Enhancing anti-tumor immunity in head and neck neoplasms

我们计划的主要活动包括HNSCC和RRP的进展。我们最近在HNSCC方面的工作主要集中在对新诊断的HNSCC患者进行免疫检查点阻断(ICB)免疫治疗和手术的基本原理排序。我们实验室以前的小鼠实验表明，当ICB在手术切除肿瘤之前给药时，可以产生持久的、系统性的抗肿瘤免疫，而当ICB在手术后给药时，ICB不能。这一观察结果令人震惊，但这一发现背后的机制尚不清楚。为了研究患者中的这种现象，我们设计并完成了新辅助ICB在HNSCC患者中的II期研究，并研究了治疗前后的肿瘤活检和血样。我们观察到治疗后肿瘤特异性T细胞在肿瘤中被激活和扩增。此外，我们观察到肿瘤通过诱导组织驻留基因表达程序作为肿瘤特异性T细胞的储存库。通过ICB治疗，一定比例的肿瘤特异性T细胞从肿瘤释放到循环中，导致系统抗肿瘤免疫增强。这些数据表明，在没有新辅助ICB治疗的情况下，大多数患者的抗肿瘤免疫反应将通过手术切除肿瘤而被移除。相反，新佐剂ICB会诱导一些T细胞从肿瘤中流出，增强患者的系统免疫力。这些发现是迄今为止支持在HNSCC患者中使用新辅助ICB的最有力的科学论据。接下来，我们在实验室探索了肿瘤特异性T细胞中这种组织驻留基因表达程序的机制驱动因素，发现转化生长因子-b是主要驱动因素。在临床前的小鼠研究中，我们观察到，与单独使用ICB相比，在ICB中加入转化生长因子-b阻滞剂进一步增强了系统抗肿瘤免疫的程度。我们正在进行的工作旨在确定是否有其他途径参与努力，以发现更多可能的治疗策略，以增强新诊断的HNSCC患者的全身抗肿瘤免疫。我们最近在RRP上的工作集中在为这种罕见的、难以治疗的疾病寻找非手术、药物治疗的选择。RRP的标准治疗是重复手术，以消除疾病并维持功能正常的嗓音和呼吸道。我们的团队已经率先采用免疫疗法来解决RRP的根本原因，即慢性HPV感染。免疫检查点阻断(ICB)的初步试验对一些患者产生了临床益处，但没有患者被治愈。我们对这些试验样本的相关分析表明，ICB没有释放乳头状瘤中HPV特异性T细胞的活性，至少部分原因是这些乳头状瘤中存在的HPV特异性T细胞在基线水平上很少。接下来，我们与一家行业合作伙伴合作开发了一种治疗性疫苗，旨在为RRP患者产生新的或扩大现有的HPV特异性T细胞。这种新疫苗的I期临床研究产生了强劲的临床活性，并在50%的患者中确定了完全应答。这项试验的相关研究显示，接种疫苗后，HPV特异性T细胞在外周显著的多克隆扩张，以及这些T细胞在应答患者中运输和渗透到乳头状瘤的能力。该疫苗正在进行的第二阶段研究已获得FDA的突破性指定。这些数据表明，增强外周HPV特异性T细胞免疫可以导致乳头状瘤的破坏，并在HPV驱动的肿瘤患者中临床受益。然而，治疗性疫苗接种并不会导致所有患者的外周HPV特异性T细胞免疫扩大。需要其他方法来增强这些患者的系统HPV特异性免疫。过继转移表达HPV特异性T细胞受体(TCR)的自体T细胞已被证明对HPV相关的恶性肿瘤有效，并可能成为治疗危及生命的RRP病例的一种新方法。目前尚不可能用嵌合抗原受体(CAR)T细胞治疗，因为目前还没有针对HPV感染的乳头状瘤细胞的细胞表面标志物。TCR工程T细胞治疗方法需要发现一个或多个识别HPV6或11型抗原的TCRs。发现针对HPV6或11型抗原的新型TCRs是我们实验室目前的主要研究工作。

Major activities of our program include progress in both HNSCC and RRP. Our recent work on HNSCC has focused on the rationale sequencing of immune checkpoint blockade (ICB) immunotherapy and surgery for patients with newly diagnosed HNSCC. Previous mouse work in our laboratory revealed that ICB resulted in the development of durable, systemic anti-tumor immunity when administered prior to surgical resection of tumors but not when the ICB was administered after surgery. This observation was striking, but the mechanisms underlying this finding were unclear. To study this phenomenon in patients, we designed and completed a phase II study of neoadjuvant ICB in patients with HNSCC and studying pre- and post-treatment tumor biopsies and blood samples. We observed that tumor-specific T cells became activated and expanded in the tumor after treatment. Additionally, we observed that tumors act as a reservoir for tumor-specific T cells through induction of a tissue residency gene expression program. With ICB treatment, a proportion of the tumor-specific T cells were released from the tumor into circulation, leading to enhanced systemic anti-tumor immunity. These data indicate that without neoadjuvant ICB treatment, most of a patient's anti-tumor immune response would be removed with surgical removal of the tumor. Conversely, neoadjuvant ICB induces egress of some T cells from the tumor, enhancing the patient's systemic immunity. These findings are the strongest scientific argument to date supporting the use