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(由申请人提供)：治疗公司专注于开发具有所需免疫活性的佐剂系统，用于靶向适应症。该公司的免疫刺激佐剂平台建立在免疫激动剂的组合使用基础上，这些免疫激动剂具有不同的免疫目标和作用机制，可产生治疗性免疫反应。这一平台技术的关键是使用新形式的肿瘤坏死因子配体(TNFL)共刺激家族药物，这些药物直接调节先天、适应性和调节性免疫，并与模式识别受体相互作用，以实现持续的免疫效应反应。该公司的先导佐剂系统IAS-01构成了一种新形式的4-1BBL/Streptavidin嵌合分子，它是以单磷酰脂A(MPL)作为Toll样受体4(TLR4)的激动剂而配制的。4-1BBL的选择基于多效性效应 4-1BB共刺激信号在天然(NK细胞、NKT细胞、巨噬细胞、中性粒细胞和DC)、获得性(CD4+和CD8+T细胞)和调节性(CD4+CD25+FoxP3+T调节(Treg)细胞)免疫细胞中的作用，以及这些细胞群体在协调反应中的关键作用 根除癌症和控制复发。MPL通过上调抗原提呈细胞上的4-1BB受体和配体来补充4-1BBL的免疫活性，并且4-1BBL与TLRs物理上相互作用以维持天然免疫反应。因此，这两种药物的联合使用有可能产生强大的免疫效应器反应，克服免疫逃避机制，最终达到根除癌症和控制复发的目的。为了支持这一点，我们最近表明，ISAS-01作为基于TAA的蛋白疫苗的佐剂成分，在各种临床前模型中对肿瘤的根除是有效的。默克KGaA正在开发的一种基于粘蛋白1(MUC1)TAA的非小细胞肺癌疫苗tecemotie在一项III期临床研究中未能达到提高患者总体生存率的主要终点。导致Vaccie无效的因素尚不清楚。我们推测，作为疫苗配方的一部分，缺乏能够产生强大免疫效应器反应的有效佐剂系统，以及需要克服肿瘤免疫逃避机制，可能是疫苗失败的原因之一。因此，这一阶段STTR应用的主要目标是测试ISAS-01佐剂系统是否能产生针对MUC1TAA的强大细胞免疫反应，并使用MUC1转基因(TG)小鼠作为严格的临床前肿瘤模型来提高基于替克莫肽的疫苗配方的治疗效果。设计的三个具体目标是：i)建立一种能对MUC1TAA产生强大的Th1反应的重新配方疫苗，ii)评估该疫苗在根除MUC1TAA小鼠肺癌方面的治疗效果，以及iii)调查与疫苗疗效/失败相关的免疫反应。重新配制的疫苗比基于替莫肽的疫苗具有更好的疗效，这将表明需要进一步开发这种疫苗，并有可能进入肺癌的I期临床试验。