Co-targeting the HER3 oncogenic signaling circuitry and PD-1 as a novel multimodal precision immunotherapy for HNSCC

联合靶向 HER3 致癌信号通路和 PD-1 作为 HNSCC 的新型多模式精准免疫疗法

基本信息

批准号：
9917561
负责人：
Ezra Cohen
金额：
$ 51.31万
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：
2019
资助国家：
美国
起止时间：
2019-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9917561
关键词：
Bar Codes Biological Biological Models Cancer Remission Cells Cessation of life Clinical Clinical Trials Cytometry DNA Sequence Alteration Development Disease remission ERBB3 gene Exhibits FRAP1 gene Future Genetic Genetic Engineering Genomics Grant Head and Neck Squamous Cell Carcinoma Human Immune Immune Evasion Immune Targeting Immune response Immunooncology Immunotherapy In complete remission Laboratories Lesion Ligands Malignant Neoplasms Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Mutation Nivolumab Oncogenes Oncogenic PD-1 blockade PIK3CA gene Pathway interactions Patient Selection Patients Pharmacodynamics Phase II Clinical Trials Population Precision therapeutics Predictive Value RNA interference screen Resistance Resolution Signal Transduction System Therapeutic Tobacco Treatment Efficacy Treatment Protocols Tumor Suppressor Genes Tyrosine Phosphorylation United States Xenograft procedure anti-PD1 therapy anti-cancer anti-tumor immune response cancer cell chromatin immunoprecipitation genome editing immune checkpoint immune checkpoint blockade improved mTOR Signaling Pathway mTOR inhibition mortality multimodality novel novel therapeutics oncology trial outcome forecast patient stratification personalized immunotherapy predictive signature programmed cell death protein 1 response single-cell RNA sequencing targeted agent targeted treatment transcriptomics tumor tumor growth tumor xenograft tumor-immune system interactions

项目摘要

Summary Despite recent advances in treatment, the overall mortality for head and neck squamous cell carcinoma (HNSCC) remains high and current treatment regimens incur significant long-term morbidity. Targeting the immune checkpoint PD-1 with pembrolizumab and nivolumab has revolutionized HNSCC treatment. However, the overall response rate of these immunotherapies remains low, around 15-20%. This highlights the urgent need to identify novel therapeutic options for HNSCC to improve mortality, reduce morbidity, and enhance the activity and response rate of immune oncology (IO) approaches for HNSCC. We hypothesize that targeting HNSCC oncogenic signaling networks and disabling their immune evasive mechanisms may increase the response to anti-PD-1 treatment as part of a novel rational therapeutic strategy. In this regard, our laboratory contributed to the discovery that the persistent activation of the PI3K/mTOR signaling circuitry is the most frequent dysregulated signaling mechanism in HNSCC, and that mTOR inhibition exerts potent antitumor activity in multiple experimental HNSCC model systems and in a Phase 2 clinical trial (NCT01195922). Remarkably, ~20% of HNSCC lesions harbor driver PIK3CA mutations encoding active PI3Kα subunits, and yet ~90% of HNSCC lesions exhibit aberrant PI3K/mTOR pathway signaling. In search for the underlying mechanisms, we conducted a kinome wide RNAi screen, which revealed that persistent HER3 tyrosine phosphorylation and association with PI3Kα sustain pathway activation in most of the HNSCC lesions. Indeed, HER3 is highly expressed and persistently activated in most HNSCC lesions, correlating with poor prognosis. The best-in-class anti-HER3 monoclonal antibody CDX-3379 inhibits the ligand-dependent and -independent activation of human and murine HER3 by locking HER3 in its auto-inhibited configuration, and has demonstrated pharmacodynamic and clinical activity in HNSCC patients. CDX-3379 exhibits potent antitumor activity in PIK3CA wild type HNSCC tumor xenografts and patient derived xenografts (PDXs). Furthermore, we have obtained strong preliminary results supporting that CDX-3379 administration 1) abolishes PI3K-mTOR signaling, 2) reverses the immune evasive HNSCC microenvironment, and 3) can result in complete remission when combined with anti-PD-1 therapies in recently developed syngeneic mouse HNSCC models. Our premise is that co-targeting the HER3 signaling circuitry combined with anti-PD-1 blockade may represent a novel multimodal precision therapeutic approach for HNSCC aimed at achieving durable responses and cancer remission. We will now aim 1) to elucidate the contribution of genomic alterations in the PI3K-mTOR signaling network to anti-HER3 sensitivity and resistance, and 2) to establish the impact of targeting and co-targeting the HER3-PI3K/mTOR signaling network on the tumor immune microenvironment and response to PD-1 blockade, aiming at achieving a single cell level understanding of the anti-cancer immune response. These studies will inform the molecular stratification for patient selection in future multimodal precision immune oncology trials.

概括尽管最近的治疗进展，但头部和颈部鳞状细胞癌的总死亡率（HNSCC）保持高，目前的治疗方案会引起显着的长期发病率。定位 pembrolizumab和nivolumab的免疫检查点PD-1已彻底改变了HNSCC治疗。然而，这些免疫疗法的总反应率仍然很低，约为15-20％。这突出了紧急需要确定HNSCC的新型热选择，以提高死亡率，降低发病率并增强 HNSCC的免疫肿瘤学（IO）方法的活性和反应率。我们假设目标 HNSCC致癌信号网络并禁用其免疫回避机制可能会增加对抗PD-1治疗的反应是新型理性治疗策略的一部分。在这方面，我们的实验室有助于发现PI3K/MTOR信号传导电路的持续激活是最多的 HNSCC中经常失调的信号传导机制，MTOR抑制作用执行潜在的抗肿瘤活性在多个实验性HNSCC模型系统和2期临床试验中（NCT01195922）。值得注意的是〜20％的HNSCC病变港口驱动器PIK3CA突变编码主动PI3Kα亚基，但约有90％ HNSCC病变表现出异常的PI3K/mTOR途径信号传导。在寻找基本机制时，我们进行了一个宽的RNAi屏幕，揭示了持续的Her3酪氨酸磷酸化和在大多数HNSCC病变中，与PI3Kα的相关性维持途径激活。确实，Her3很高在大多数HNSCC病变中表达并持续激活，与预后不良相关。一流的抗HER3单克隆抗体CDX-3379抑制了人体的配体依赖性和非依赖性激活和Murine Her3通过将HER3锁定在其自动抑制配置中，并展示了药效学和HNSCC患者的临床活动。 CDX-3379在PIK3CA野生型HNSCC中表现出潜在的抗肿瘤活性肿瘤Xenographics和患者衍生的Xenographathics（PDXS）。此外，我们获得了强大的初步结果支持CDX-3379管理1）废除PI3K-MTOR信号，2）逆转免疫回避HNSCC微环境和3）与抗PD-1结合时可能会完全缓解最近开发的合成小鼠HNSCC模型的疗法。我们的前提是共同针对HER3 信号传导电路与抗PD-1封锁结合可能代表一种新型的多模式治疗 HNSCC的方法旨在实现持久的反应和癌症缓解。我们现在将目标1）阐明PI3K-MTOR信号网络中基因组改变对抗HER3灵敏度的贡献和电阻，以及2）建立靶向和靶向HER3-PI3K/mTOR信号传导的影响肿瘤免疫微环境的网络和对PD-1封锁的反应，旨在实现单个细胞水平对抗癌免疫反应的理解。这些研究将告知分子将来的多模式精度免疫肿瘤学试验中的患者选择分层。