of neoadjuvant ICB in patients with HNSCC. We next explored the mechanistic drivers of this tissue resident gene expression program in tumor-specific T cells in the laboratory and found TGF-b to be a major driver. In pre-clinical mouse studies, we observe that the addition of TGF-b blockade to ICB further enhanced the degree of systemic antitumor immunity that develops compared to ICB alone. Our ongoing work aims to determine if other pathways are involved in efforts to uncover more possible therapeutic strategies to enhance systemic anti-tumor immunity in patients with newly diagnosed HNSCC. Our recent work on RRP has focused on identifying non-surgical, medical treatment options for this rare, hard to treat disease. The standard-of-care treatment for RRP is repeat surgery to debulk disease and maintain a functional voice and airway. Our team has pioneered approaches to address the underlying cause of RRP, chronic HPV infection, with immunotherapy. Initial trials with immune checkpoint blockade (ICB) resulted in clinical benefit for some patients, but no patients were cured. Our correlative analyses on specimens from these trials revealed that ICB was not unleashing the activity of HPV-specific T cells in papillomas, due at least in part to the paucity of HPV-specific T cells present in these papillomas at baseline. We next worked with an industry partner to develop a therapeutic vaccine designed to generate new or expand existing HPV-specific T cells in patients with RRP. Phase I clinical study with this new vaccine resulted in robust clinical activity and protocol defined complete responses in 50% of patients. Correlative studies from this trial revealed significant, polyclonal expansion of HPV-specific T cells in the periphery after vaccination and the ability of these T cells to traffic and infiltrate into papillomas in responder patients. Ongoing phase II study with this vaccine has led to FDA Breakthrough Designation. These data indicated that enhancement of peripheral HPV-specific T cell immunity can lead to papilloma destruction and clinical benefit in patients with HPV-driven neoplasms. Yet, therapeutic vaccination does not result in the expansion peripheral HPV-specific T cell immunity in all patients. Other approaches are needed to enhance systemic HPV-specific immunity in these patients. Adoptive transfer of autologous T cells engineered to express a T cell receptor (TCR) specific for HPV has proven efficacy in HPV-associated malignancies and could be a new approach for life-threatening cases of RRP. Treatment with chimeric antigen receptor (CAR) T cells is not possible currently as no cell surface markers specific for HPV infected papilloma cells are known. A TCR-engineered T cell therapy approach necessitates the discovery of one or more TCRs that recognize antigen derived from HPV 6 or 11. Discovery of novel TCRs that target HPV 6 or 11 antigens is a major research effort currently in our laboratory.