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

摘要 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的发病率仍然很高，目前的治疗方案导致了显著的长期发病率。目标是 Pembrolizumab和nivolumab的免疫检查点PD-1使HNSCC的治疗发生了革命性的变化。然而， 这些免疫疗法的总体应答率仍然很低，约为15%-20%。这凸显了当务之急 需要确定HNSCC的新治疗方案，以提高死亡率，降低发病率，并提高 免疫肿瘤学(IO)方法治疗HNSCC的活动性和应答率。我们假设目标是 HNSCC的致癌信号网络和禁用其免疫逃避机制可能会增加 作为新的合理治疗策略的一部分，对抗PD-1治疗的反应。在这方面，我们的实验室 有助于发现PI3K/mTOR信号通路的持续激活是 HNSCC中频繁的信号失控机制以及mTOR抑制发挥强大的抗肿瘤活性 在多个实验性HNSCC模型系统和第二阶段临床试验中(NCT01195922)。值得注意的是， ~20%的HNSCC病变含有编码活性PI3Kα亚单位的驱动因子PIK3CA突变，而~90%的HNSCC病变含有编码活性PI3K亚基的PIK3CA突变 HNSCC病变表现为PI3K/mTOR信号通路异常。在寻找潜在机制的过程中，我们 进行了动态组广泛的RNAi筛查，结果显示持久的HER3酪氨酸磷酸化和 在大多数喉癌病变中，与PI3Kα相关的通路持续激活。事实上，HER3是高度 在大多数HNSCC皮损中表达并持续激活，与预后不良相关。同类中最好的 抗HER3单抗CDX-3379抑制人HER3配体依赖和非依赖激活 和小鼠HER3通过将HER3锁定在其自动抑制的配置中，并已证明了药效学 和HNSCC患者的临床活动性。CDX-3379对PIK3CA野生型HNSCC具有较强的抗肿瘤活性 肿瘤异种移植和患者来源异种移植(PDX)。此外，我们已经获得了很强的初步 结果支持CDX-3379应用1)取消PI3K-mTOR信号，2)逆转免疫 回避的HNSCC微环境；3)联合抗PD-1可导致完全缓解 最近开发的同基因小鼠HNSCC模型的治疗。我们的前提是共同瞄准HER3 信号通路与抗PD-1阻断相结合可能代表一种新的多模式精确治疗 旨在实现持久反应和癌症缓解的HNSCC方法。我们现在的目标是 阐明PI3K-mTOR信号网络中的基因组改变对抗HER3敏感性的影响 和耐药性，以及2)建立靶向和共靶向HER3-PI3K/mTOR信号的影响 网络对肿瘤免疫微环境和PD-1阻断反应的影响，旨在实现单一 在细胞水平上了解抗癌免疫反应。这些研究将告知分子 未来多模式精确免疫肿瘤学试验中患者选择的分层。

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.