In Aim 1, we will develop in vitro and in vivo models to study the biology of molecularly-defined resistance mechanisms with the goal of providing full mechanistic understanding of how they mediate resistance. This is based on our discovery of homozygous loss of function (LoF) mutations in the interferon (IFN) receptor pathway and in the antigen presenting machinery (APM) in biopsies of patients with primary and acquired resistance to PD-1 blockade therapy, both confirmed with data from other groups. With this information, we will be in the position to test combination approaches to overcome resistance to anti-PD-1/L1 therapy. These include approaches aimed at inducing a local IFN response that may activate this pathway downstream, such as toll-like receptor (TLR) or MDA5 agonists in JAK1/2 knockout models, and activating natural killer (NK) cells in B2M knockout models. In Aim 2, we will study a new cancer cell-intrinsic mechanisms of T cell exclusion mediated by the expression of the p21 associated kinase 4 (PAK4), which we have recently uncovered by comparing gene expression in T cell-rich versus T cell-poor biopsies of patients with melanoma on therapy with anti-PD-1. We will examine the mechanisms leading to T cell exclusion induced by PAK4 in mouse models, and we will analyze the mechanisms in biopsies obtained from patients enrolled in a clinical trial combining the PAK4 inhibitor KPT-9274 and the anti-PD-1 antibody nivolumab. Sample analyses for the two aims will benefit from the collaboration with investigators from the other two projects and cores of this P01. In conclusion, this Project will analyze defined mechanisms of therapeutic resistance to cancer immunotherapy to provide improved understanding on their effects, and show how to overcome the resistance using rationally designed combination studies. 1

项目 3 摘要我们已经开始在定义导致原发性和获得性抗药性抵抗的机制方面取得进展。分子水平的PD-1/L1治疗。在这个项目中，我们建议描述它们的生物学特征，发现如何克服基于机械理解的阻力，并研究如何改进这些知识病人护理。在目标 1 中，我们将开发体外和体内模型来研究分子定义的生物学抵抗机制的目标是提供对其如何调解的完整机械理解反抗。这是基于我们发现干扰素中的纯合功能丧失 (LoF) 突变 (IFN) 受体途径和原发性和获得了对 PD-1 阻断疗法的耐药性，这两种情况均得到其他组的数据证实。有了这个信息，我们将能够测试组合方法以克服抗 PD-1/L1 耐药性治疗。其中包括旨在诱导可能激活该通路的局部干扰素反应的方法下游，例如 JAK1/2 敲除模型中的 Toll 样受体 (TLR) 或 MDA5 激动剂，并激活 B2M 敲除模型中的自然杀伤 (NK) 细胞。在目标 2 中，我们将研究一种新的癌细胞固有的 p21 相关激酶 4 (PAK4) 表达介导的 T 细胞排斥机制最近通过比较富含 T 细胞和缺乏 T 细胞的患者活检中的基因表达发现患有黑色素瘤并接受抗 PD-1 治疗。我们将研究导致 T 细胞排斥的机制 PAK4 在小鼠模型中诱导，我们将分析从患者身上获得的活检中的机制参加了一项结合 PAK4 抑制剂 KPT-9274 和抗 PD-1 抗体 nivolumab 的临床试验。这两个目标的样本分析将受益于与其他两个目标的研究人员的合作本 P01 的项目和核心。总之，该项目将分析治疗的明确机制对癌症免疫疗法的耐药性，以更好地了解其效果，并展示如何使用合理设计的组合研究克服阻力。 1