Preclinical GEM and GDA Models of Primary and Metastatic Melanoma

原发性和转移性黑色素瘤的临床前 GEM 和 GDA 模型

基本信息

批准号：
10926299
负责人：
SHYAM SHARAN
金额：
$ 128.6万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10926299
关键词：
Adjuvant Allografting Anatomy Animals Antibodies Apoptosis BRAF gene Biocompatible Materials Biotechnology Characteristics Clinical Clinical Management Collaborations Complement Complex Cooperative Research and Development Agreement Cutaneous Melanoma Disease Disease model Engineering Evaluation Evaluation Research Excision Fc Receptor Generations HGF gene IgG1 Immune checkpoint inhibitor Immune system Immunocompetent Immunologics Immunooncology Immunotherapeutic agent Incidence Infiltration Intervention Laboratories Lesion Measurable Metastatic Melanoma Modality Modeling Molecular Monitor Mus Mutation Neoadjuvant Therapy Neoplasm Metastasis Operative Surgical Procedures Outcome PD-1 blockade PD-L1 blockade Pathway interactions Patients Pattern Primary Neoplasm Privatization Procedures Recurrent tumor Resected Resistance Severities Site Surgical Models Therapeutic Therapeutic Effect Therapeutic Use Study Tumor-infiltrating immune cells Vaccines anti-CTLA4 antibodies anti-PD-1 anti-PD-L1 antibodies anti-PD-L1 therapy biomarker evaluation checkpoint therapy clinically relevant cohort drug development efficacy evaluation experimental study follow-up imaging probe immune checkpoint blockade immune modulating agents melanoma melanomagenesis mouse model multidisciplinary mutant neoplastic cell novel patient subsets pre-clinical predictive signature programs repaired response targeted treatment timeline tool tumor wound healing

项目摘要

As an essential part of the collaborative program with Dr. Glenn Merlino's laboratory at the NCI, we have previously developed several immunocompetent allograft models for metastatic melanoma that appeared sensitive to immune checkpoint blockade (ICB) with an anti-CTLA-4 antibody. This collaboration included an NCI CRADA to evaluate sensitivity to AstraZeneca's proprietary mouse anti-PD-L1 antibody in the Hgftg;Cdk4R24C/R24C GEM-derived allograft model. This antibody (designated clone 80) is the mouse isotype IgG1 engineered to correspond to durvalumab, carrying the D265A mutation to minimize Fc receptor interaction and tumor cell apoptosis. Consistent with clinical observations for ICB in melanoma, anti-PD-L1 treatment elicited complete and durable response in a subset of melanoma-bearing mice, mirroring the comparable subset of patients with melanoma that respond to the same immunotherapeutic intervention. In the recent round of experiments, two GEM-derived allograft models prepared from metastatic lesion sites and featuring clinically relevant aberrations in either BRAF or HGF/MET pathways have been characterized in terms of tumor latency in corresponding GDA allografted animals, severity of primary disease, incidence of metastasis, as well as rate and velocity of tumor recurrence upon surgical resection. These studies enabled to determine characteristic disease timelines in both models thus preparing these preclinical tools for evaluation of melanoma therapeutics in adjuvant and neo-adjuvant settings. Anti-PD-1 efficacy experiments have been completed in both models, as well as a follow-up efficacy experiment with PD-L1 blockade therapy conducted on small early measurable primary tumors in one of the aforementioned models. All studies have been complemented by a full biomarker evaluation and analysis of tumor infiltrating immune system landscapes and alteration thereof by examined immuno-oncology intervention modalities.

作为与Glenn Merlino博士在NCI的合作计划的重要组成部分，我们以前已经开发了几种用于转移性黑色素瘤的免疫能力同种异体移植模型，这些模型似乎对具有抗CTLA-4抗体的免疫检查点阻断（ICB）敏感。这种合作包括NCI CRADA，以评估HGFTG中对Astrazeneca专有小鼠抗PD-L1抗体的敏感性； CDK4R24C/R24C GEM衍生的同种异体移植模型。该抗体（指定的克隆80）是与Durvalumab相对应的小鼠同种型IgG1，携带D265A突变，以最大程度地减少FC受体相互作用和肿瘤细胞细胞凋亡。与黑色素瘤中ICB的临床观察结果一致，抗PD-L1治疗在含黑色素瘤小鼠的一部分中引起了完整和耐用的反应，这反映了黑色素瘤患者可比的子集对相同的免疫治疗干预的反应。在最近的一轮实验中，通过转移性病变部位制备的两个宝石衍生的同种异体移植模型，并在BRAF或HGF/MET途径中具有临床相关的畸变，以相应的GDA同种异体移植动物的肿瘤潜伏期为特征，在原发性疾病的严重性，转移的发生率以及veLoctial contifity contripity和Veloctial contripity contripity contrictity contripity cormorcience。这些研究能够确定两个模型中的特征性疾病时间表，从而为辅助和新辅助环境中的黑色素瘤治疗剂评估这些临床前工具。在这两个模型中，抗PD-1功效实验均已完成，以及对上述模型之一对小型早期可测量原发性肿瘤进行的PD-L1阻断治疗的后续疗效实验。所有研究都通过对肿瘤浸润免疫系统景观的全面评估和分析进行了补充，并通过检查的免疫肿瘤干预方式改变了其改变。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.

DOI：
10.1038/s41591-020-0818-3
发表时间：
2020-05
期刊：
Nature medicine
影响因子：
82.9
作者：
Pérez-Guijarro E;Yang HH;Araya RE;El Meskini R;Michael HT;Vodnala SK;Marie KL;Smith C;Chin S;Lam KC;Thorkelsson A;Iacovelli AJ;Kulaga A;Fon A;Michalowski AM;Hugo W;Lo RS;Restifo NP;Sharan SK;Van Dyke T;Goldszmid RS;Weaver Ohler Z;Lee MP;Day CP;Merlino G
通讯作者：
Merlino G

Distinct Biomarker Profiles and TCR Sequence Diversity Characterize the Response to PD-L1 Blockade in a Mouse Melanoma Model.

DOI：
10.1158/1541-7786.mcr-20-0881
发表时间：
2021-08
期刊：
Molecular cancer research : MCR
影响因子：
0
作者：
通讯作者：

Author Correction: Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy.

作者更正：多模型临床前平台预测黑色素瘤对免疫治疗的临床反应。

DOI：
10.1038/s41591-021-01252-6
发表时间：
2021
期刊：
Nature medicine
影响因子：
82.9
作者：
Pérez-Guijarro,Eva;Yang,HowardH;Araya,RominaE;ElMeskini,Rajaa;Michael,HelenT;Vodnala,SumanKumar;Marie,KerrieL;Smith,Cari;Chin,Sung;Lam,KhiemC;Thorkelsson,Andres;Iacovelli,AnthonyJ;Kulaga,Alan;Fon,Anyen;Michalowski,Alek
通讯作者：
Michalowski,Alek