Lymph node-targeted molecular vaccines

淋巴结靶向分子疫苗

• 批准号: 9330154
• 负责人: Darrell J Irvine
• 金额: $ 34.77万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330154
• 关键词: Adjuvant; Adjuvant Therapy; Affinity; Albumins; Amino Acids; Antigen-Presenting Cells; Antigens; Area; Binding; Biodistribution; Biology; Blood; CD8-Positive T-Lymphocytes; Cancer Vaccines; Cells; Clinical; Cues; Cytokine Receptors; Data; Disseminated Malignant Neoplasm; Drug Targeting; Drug or chemical Tissue Distribution; Dyes; Excision; Exhibits; FDA approved; Genetic Heterogeneity; Homing; Human; Immune Cell Activation; Immune response; Immunologics; Immunomodulators; Immunotherapy; Injection of therapeutic agent; Lipids; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lymph Node Mapping; Lymphatic; Malignant Neoplasms; Malignant neoplasm of lung; Metastatic Neoplasm to the Lung; Modeling; Molecular; Molecular Target; Molecular Vaccines; Mucous Membrane; Mus; Nature; Oligonucleotides; Operative Surgical Procedures; Parents; Patients; Pattern; Peptide Vaccines; Peptides; Polymers; Population; Primary Neoplasm; Process; Reagent; Reporting; Sentinel Lymph Node; Serum Albumin; Serum Proteins; Site; T cell response; T-Lymphocyte; TLR3 gene; TLR7 gene; TP53 gene; Tail; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Vaccination; Vaccines; Viral Vector; Visual; amphiphilicity; base; cancer immunotherapy; cancer therapy; chemotherapy; clinical efficacy; cytokine; design; immune checkpoint blockade; immunoregulation; improved; in vivo; interest; interleukin-15 receptor; lipophilicity; lymph nodes; mucosal vaccination; mutant; novel; polypeptide; public health relevance; research clinical testing; response; success; synergism; therapeutic vaccine; tumor; tumor microenvironment; vaccine efficacy; vaccine response

 DESCRIPTION (provided by applicant): Therapeutic strategies aiming to promote immune responses against tumors are of great interest for their potential to destroy metastatic cancer despite its genetic heterogeneity and ability to evade traditional chemotherapy or targeted drugs. Therapeutic vaccines are particularly compelling, because of their low toxicity and broad applicability to diverse human cancers. Recently, the first signs of therapeutic efficacy in cancer vaccines have begun to be reported, and the first cancer vaccine to be approved by the FDA (the cellular vaccine Provenge) was licensed in 2010. Vaccines based on polypeptide antigens, such as "long" peptides (peptides of 20-40 amino acids that can be processed and presented by diverse human HLAs) are much simpler to manufacture and have also recently begun to show signs of efficacy in patients. However, such vaccines, typically formulated as soluble polypeptides mixed with various adjuvant compounds, leave much room for improvement in terms of their potency in promoting T-cell responses. In an effort to enhance polypeptide vaccines, we sought a readily translatable strategy to enhance vaccine targeting to lymph nodes, where immune responses are initiated. Taking cues from another area of clinical cancer management, we noted that identification of sentinel lymph nodes (LNs) draining sites of primary tumor resection is often performed by the injection of dyes that avidly bind to the ubiquitous serum protein albumin. Albumin-binding dyes are efficiently carried through lymphatics and accumulate in the lymph node, allowing visual identification of the draining nodes following surgery. Mimicking this process, we designed molecular vaccines composed of peptide antigens or immunostimulatory oligonucleotides (single-stranded CpG oligos) conjugated to lipophilic tails with an intervening polymer or oligonucleotide spacer. Strikingly, when these lipid-polar block vaccine amphiphiles were synthesized with (i) lipophilic tails exhibiting high affinity for albumin and (ii) long polar spacers/cargos, they exhibited dramaticall enhanced (>10-fold) accumulation in LNs following parenteral injection relative to soluble peptide/CpG. This enhanced LN targeting of both antigens and molecular adjuvants elicited dramatically enhanced CD8+ T-cell responses, comparable to viral vectors. Based on this promising preliminary data, we propose to establish the mechanisms by which these "albumin-hitchhiking" amphiphile vaccines function and to test the extensibility of this approach to other adjuvant and immunomodulatory factors. In addition, we have discovered that amph-vaccines efficiently transit across the airway mucosa, and we will test the capacity of pulmonary amphiphiles to serve as simultaneous vaccines priming new T-cell responses in draining LNs and direct modulators of the lung tumor microenvironment in models of lung metastasis and primary GEM lung adenocarcinomas.

 描述（由适用提供）：旨在促进对肿瘤的免疫反应的治疗策略，尽管其遗传异质性和逃避传统的化学疗法或靶向药物的能力，但它们有可能破坏转移性癌症。治疗性疫苗尤其引人注目，因为它们对潜水人类癌症的毒性低和广泛的适用性。最近，癌症热效率的第一个迹象 疫苗已经开始报道，并且第一种由FDA批准的癌症（细胞疫苗预备）于2010年获得许可。基于多肽抗原的疫苗，例如“长” PETIDE（诸如20-40个氨基酸的肽），可以由Divers Human Hlas进行处理并呈现出来的范围，以便于制造效果，并启用了范围的效果，并既既可以又有范围。但是，这种疫苗通常以可溶性多肽和各种调节化合物的形式配制，在促进T细胞反应方面有很大的改善空间。为了增强多肽疫苗，我们寻求一种容易转换的策略，以增强对淋巴结的疫苗靶向，在该淋巴结中启动免疫反应。从另一个临床癌症管理领域获取线索，我们注意到，诊断前肿瘤切除的前哨淋巴结（LNS）排水位点通常是通过注射染料与无处不在的血清蛋白相册的注射来进行的。白蛋白结合染料通过淋巴结有效地携带并积聚在淋巴结中，从而可以在手术后视觉鉴定排水节点。我们模仿了这一过程，我们设计了由胡椒抗原或免疫刺激性寡核苷酸（单链的CPG寡核苷）组成的分子疫苗，该疫苗与亲脂性尾巴相结合，并带有中等的聚合物或寡核苷酸间距。令人惊讶的是，当这些脂极块疫苗的两亲物与（i）对白蛋白的高亲和力（II）长极间隔剂/cargos合成（i）的（i）亲脂性尾巴时，它们暴露了相对于固体肽/CPG的固体固体损伤后LN中的急剧增强（> 10倍）的累积（> 10倍）。这种增强的LN靶向抗原和分子调节器引起的CD8+ T细胞反应显着增强，与病毒载体相当。基于此承诺的初步数据，我们建议建立这些“途径”两亲疫苗功能的机制，并测试这种方法对其他可调节和免疫调节因子的可扩展性。 In addition, we have discovered that amph-vaccines efficiently transit across the airway mucosa, and we will test the capacity of pulmonary amphiphiles to serve as simple vaccines priming new T-cell responses in draining LNs and direct modulators of the lung tumor microenvironment in models of lung metastasis and primary GEM lung adenocarcinomas.