Development of a novel Virus-Like Particle vaccine-based cancer immunotherapy targeting PD-L1.

开发一种新型病毒样颗粒疫苗为基础的针对 PD-L1 的癌症免疫疗法。

• 批准号: 9409414
• 负责人: Wataru Akahata
• 金额: $ 29.87万
• 依托单位: VLP THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-20 至 2018-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409414
• 关键词: Adverse effects; Adverse event; Alphavirus; Antibodies; Antibody Formation; Antibody Therapy; Antigens; Apoptosis; Autoimmunity; B-Lymphocyte Epitopes; Benchmarking; Binding; Blocking Antibodies; Blood; CD4 Positive T Lymphocytes; Cancer Vaccines; Cancerous; Cells; Clinical Trials; Development; Future; Goals; Histologic; Immune; Immune response; Immunosuppressive Agents; Immunotherapy; Incubated; Injectable; Injection of therapeutic agent; Intramuscular; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Measures; Medical; Medical center; Memory B-Lymphocyte; Modality; Modeling; Molecular Conformation; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Patients; Pharmacodynamics; Phase I Clinical Trials; Play; Production; Proteins; Regimen; Route; Safety; Societies; Spleen; Staining method; Stains; Structure; Surface; Survival Rate; T-Lymphocyte; Therapeutic; Therapeutic Effect; Tissues; Toxicology; Vaccinated; Vaccination; Vaccines; Viral Genome; Virus; Virus-like particle; aluminum sulfate; antitumor effect; base; cancer immunotherapy; cancer subtypes; checkpoint therapy; chemotherapy; chikungunya; cost; cost shifting; cytokine; effective therapy; immune checkpoint; innovation; insight; intraperitoneal; malignant breast neoplasm; melanoma; mouse model; nonhuman primate; novel; novel virus; outcome forecast; particle; phase 1 study; phase 2 study; receptor; response; success; triple-negative invasive breast carcinoma; tumor; tumor growth; vaccination schedule; vaccine efficacy; virtual

Abstract Cancer immunotherapy has revolutionized today’s treatments for many forms of cancers. In particular, blocking antibodies to immune checkpoint proteins, such as programmed cell death-1 (PD-1) and its ligand, programmed cell death-ligand 1 (PD-L1), effectively unleash immune cell destruction of cancerous cells. However, the high cost of these antibody-based immunotherapies, their intensive therapeutic regimen and availability only at specialized medical centers make current immunotherapies impractical in all but the most advantaged societies. We hypothesize that an effective vaccine which can overcome these significant shortcomings of antibody-based immunotherapies while simultaneously mimicking their potent therapeutic benefits can impact the lives of countless more patients: in particular, a vaccine that induces durable levels of host antibodies against the tumor-associated PD-L1 protein will have powerful anti-tumor effects by inhibiting the PD-L1:PD1 immunosuppressive checkpoint interaction. We, at VLP Therapeutics, have developed a proprietary, ‘plug-and-play’ vaccine platform called inserted alphavirus virus-like particle (i-αVLP) using the Chikungunya (CHIK) VLP. VLPs mimic the conformation of native viruses without the viral genome, thus capable of stimulating a robust host response absent safety issues. Foreign antigens can be inserted into the surface loop domains of i-αVLP. Due to its unique structure, i-αVLP can efficiently present a dense array of 240 copies of the inserted antigen on the particle surface. i-αVLP induces highly effective immune responses to the inserted antigen, and CHIK VLPs have shown acceptable safety profiles in a Phase I clinical trial. We propose to establish proof of concept of our PD-L1-targeting vaccine’s efficacy in a triple negative breast cancer (TNBC)-like model given that (1) TNBCs have shown some responsiveness to PD-L1/PD-1 antibody therapies in clinical trials; and (2) there remains a high unmet need for effective therapies against this particularly aggressive form of breast cancer which has the worst five- year survival prognosis among all breast cancers and for which standard chemotherapy treatment is largely ineffective. The goal of this proposal is to determine the extent to which vaccination with our proprietary i-αVLP-based PD-L1 vaccine (PD-L1- αVLP) can mimic the effects of passive PD-L1 monoclonal antibody therapy. This study will provide the basis for advancing this exciting approach into clinical trials. To create this vaccine, we propose the following Specific Aims: Aim 1: Determine the ability of PD-L1-αVLP to stimulate the production of antibodies that bind to tumor- associated PD-L1 and inhibit its binding to the T-cell immune checkpoint receptor, PD-1, in murine models. Aim 2. Determine the therapeutic effects of PD-L1-αVLP vaccination in a PD-1/PD-L1 antibody therapy-sensitive murine tumor model benchmarked against PD-L1 monoclonal antibody treatment. Aim 3: Determine whether potential immune-related adverse events including autoimmunity can be induced by our PD-L1-αVLP vaccine.

