Project 2: Combination immunotherapy approaches to overcome therapeutic resistance in HER2-positive breast cancer

项目总结 尽管转移性HER2+乳腺癌(BC)的治疗取得了重大进展，但它仍然是无法治愈的。 这样做的原因是癌症总是对标准疗法产生耐药性--这两种疗法都具有细胞毒性。 化疗药物和那些专门针对HER2的药物。现代试图改进标准疗法 主要集中在更有效地抑制HER2下游信号的药物上，但这些已经产生了 只有递增的好处。因此，迫切需要新的治疗方法。最近，它已经变成了 明确HER2+BCs具有免疫原性。HER2是一种很强的肿瘤抗原，有一定比例的HER2+BCS 有淋巴细胞渗入，这预示着预后的改善。此外，抗HER2抗体对 它们的作用部分是通过刺激免疫效应细胞来实现的。总而言之，这些事实为测试提供了理由 HER2+转移性结直肠癌的免疫治疗我们的合作研究员卢博士最近进行了一项第二阶段的研究 曲妥珠单抗和pembrolizumab(PD-1抑制剂)对HER2+转移性BC患者的治疗(万能药)。这个 这项研究达到了它的主要终点，从而为HER2+免疫疗法的使用提供了原则证明 疾病--然而，只有一小部分患者受益。因此，在项目2中，我们将研究两部小说 旨在进一步增强针对HER2+BC的抗肿瘤免疫反应的治疗方法：使用 CDK4/6抑制剂，与曲妥珠单抗和PD-1阻滞剂(目标一)一起给予；以及添加PD-1。 L1阻滞剂和4-1BB激动剂，用于化疗和曲妥珠单抗(目标2)。这两种方案都是合理的 根据我们令人信服的临床前数据设计的，这些方法显著增强了抗肿瘤作用 豁免权。在每个目标中，我们将进行随机的、多中心的二期临床试验来确定疗效。 这些新颖的方法。每个目标还将采用“联合临床试验”模式，同时进行小鼠研究。 与人体试验平行。动物实验将使用我们最先进的转基因模型进行 人类HER2驱动的乳腺癌(MMTV-RTTA/Teto-HER2)。我们的老鼠研究包括切割- 边缘技术，以了解这些新的免疫治疗方法的活动机制，如 以及对抗性机制的详细研究(包括下一代测序和多路传输 肿瘤组织的免疫荧光分析)。与此同时，这些试验涉及到对肿瘤活检组织的系列收集。 还有血样。来自小鼠和病人的生物样本将被平行分析，每个生物样本都将向 其他的。最终，这些研究将：(1)表征晚期HER2阳性BC的免疫状况。 前所未有的细节；(2)确定这两种新方法中的任何一种是否是有效的临床策略； (3)建立每种疗法的细胞活性机制；(4)探索治疗机制 抵抗。这项工作有可能发现增强免疫反应的新疗法。 HER2阳性的BC，从而显著改善患者的预后。

PROJECT SUMMARY Despite significant advances in the management of metastatic HER2+ breast cancer (BC), it remains incurable. The reason for this is that cancers invariably develop resistance to standard therapies – both cytotoxic chemotherapies and those that specifically target HER2. Modern attempts to improve upon standard therapies have largely focused on agents that inhibit HER2 downstream signaling more potently, but these have yielded only incremental benefits. Therefore, new treatment approaches are urgently needed. Recently it has become clear that HER2+ BCs are immunogenic. HER2 is a strong tumor antigen, and a proportion of HER2+ BCs harbor a lymphocytic infiltrate, which predicts for improved outcomes. In addition, anti-HER2 antibodies exert their effects in part by stimulating immune effector cells. Collectively, these facts provide rationale for testing immunotherapy in HER2+ metastatic BC. Our co-investigator Dr. Loi recently conducted a phase II study of trastuzumab and pembrolizumab (a PD-1 inhibitor) in patients with HER2+ metastatic BC (PANACEA). The study met its primary endpoint and thus provides proof-of-principle for the use of immunotherapy in HER2+ disease – however, only a small minority of patients benefited. In Project 2, we will therefore study two novel therapeutic approaches designed to boost the anti-tumor immune response against HER2+ BC further: the use of CDK4/6 inhibitors, given together with trastuzumab and PD-1 blockade (Aim One); and the addition of PD- L1 blockade and a 4-1BB agonist to chemotherapy and trastuzumab (Aim Two). Both regimens are rationally designed, based on our convincing preclinical data showing that these approaches markedly amplify anti-tumor immunity. In each Aim, we will perform a randomized, multicenter phase II clinical trial to determine the efficacy of these novel approaches. Each Aim will also employ a “co-clinical trial” model, with mouse studies running in parallel to human trials. The animal experiments will be performed using our state-of-the-art transgenic model of human HER2- driven mammary carcinoma (MMTV-rtTA/tetO-HER2). Our mouse studies incorporate cutting- edge technologies to understand the mechanisms of activity for these novel immunotherapy approaches, as well as detailed studies of resistance mechanisms (including next-generation sequencing and multiplexed immunofluorescent profiling of tumor tissue). Meanwhile, the trials involve serial collection of tumor biopsies and blood samples. Biospecimens from mice and patients will be analyzed in parallel, with each informing the other. Ultimately, these studies will: (1) characterize the immune landscape of advanced HER2-positive BC in unprecedented detail; (2) determine whether either of the two novel approaches is an effective clinical strategy; (3) establish cellular mechanisms of activity for each regimen; and (4) explore mechanisms of therapeutic resistance. This work has the potential to uncover new therapies that enhance immune responses against HER2-positive BC, and thus significantly improve patient outcomes.