Investigating Mechanisms of Hyperprogression on Anti-PD-1 Immunotherapy

研究抗 PD-1 免疫疗法超进展的机制

基本信息

批准号：
10320045
负责人：
Andrew B. Sharabi
金额：
$ 21.72万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320045
关键词：
Acceleration Aftercare Apoptosis Apoptotic Cancer Patient Cell Cycle Cell Proliferation Cells Clinical Trials Cytotoxic T-Lymphocytes Data Development Disease Disease Progression Drug Targeting EGF gene Epidermal Growth Factor Receptor Gene Mutation Growth Growth Factor Head and Neck Neoplasms Hypersensitivity Image Immunocompetent Immunotherapy In Vitro Investigation Lead Lesion MDM2 gene Malignant Neoplasms Mediating Modeling Molecular Mus Mutation PD-1 blockade PD-1/PD-L1 PDL1 pathway Patients Pattern Play Progressive Disease Reporting Resistance Risk Role Serum Signal Pathway Signal Transduction TNF gene Testing Therapeutic Time Translating Treatment Failure Tumor Burden anti-PD-1 anti-PD-1/PD-L1 cancer type cell growth cytokine immune checkpoint blockade improved improved outcome in vivo inhibitor melanoma mouse model novel novel drug combination objective response rate overexpression patient subsets pre-clinical prevent profiles in patients prospective response standard of care tumor tumor growth tumor necrosis factor-alpha inhibitor

项目摘要

Abstract The number of cancer patients being treated with checkpoint blockade immunotherapy (CBI) targeting the PD- 1/PD-L1 pathway is increasing dramatically. Recently a novel and unfavorable response pattern termed hyperprogression (HPD) has been identified which is characterized by a rapid worsening and acceleration of tumor growth after starting CBI. Our group was the first to report the genetic alterations associated with HPD, namely MDM2 amplifications and EGFR alterations. However, mechanisms of action or strategies to circumvent HPD have not been reported. Using novel tumor models, our preliminary data has identified that MDM2 amplified cells are hypersensitive to TNFα induced proliferation compared to non-MDM2 amplified tumor lines. Mechanistically we have identified that MDM2 amplification dramatically alters TNF-alpha signaling pathways, blocking apoptotic signals while simultaneously promoting NFκβ mediated cell growth and proliferation. In this study we will elucidate mechanisms of HPD and determine whether MDM2 amplification alone is sufficient to cause HPD and whether HPD can occur with other checkpoint blockade agents. We will then test whether novel MDM2/4 or TNFα inhibitors can block or prevent HPD in our unique tumor models. Our hypothesis that MDM2 amplified tumors are resistant to TNF-alpha induced apoptosis and hypersensitive to TNFα induced cell cycling which results in uncontrolled proliferation and HPD after treatment with CBI. Together these studies will significantly improve our mechanistic understanding of HPD and identify targeted drug strategies that can be rapidly translated into clinical trials to improve outcomes in cancer patients treated with CBI.

抽象的针对PD- 1/PD-L1途径正在急剧增加。最近一种小说和不利的响应模式已经鉴定出了高度进化（HPD），其特征是迅速的愿望和加速开始CBI后肿瘤生长。我们的小组是第一个报告与HPD相关的遗传变化的人即MDM2扩增和EGFR改变。但是，行动机制或策略的机制尚未报告围绕HPD。使用新型肿瘤模型，我们的初步数据已经确定与非MDM2膨胀相比肿瘤线。从机械上讲，我们已经确定MDM2扩增大大改变了TNF-Alpha信号传导途径，阻止凋亡信号，同时促进NFκβ介导的细胞生长和增殖。在这项研究中，我们将阐明HPD的机制，并确定MDM2扩增是否仅凭其他检查点封锁药物就可以引起HPD以及是否可能发生HPD。我们将然后测试新型MDM2/4或TNFα抑制剂是否可以阻止或防止我们独特的肿瘤模型中的HPD。我们的假设MDM2扩增的肿瘤对TNF-α诱导的凋亡具有抗性，并且对 TNFα诱导细胞循环，从而导致用CBI处理后不受控制的增殖和HPD。这些研究将大大改善我们对HPD的机械理解，并确定目标可以快速转化为临床试验以改善接受治疗的癌症预后的药物策略与CBI。