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

• 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
• 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

 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（由应用程序提供）：治疗药物集中于开发具有预期的免疫活动的调整系统，以实现靶向指示。该公司的免疫刺激调整平台建立在具有独特的免疫靶标的免疫范围的组合使用基础上，并为产生热免疫反应的作用机制。对该平台技术至关重要的是使用新型的肿瘤坏死因子配体（TNFL）的共同刺激家族药物的使用，这些家族药物直接调节先天性，适应性和调节性免疫学和串扰，并带有模式识别受体，以进行持续的免疫反应。该公司的铅调节系统ISAS-01构成了一种新型形式的4-1BBL/链霉亲和蛋白嵌合分子，该分子用单磷脂质A（MPL）作为Toll-like受体4（TLR4）的激动剂。 4-1BBL的选择是基于多效效应。的 4-1BB先天细胞（NK细胞，NKT细胞，巨噬细胞，中性粒细胞和DCS），适应性（CD4+和CD8+ T细胞）以及调节性（CD4+ CD25+ FOXP3+ FOXP3+ T调节性（Treg）细胞）免疫史和这些细胞均质的关键作用的调节性的4-1bb cotimulation信号传导。 癌症的脱毛和复发的控制。 MPL通过在抗原呈现细胞上上调4-1BB受体和配体的4-1BBL的免疫学活性，而4-1BBL与TLR进行了物理相互作用，以实现持续的先天免疫反应。因此，这两种药物的综合使用具有产生强大的免疫效应子反应并克服免疫进化机制的潜力，最终导致癌症的脱毛并控制复发。对此的支持，我们最近表明，ISAS-01作为基于TAA的蛋白质疫苗的可调节成分有效地消除了各种临床前模型中的肿瘤。默克蛋白1（MUC1）基于TAA的疫苗Tecemotide针对由Merck KGAA开发的非小细胞肺癌的粘蛋白疫苗未能满足其在III期临床研究中改善总体患者存活的主要终点。导致真空无效的因素尚不清楚。我们假设缺乏潜在的调整系统可以作为疫苗配方的一部分产生强大的免疫效应子反应，以及克服肿瘤免疫效应机制的需求可能导致疫苗衰竭。因此，该阶段ISTTR应用的主要目的是测试ISAS-01调整系统是否使用MUC1转基因（TG）小鼠作为严格的临床上肿瘤模型产生了针对MUC1 TAA的强大细胞免疫反应，并提高基于Tecemotide的疫苗式的治疗效率。 i）建立了三个特定的目标，建立了一种改革的疫苗，该疫苗对MUC1 TAA产生强大的Th1反应，ii）评估疫苗在消除MUC1 TG小鼠中肺癌中的治疗效率，以及III）研究与疫苗效率/失败相关的免疫膜。改革后的疫苗比基于tecemotide的疫苗配方的效率更高，将表明需要进一步开发这种疫苗，并有可能进入I期肺癌临床试验。