Enhancing anti-tumor immunity in head and neck neoplasms

我们项目的主要活动包括HNSCC和RRP的进展。我们最近对HNSCC的研究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。我们实验室之前的小鼠研究表明，在手术切除肿瘤之前给药ICB可以产生持久的、全身的抗肿瘤免疫，而在手术后给药ICB则不会。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HNSCC患者新辅助ICB的II期研究，并研究了治疗前和治疗后的肿瘤活检和血液样本。我们观察到肿瘤特异性T细胞在治疗后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，一部分肿瘤特异性T细胞从肿瘤中释放到循环中，从而增强了全身抗肿瘤免疫。这些数据表明，如果没有新辅助的ICB治疗，大多数患者的抗肿瘤免疫反应将随着手术切除肿瘤而消失。相反，新辅助ICB诱导一些T细胞从肿瘤中排出，增强患者的全身免疫力。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，我们在实验室中探索了肿瘤特异性T细胞中组织驻留基因表达程序的机制驱动因素，发现TGF-b是一个主要驱动因素。在临床前小鼠研究中，我们观察到，与单独使用ICB相比，在ICB中添加TGF-b阻断剂进一步增强了全身抗肿瘤免疫的程度。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方面的工作重点是为这种罕见的、难以治疗的疾病确定非手术的药物治疗方案。RRP的标准治疗方法是重复手术以清除疾病并维持声音和气道的功能。我们的团队率先采用免疫疗法来解决RRP（慢性HPV感染）的根本原因。免疫检查点阻断（ICB）的初步试验为一些患者带来了临床益处，但没有患者被治愈。我们对这些试验标本的相关分析显示，ICB并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在基线时缺乏hpv特异性T细胞。接下来，我们与一个行业合作伙伴合作开发一种治疗性疫苗，旨在在RRP患者体内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大的临床活性，50%的患者中有方案定义的完全缓解。本试验的相关研究显示，接种疫苗后，hpv特异性T细胞在外周血显着多克隆扩增，这些T细胞在应答患者中运输和浸润乳头状瘤的能力。该疫苗正在进行的II期研究已获得FDA的突破性认定。这些数据表明，增强外周hpv特异性T细胞免疫可导致hpv驱动肿瘤患者的乳头状瘤破坏和临床获益。然而，治疗性疫苗接种并不能使所有患者外周血hpv特异性T细胞免疫扩增。需要其他方法来增强这些患者的全身hpv特异性免疫。经工程改造表达HPV特异性T细胞受体（TCR）的自体T细胞过继转移已被证明对HPV相关恶性肿瘤有效，可能是治疗危及生命的RRP病例的新方法。嵌合抗原受体（CAR） T细胞治疗目前是不可能的，因为没有细胞表面标记特异性HPV感染的乳头状瘤细胞是已知的。tcr工程T细胞治疗方法需要发现一种或多种识别HPV 6或11衍生抗原的tcr。发现针对HPV 6或11抗原的新型tcr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.