Developing a novel adjuvant system for therapeutic vaccines against lung cancer

开发用于肺癌治疗疫苗的新型佐剂系统

基本信息

批准号：
9138899
负责人：
Haval Shirwan
金额：
$ 22.5万
依托单位：
FASCURE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9138899
关键词：
Adjuvant Agonist Antigen-Presenting Cells Antigens Benchmarking CD28 gene CD8B1 gene Cancer Control Cancer Vaccines Cells Cessation of life Clinical Research Clinical Trials Communication Complement Dendritic Cells Development Effector Cell Extracellular Domain FDA approved Face Failure Family Family member Formulation Generations Goals Human IL2RA gene Immune Immune Targeting Immune response Immunity Immunologic Adjuvants Inflammatory Response Investigational New Drug Application Lead Ligands Lipid A Malignant Neoplasms Malignant neoplasm of lung Memory Modeling Mucin 1 protein Natural Immunity Natural Killer Cells Nature Non-Small-Cell Lung Carcinoma Pathway interactions Patients Pattern recognition receptor Peptides Phase Phase I Clinical Trials Phase III Clinical Trials Population Pre-Clinical Model Preparation Proteins Public Health Publishing Recurrence Regulatory T-Lymphocyte Research Role Signal Transduction Small Business Technology Transfer Research Specificity Streptavidin System T cell anergy T cell response T-Cell Activation T-Lymphocyte TLR4 gene TNF gene Technology Testing Therapeutic Toxic effect Toxicology Transgenic Mice Treatment Efficacy Tumor Necrosis Factor Receptor United States Vaccine Antigen Vaccines base combinatorial conventional therapy cross immunity design improved lung Carcinoma macrophage meetings mouse model neutrophil novel pleiotropism pre-clinical public health relevance receptor response standard care therapeutic development therapeutic vaccine tumor tumor eradication vaccine development vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Therapeutics is focused on the development of adjuvant systems with desired immune activities for targeted indications. The Company's immune stimulatory adjuvant platform builds on combinatorial use of immune agonists with distinct immune targets and mechanisms of action for the generation of therapeutic immune responses. Critical to this platform technology is the use of novel forms of tumor necrosis factor ligand (TNFL) costimulatory family agents that directly modulate innate, adaptive, and regulatory immunity and cross- talk with pattern recognition receptors for sustained immune effector responses. The Company's lead adjuvant system, ISAS-01, constitutes a novel form of 4-1BBL/streptavidin chimeric molecule formulated with monophosphoryl lipid A (MPL) as an agonist of toll-like receptor 4 (TLR4). The choice of 4-1BBL is based on the pleiotropic effects of 4-1BB costimulatory signaling in cells of innate (NK cells, NKT cells, macrophages, neutrophils, and DCs), adaptive (CD4+ and CD8+ T cells), and regulatory (CD4+CD25+FoxP3+ T regulatory (Treg) cells) immunity, and the critical role of coordinated responses of these cell populations in the eradication of cancer and control of recurrences. MPL complements the immune activities of 4-1BBL by upregulating the 4-1BB receptor and ligand on antigen presenting cells, and 4-1BBL physically interacts with TLRs for sustained innate immune responses. Therefore, the combined use of these two agents has the potential to generate robust immune effector responses and overcome immune evasion mechanisms, culminating in the eradication of cancer and control of recurrences. In support of this, we have recently shown that ISAS-01 as the adjuvant component of TAA-based protein vaccines was effective in eradicating tumors in various preclinical models. A mucin 1 (MUC1) TAA-based vaccine, tecemotide, against non-small cell lung cancer being developed by Merck KGaA has failed to meet its primary endpoint of improving overall patient survival in a phase III clinical study. Factors contributing to the vaccie inefficacy are unknown. We hypothesize that the lack of a potent adjuvant system able to generate a robust immune effector response as part of vaccine formulation, as well as the need to overcome tumor immune evasion mechanisms may have contributed to the vaccine failure. Therefore, the main objective of this Phase I STTR application is to test if the ISAS-01 adjuvant system generates robust cellular immune responses against MUC1 TAA and improves therapeutic efficacy of the tecemotide-based vaccine formulation using MUC1 transgenic (TG) mice as a stringent preclinical tumor model. Three specific Aims are designed to i) establish a reformulated vaccine that generate robust Th1 responses to MUC1 TAA, ii) assess the therapeutic efficacy of the vaccine in eradicating lung carcinoma in MUC1 TG mice, and iii) investigate immune responses associated with vaccine efficacy/failure. A better efficacy for the reformulated vaccine over the tecemotide-based vaccine formulation will indicate the need for further development of this vaccine and potential for entry into phase I clinical trials for lung cancer.

描述（由申请人提供）：治疗重点是开发具有针对目标适应症的所需免疫活性的佐剂系统，该公司的免疫刺激佐剂平台建立在免疫激动剂与不同免疫靶点和作用机制的组合使用的基础上，以产生治疗药物。该平台技术的关键是使用新型肿瘤坏死因子配体（TNFL）共刺激家族药物，直接调节先天性、适应性和调节性免疫反应。该公司的主要佐剂系统 ISAS-01 是一种新型 4-1BBL/链霉亲和素嵌合分子，与单磷酰脂质 A (MPL) 一起作为 Toll 样激动剂配制。受体 4 (TLR4) 的选择是基于 4-1BBL 的多效性效应。先天性（NK 细胞、NKT 细胞、巨噬细胞、中性粒细胞和 DC）、适应性（CD4+ 和 CD8+ T 细胞）和调节性（CD4+CD25+FoxP3+ T 调节性 (Treg) 细胞）免疫细胞中的 4-1BB 共刺激信号传导，以及这些细胞群协调反应的关键作用 MPL 通过上调抗原呈递细胞上的 4-1BB 受体和配体来补充 4-1BBL 的免疫活性，并且 4-1BBL 与 TLR 物理相互作用以实现持续的先天免疫反应。使用这两种药物有可能产生强大的免疫效应反应并克服免疫逃避机制，最终消除癌症并控制复发。我们最近的研究证明了这一点。默克公司正在开发一种基于粘蛋白 1 (MUC1) TAA 的疫苗 tecemotide，用于治疗非小细胞肺癌，ISAS-01 作为基于 TAA 的蛋白质疫苗的佐剂成分可有效根除肿瘤。在一项 III 期临床研究中，未能达到改善患者总体生存率的主要终点。导致疫苗无效的因素尚不清楚。我们发现缺乏有效的佐剂系统。作为疫苗配方的一部分，能够产生强大的免疫效应反应，以及克服肿瘤免疫逃避机制的需要可能是导致疫苗失败的原因，因此，第一阶段 STTR 应用的主要目标是测试 ISAS 是否有效。 -01 佐剂系统针对 MUC1 TAA 产生强大的细胞免疫反应，并使用 MUC1 转基因 (TG) 小鼠作为严格的临床前肿瘤模型，提高基于替西莫肽的疫苗制剂的治疗效果。 i) 建立一种重新配制的疫苗，对 MUC1 TAA 产生强烈的 Th1 反应，ii) 评估疫苗在根除 MUC1 TG 小鼠肺癌方面的治疗效果，以及 iii) 研究与疫苗功效/失败相关的免疫反应。与基于替西莫肽的疫苗配方相比，重新配制的疫苗将表明需要进一步开发该疫苗以及进入肺癌一期临床试验的潜力。