Project 2: Characterizing and overcoming failure to respond to PD-1 blockade therapy

项目 2：描述和克服对 PD-1 阻断疗法无反应的问题

基本信息

批准号：
10380818
负责人：
PAUL NGHIEM
金额：
$ 40.78万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-04 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380818
关键词：
Antigens Archives Biological Assay Biopsy Specimen CD 200 CD276 gene CD47 gene Cancer Etiology Cell Count Cell Death Cell Survival Characteristics Clinical Clinical Trials Clinical Trials Design Clonality Clone Cells Collaborations Collection Combined Modality Therapy Core Biopsy Correlation Studies Country Cryopreservation Cytotoxic Chemotherapy Data Development Down-Regulation Epitopes Etiology Evaluation Failure Flow Cytometry Freezing Frequencies Functional disorder Goals Immune Immune Evasion Immune response Immunization Immunobiology Immunooncology Immunotherapy Impairment Induced Mutation Infiltration Lead Leadership Letters Malignant Epithelial Cell Malignant Neoplasms Mediating Merkel Cells Merkel cell carcinoma Mus Natural Immunity Natural Killer Cells Oncoproteins Outcome PD-1 blockade PD-1 pathway PD-1/PD-L1 PD-L1 blockade Pathway interactions Patients Pattern Phagocytes Phenotype Play Polyomavirus Polyomavirus Transforming Antigens Publishing Refractory Resistance Role Sampling Scientist Skin Cancer Slice Solid Neoplasm Specimen System T-Cell Receptor T-Lymphocyte Talents Technology Testing Therapeutic Intervention Time Tumor Cell Line Tumor Expansion Tumor-infiltrating immune cells UV induced Viral Virus adaptive immunity base cancer care cell type clinical biomarkers effector T cell exhaustion immune checkpoint immune checkpoint blockade immunogenic immunological intervention improved improved outcome in vitro Model innate immune mechanisms macrophage neoantigens neoplastic cell next generation novel pathogen patient derived xenograft model peripheral blood predicting response predictive marker prognostic significance programmed cell death ligand 1 programmed cell death protein 1 prospective protein expression repository resistance mechanism response single-cell RNA sequencing standard of care therapeutic target tool tumor tumor microenvironment virus related cancer

项目摘要

SUMMARY PROJECT 2: Merkel cell carcinoma (MCC) is a rare but often deadly skin cancer caused by the Merkel cell polyomavirus (MCPyV) in 80% of cases. MCPyV T-antigen oncoproteins are persistently expressed in virus- positive MCCs (VP-MCC), while remarkably high numbers of UV-induced neoantigens are detected in virus-negative MCCs (VN-MCC), suggesting both MCC subsets harbor immunogenic epitopes. Based on our early studies of the immune response in MCC, our group led multiple clinical trials that have recently changed the standard of care for this cancer. PD-1 blockade has yielded high response rates in MCC as compared with other solid tumors, and markedly improved outcomes compared to cytotoxic chemotherapy, the only prior option for advanced MCC. Unfortunately, 40% of MCC patients do not initially benefit from PD-1 blockade and ~20% of responders later develop acquired resistance. Consequently, there is an urgent need to identify therapeutically targetable mechanisms of resistance. In this proposal, we seek to identify reversible mechanisms of resistance to PD-1 blockade by analyzing three critical components across this Project: Aim 1: MCC-specific T lymphocytes. We will determine whether T cell infiltration patterns into tumors, T cell clonal diversity, or dysfunctional status are associated with failure to respond to PD-1 blockade therapy. Aim 2: MCC tumor cells. We will determine whether MCC cell intrinsic immune characteristics including expression of additional checkpoint molecules or impaired antigenicity are associated with response/resistance to PD-1 blockade. Aim 3: MCC innate immunity. We will study the correlation between intratumoral infiltration of two innate immune cell types (macrophages and NK cells) and MCC outcome to determine whether therapeutic intervention with innate immune stimulation can augment MCC adaptive immunity. Notably, we have made several significant advances since our May 2017 submission which will greatly increase our ability to identify and test the functional relevance of immune mechanisms mediating resistance to PD-1 blockade. These advances include: (1) A scRNAseq workflow which can be performed on small amounts (1 core biopsy) of cryopreserved material, enabling careful collection and selection of highly informative patient samples and improved depth of analysis; (2) MCC tumor expansion in patient derived xenograft (PDX) mice for subsequent use in functional assays including a slice-culture/explant system. Unbiased approaches including scRNAseq, will be initially employed to optimize our capacity to identify novel and significant immune evasion mechanisms, as we have demonstrated since the time of our initial submission. Under the guidance of our External and Internal Advisory Boards, we will then select the pathways most strongly associated with PD-1 blockade response. These immune evasion pathways will be studied in a larger number of patients and their functional significance/reversibility will be determined. This project will be greatly enabled by our established collaborations with experts in dissecting immuno-oncology mechanisms including Drs. Martin “Mac” Cheever (FHCRC), Christian Hinrichs (NCI), Drew Pardoll (Hopkins), John Thompson (UW), Suzanne Topalian (Hopkins), John Wherry (UPenn) and Catherine Wu (Harvard).

摘要项目2：默克尔细胞癌（MCC）是默克尔引起的罕见但通常是致命的皮肤癌在80％的病例中，细胞多瘤病毒（MCPYV）持续表达阳性MCC（VP-MCC）虽然在病毒阴性中检测到了大量的紫外线新抗原数量的显着数量 MCC（VN-MCC）表明，这两个MCC子集均基于对YELLE的表位。 MCC的免疫反应，我们的小组领导了多个Clials，hat habe habe录制了护理标准癌症。与其他肿瘤相比与细胞毒性化学疗法相比，结果改善 40％的MCC患者最初不会受益于PD-1封锁，后来有20％的响应者被收购阻力。在此提案中，我们试图通过分析三个该项目中的关键组成部分：目标1：MCC特异性T淋巴细胞。浸润模式进入肿瘤，T细胞克隆多样性或功能失调状态与无法反应的失败有关 PD-1封锁治疗2：MCC肿瘤细胞。包含其他检查点分子或抗原性受损的表达与对PD-1封锁的反应/电阻。两种先天免疫细胞类型（巨噬细胞和NK细胞）和MCC结果的肿瘤内浸润以确定与先天性的治疗干预是否可以增强MCC适应性免疫。值得一提我们识别和测试介导对PD-1阻滞性的免疫机制的功能相关性的能力。这些进步包括：（1）scrnaseq workflowwich可以冷冻保存的材料，能够仔细收集并选择高度信息的皮质皮肤皮性皮肤样品并改进分析深度；（2）MCC肿瘤的扩展最初将使用包括slice培养/外植物系统的测定法。正如我们已经证明的自我们最初提交的时间以来。选择与PD-1阻滞反应最密切相关的途径。在大量患者中进行了研究，将确定功能意义/可逆性。通过我们与专家剖析免疫肿瘤学专家的合作，该项目具有更大的作用。包括Drs的机制。汤普森（UW），苏珊娜·托普利安（Suzanne Topalian）（霍普金斯），约翰·沃里（John Wherry）（Upenn）和Caterine Wu（哈佛）。