Lymph node-targeted molecular vaccines

淋巴结靶向分子疫苗

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：旨在促进针对肿瘤的免疫反应的治疗策略因其消灭转移性癌症的潜力而受到极大关注，尽管其具有遗传异质性并且能够逃避传统化疗或靶向药物，但由于其治疗性疫苗特别引人注目。低毒性和对多种人类癌症的广泛适用性最近出现了对癌症治疗功效的第一个迹象。疫苗已经开始有报道，第一个获得 FDA 批准的癌症疫苗（细胞疫苗 Provenge）于 2010 年获得许可。基于多肽抗原的疫苗，例如“长”肽（由 20-40 个氨基酸组成的肽）可以由不同的人类 HLA 加工和呈递），制造起来更加简单，并且最近也开始在患者中显示出疗效的迹象。然而，此类疫苗通常配制为与各种佐剂化合物混合的可溶性多肽，在促进 T 细胞反应的效力方面还有很大的改进空间为了增强多肽疫苗，我们寻求一种易于转化的策略来增强疫苗对淋巴结的靶向性，从其他区域获取线索。在临床癌症管理的过程中，我们注意到，原发性肿瘤切除术中前哨淋巴结（LN）引流部位的识别通常是通过注射与普遍存在的血清白蛋白结合染料有效结合的染料来进行的。通过淋巴管携带并积聚在淋巴结中，从而可以在手术后目视识别引流节点。模仿这一过程，我们设计了由肽抗原或免疫刺激性寡核苷酸（单链 CpG 寡核苷酸）与中间聚合物缀合而成的分子疫苗。引人注目的是，当这些脂质极性阻断疫苗两亲物合成时具有（i）对白蛋白和表现出高亲和力的亲脂性尾部。 (ii) 长极性间隔基/货物，相对于可溶性肽/CpG，它们在肠胃外注射后在 LN 中的积累显着增强（>10 倍），这种增强的 LN 对抗原和分子佐剂的靶向性显着增强了 CD8+ T 细胞反应。，与病毒载体相比，基于这些有希望的初步数据，我们建议建立这些“白蛋白搭便车”两亲疫苗的作用机制并测试其可扩展性。这种针对其他佐剂和免疫调节因子的方法此外，我们发现两亲疫苗可以有效地穿过气道粘膜，并且我们将测试肺两亲分子作为同时疫苗在引流淋巴结和中引发新的 T 细胞反应的能力。肺转移和原发性 GEM 肺腺癌模型中肺肿瘤微环境的直接调节剂。