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

个体化疫苗免疫疗法联合抗 PD 1 抗体治疗复发性或转移性头颈部鳞状细胞癌

• 批准号: 10658577
• 负责人: DONG M SHIN
• 金额: $ 62.55万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-18 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658577
• 关键词: Address; Adjuvant; Adult; Animal Model; Antigen Targeting; Antigens; Antitumor Response; Applications Grants; Autologous; Biological; Blood; Cancer Etiology; Cancer Model; Cancer Vaccines; Carbohydrates; Cells; Cessation of life; Clinical; Clinical Trials; Clinical Trials Design; Complement; Data; Dependence; Dose; Epitopes; Exhibits; Gene Mutation; Gene Targeting; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Heterogeneity; Human; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunologic Markers; Immunologic Stimulation; Immunotherapy; In Vitro; Lead; Link; Logistics; Major Histocompatibility Complex; Malignant Neoplasms; Membrane; Metastatic Squamous Cell Carcinoma; Monoclonal Antibodies; Mus; Nature; Neoplasm Metastasis; Operative Surgical Procedures; Particulate; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase Ib Clinical Trial; Play; Progression-Free Survivals; Proteins; Recommendation; Recurrence; Reporting; Resistance; Role; Safety; Schedule; Source; T cell infiltration; T cell response; T-Lymphocyte; Testing; Translating; Tumor Antigens; Tumor Cell Derivative Vaccine; Tumor Expansion; Tumor Immunity; Tumor Tissue; Vaccination; Vaccines; Vesicle; Weight; Whole Cell Vaccine; Work; anti-PD-1; anti-PD1 antibodies; anti-tumor immune response; antigen-specific T cells; cancer cell; checkpoint therapy; clinically relevant; cohort; cost effective; dose information; established cell line; exhaustion; improved; malignant mouth neoplasm; mouse model; novel; novel vaccines; patient variability; pembrolizumab; personalized immunotherapy; prevent; primary endpoint; programmed cell death protein 1; response; scaffold; secondary endpoint; small molecule; synergism; therapeutic vaccine; therapeutically effective; tumor; tumor growth; tumor heterogeneity; vaccine development; vaccine immunotherapy; vaccine trial

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.

项目概要/摘要 免疫检查点抑制剂（ICI），例如抗 PD-1 抗体，可以改善患有癌症的患者的生存率 然而，仅部分患者（<20%）患有转移性头颈鳞状细胞癌（HNSCC）。 由于 ICI 通过阻断预先存在的抗肿瘤 T 细胞的负调节因子来发挥作用。 免疫，大多数 HNSCC 患者对抗 PD-1 mAb 缺乏反应，这表明大多数 HNSCC 患者要么没有预先存在的抗肿瘤免疫力，要么其他免疫抑制途径发挥了作用 因此，将抗 PD-1 mAb 与疫苗接种方法相结合，可以诱导抗肿瘤 T。 细胞免疫可能比单药 ICI 更有效，但不同患者的目标存在差异。 抗原使 HNSCC 成为开发有效治疗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型疫苗免疫疗法来治疗 HNSCC，其方法如下： 是个性化的，因此将患者与患者之间的抗原特征差异结合起来。 疫苗由肿瘤膜囊泡 (TMV) 组成，该膜囊泡由患者肿瘤制成，与强效疫苗缀合 与之前的自体肿瘤裂解物相比，通过蛋白质转移产生免疫刺激分子（ISM）。 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特征和 ISM 呈现给免疫细胞以诱导 抗原和佐剂的这种物理连接已被证明可以诱导有效的抗肿瘤反应。 比未结合的抗原和佐剂的混合物更有效的免疫反应。 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 来自我们初步的主要组织相容性复合物相关肽形式的胞浆蛋白。 研究表明，TMV 疫苗与 ICI 联合治疗小鼠口腔癌比单独使用 ICI 更有效 我们认为个性化疫苗免疫疗法将扩大肿瘤特异性 T 细胞和 添加 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 反应并显着增强对 HNSCC 肿瘤无反应的临床反应 目前已批准的免疫疗法将在以下具体目标中进行测试： 目标 1： 确定剂量和时间表是否可以增加抗肿瘤免疫反应和 TMV 疫苗在 HNSCC 小鼠模型中的功效，目标 2：研究 TMV 疫苗是否抑制 转移/复发并在临床相关环境中延长小鼠的生存期，目标 3：进行 基于 TMV 的免疫疗法单独和联合的 1b 期剂量递增临床试验 派姆单抗治疗复发性或转移性 HNSCC 的拟定工作将提前完成。 一种针对复发性和/或转移性 HNSCC 患者的新型个性化疫苗免疫治疗方法。