摘要 癌症免疫疗法已经彻底改变了当今许多形式癌症的治疗方法。特别是， 免疫检查点蛋白的抗体，例如程序性细胞死亡-1（PD-1）及其配体、程序性细胞死亡蛋白（PD-L1）及其配体、程序性细胞死亡蛋白（PD-L2）及其配体、程序性细胞死亡蛋白（PD-L3）及其配体。 死亡配体1（PD-L1），有效地释放癌细胞的免疫细胞破坏。然而，这些高成本 基于抗体的免疫疗法，其强化治疗方案和仅在专业医疗中心可用 使当前的免疫疗法在除最有利的社会之外的所有社会都不切实际。我们假设一个有效的 疫苗，其可以克服基于抗体的免疫疗法的这些显著缺点， 同时模仿其强大的治疗益处可以影响无数患者的生活： 特别地，诱导针对肿瘤相关PD-L1蛋白的持久水平的宿主抗体的疫苗将 通过抑制PD-L1：PD 1免疫抑制检查点相互作用，具有强大的抗肿瘤作用。我们，在 VLP Therapeutics开发了一种专有的“即插即用”疫苗平台，称为插入的甲病毒样病毒 粒子（i-αVLP）使用基孔肯雅病毒（CHIK）VLP。VLP模拟天然病毒的构象，而不具有病毒特异性。 基因组，因此能够刺激稳健的宿主应答而没有安全性问题。外源抗原可以插入到 i-αVLP的表面环结构域。由于其独特的结构，i-αVLP可以有效地呈现240个拷贝的密集阵列。 在颗粒表面插入抗原。i-αVLP诱导对插入抗原的高效免疫应答，和 CHIK VLP在I期临床试验中显示出可接受的安全性。我们建议建立概念证明， 我们的PD-L1靶向疫苗在三阴性乳腺癌（TNBC）样模型中的疗效， 已经在临床试验中显示出对PD-L1/PD-1抗体疗法的一些反应性;和（2）仍然存在高的 对这种特别侵袭性的乳腺癌的有效疗法的未满足的需求， 在所有乳腺癌中，标准化疗治疗在很大程度上无效。 本提案的目的是确定使用我们专有的基于i-α VLP的PD-L1疫苗接种 疫苗（PD-L1- αVLP）可以模拟被动PD-L1单克隆抗体治疗的效果。这项研究将提供 这是将这种令人兴奋的方法推进临床试验的基础。为了制造这种疫苗，我们提出了以下具体方案： 目的：目的1：确定PD-L1-αVLP刺激产生与肿瘤细胞结合的抗体的能力。 在小鼠模型中，PD-L1相关，并抑制其与T细胞免疫检查点受体PD-1的结合。目标二。 确定PD-L1-αVLP疫苗接种在PD-1/PD-L1抗体治疗敏感性小鼠肿瘤中的治疗作用 以PD-L1单克隆抗体治疗为基准的模型。目的3：确定是否存在潜在的免疫相关性 我们的PD-L1-αVLP疫苗可诱导包括自身免疫在内的不良事件。