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

总结 尽管最近在治疗方面取得了进展，但头颈部鳞状细胞癌的总死亡率 （HNSCC）仍然很高，目前的治疗方案导致显着的长期发病率。针对 pembrolizumab和nivolumab的免疫检查点PD-1彻底改变了HNSCC治疗。然而，在这方面， 这些免疫疗法的总体反应率仍然很低，约为15- 20%。这突出表明， 需要确定HNSCC的新的治疗选择，以改善死亡率，降低发病率，并提高 HNSCC的免疫肿瘤学（IO）方法的活性和应答率。我们假设， HNSCC致癌信号网络和使其免疫逃避机制失效可能会增加HNSCC的免疫应答。 作为新型合理治疗策略的一部分。为此，我们的实验室 有助于发现PI 3 K/mTOR信号通路的持续激活是最重要的 HNSCC中频繁的失调信号传导机制，并且mTOR抑制发挥有效的抗肿瘤活性 在多个实验性HNSCC模型系统和2期临床试验（NCT 01195922）中。值得注意的是， 约20%的HNSCC病变含有编码活性PI 3 K α亚基的驱动PIK 3CA突变，而约90%的HNSCC病变含有编码活性PI 3 K α亚基的驱动PIK 3CA突变。 HNSCC病变表现出异常的PI 3 K/mTOR通路信号传导。为了寻找潜在的机制，我们 进行了一项激酶组范围的RNAi筛选，结果显示持续的HER 3酪氨酸磷酸化和 在大多数HNSCC病变中与PI 3 K α维持通路激活相关。事实上，HER 3是高度 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HER 3单克隆抗体CDX-3379抑制人HER 3受体的配体依赖性和非依赖性活化 和鼠HER 3通过将HER 3锁定在其自身抑制构型，并已证明药效学 和临床活性。CDX-3379在PIK 3CA野生型HNSCC中表现出强效抗肿瘤活性 肿瘤异种移植物和患者来源的异种移植物（PDX）。此外，我们还获得了强的初步结果。 结果支持CDX-3379给药1）消除PI 3 K-mTOR信号传导，2）逆转免疫应答， 逃避性HNSCC微环境，和3）当与抗PD-1组合时可导致完全缓解 在最近开发的同基因小鼠HNSCC模型中，我们的前提是共同靶向HER 3 信号通路结合抗PD-1阻断剂可能代表一种新的多模式精确治疗 HNSCC的方法旨在实现持久的反应和癌症缓解。我们现在的目标是： 阐明PI 3 K-mTOR信号传导网络中基因组改变对抗HER 3敏感性的贡献 和抗性，以及2）建立靶向和共靶向HER 3-PI 3 K/mTOR信号传导的影响 网络上的肿瘤免疫微环境和对PD-1阻断的反应，旨在实现单一的 细胞水平的抗癌免疫反应的理解。这些研究将为分子生物学 在未来的多模式精确免疫肿瘤学试验中进行患者选择的分层。

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.