Personalized vaccine immunotherapy in combination with anti-PD 1 antibody for recurrent or metastatic squamous cell carcinoma of the head and neck

项目摘要/摘要 免疫检查点抑制物(ICI)，如抗PD-1抗体，已经改善了患者的存活率 转移性头颈部鳞癌(HNSCC)。然而，只有一小部分患者(&lt；20%) 对单一代理ICI作出响应。由于ICI通过阻断先前存在的抗肿瘤T细胞的负性调节而起作用 免疫，大多数HNSCC患者对抗PD-1单抗缺乏反应表明大多数HNSCC 患者要么没有预先存在的抗肿瘤免疫，要么其他免疫抑制途径发挥了作用 主导性角色。因此，将抗PD-1单抗与一种可诱导抗肿瘤T细胞的免疫途径相结合 细胞免疫可能比单一的ICI更有效。然而，靶点在患者之间的差异 抗原使HNSCC成为开发有效治疗性疫苗最具挑战性的癌症之一。 为了解决这个问题，我们建议开发一种新的疫苗免疫疗法来治疗HNSCC，方法是 是个性化的，因此在抗原性签名中包含了患者对患者的差异。我们的自体治疗 疫苗由肿瘤膜囊泡(TMV)组成，这些囊泡由患者的肿瘤结合而成。 免疫刺激分子(ISM)通过蛋白质转移。与以前的自体肿瘤裂解物不同 疫苗中，肿瘤抗原通过我们疫苗中的TMV支架与ISM物理连接，因此 同时将患者独特的肿瘤抗原信号和ISM呈现给免疫细胞以诱导 有效的抗肿瘤反应。抗原和佐剂的这种物理联系已经被证明可以诱导 比非结合抗原和佐剂的混合物更有效的免疫反应。此外，不同于 全细胞疫苗、TMV疫苗不分泌免疫抑制因子。TMV本质上是颗粒状的 并携带膜相关肿瘤抗原、改变的碳水化合物抗原和衍生的抗原表位 以主要组织相容性复合体相关肽的形式从胞浆蛋白中分离出来。我们的预赛 研究表明，TMV疫苗联合ICI治疗小鼠口腔癌比单独ICI更有效 模特们。我们假设，个性化疫苗免疫疗法将扩大肿瘤特异性T细胞，并 加入ICI可防止肿瘤抗原特异性T细胞耗尽，从而诱导强大的抗肿瘤T细胞 并显著提高对HNSCC肿瘤无效的临床反应 目前批准的免疫疗法。这一假设将在以下具体目标中得到检验：目标1： 确定是否可以改变剂量和时间表以增强抗肿瘤免疫反应和 TMV疫苗对HNSCC小鼠模型的疗效，目的2：研究TMV疫苗对HNSCC的抑制作用 转移/复发，并在临床相关环境中延长小鼠的生存时间，目标3：进行 单用和联合应用TMV免疫治疗的1b期剂量递增临床试验 复发或转移性HNSCC患者的培溴利珠单抗。拟议的工作将提前完成 针对复发和/或转移性HNSCC患者的一种新的个性化疫苗免疫治疗方法。

PROJECT SUMMARY/ABSTRACT Immune checkpoint inhibitors (ICI) such as anti-PD-1 antibodies, have improved the survival of patients with metastatic head and neck squamous cell carcinoma (HNSCC). However, only a subset (<20%) of patients responds to single agent ICI. Since ICI acts by blocking the negative regulators of pre-existing anti-tumor T cell immunity, the lack of response of the majority of HNSCC patients to anti-PD-1 mAb suggests that most HNSCC patients either do not have pre-existing anti-tumor immunity or that other immunosuppressive pathways play a dominant role. Therefore, combining anti-PD-1 mAb with a vaccination approach that can induce anti-tumor T cell immunity is likely to be more effective than single agent ICI. However, patient-to-patient variation in target antigens makes HNSCC one of the most challenging cancers for developing an effective therapeutic vaccine. To address this, we propose to develop a novel vaccine immunotherapy to treat HNSCC using an approach that is personalized, thus incorporating patient-to-patient variation in antigenic signature. Our autologous therapeutic vaccine consists of tumor membrane vesicles (TMVs) made from the patients’ tumors conjugated to potent immunostimulatory molecules (ISMs) by protein transfer. In contrast to previous autologous tumor lysate vaccines, the tumor antigens are physically linked to ISMs via a TMV scaffold in our vaccines, thus simultaneously presenting the patient’s unique tumor antigen signature and ISMs to the immune cells to induce effective anti-tumor responses. Such a physical linkage of antigens and adjuvants has been shown to induce a more effective immune response than a mixture of unconjugated antigens and adjuvants. Furthermore, unlike whole cell vaccines, TMV vaccines do not secrete immunosuppressive factors. TMVs are particulate in nature and carry membrane associated tumor antigens, altered carbohydrate antigens, and antigenic epitopes derived from cytosolic proteins in the form of major histocompatibility complex associated peptides. Our preliminary studies show that TMV vaccine in combination with ICI is more effective than ICI alone in murine oral cancer models. We hypothesize that a personalized vaccine immunotherapy will expand tumor-specific T cells and the addition of ICI prevents the exhaustion of tumor antigen-specific T cells to induce robust anti-tumor T cell responses and significantly enhance the clinical response against HNSCC tumors that are not responsive to currently approved immunotherapies. The hypothesis will be tested in the following specific aims: Aim 1: To determine whether the dose and schedule can be altered to increase the anti-tumor immune response and efficacy of TMV vaccine in a mouse model of HNSCC, Aim 2: To investigate whether TMV vaccine inhibits metastasis/recurrence and extends the survival of mice in a clinically relevant setting, and Aim 3: To conduct a phase 1b dose-escalation clinical trial of TMV-based immunotherapy alone and in combination with pembrolizumab in patients with recurrent or metastatic HNSCC. Completion of the proposed work will advance a novel, personalized vaccine immunotherapy approach for patients with recurrent and/or metastatic HNSCC.