Lymph node-targeted molecular vaccines

 描述（由申请人提供）：旨在促进针对肿瘤的免疫应答的治疗策略因其破坏转移性癌症的潜力而备受关注，尽管转移性癌症具有遗传异质性并且能够逃避传统化疗或靶向药物。治疗性疫苗特别引人注目，因为它们毒性低，对各种人类癌症具有广泛的适用性。最近，癌症治疗效果的第一个迹象 疫苗的研究已经开始报道，FDA批准的第一种癌症疫苗（细胞疫苗Provenge）于2010年获得许可。基于多肽抗原的疫苗，如“长”肽（20-40个氨基酸的肽，其可以被不同的人HLA加工和呈递），制造起来要简单得多，并且最近也开始在患者中显示出功效的迹象。然而，这类疫苗通常配制成与各种佐剂化合物混合的可溶性多肽，就其促进T细胞应答的效力而言，留下了很大的改进空间。在增强多肽疫苗的努力中，我们寻求了一种易于翻译的策略来增强疫苗靶向淋巴结，其中免疫应答开始。从临床癌症管理的另一个领域获得线索，我们注意到，识别原发性肿瘤切除的前哨淋巴结（LN）引流部位通常通过注射与普遍存在的血清蛋白白蛋白结合的染料来进行。白蛋白结合染料可以有效地通过淋巴结转移并在淋巴结中积累，从而可以在手术后目视识别引流淋巴结。模仿这一过程，我们设计了分子疫苗组成的肽抗原或免疫刺激性寡核苷酸（单链CpG寡核苷酸）与亲脂性尾巴与插入聚合物或寡核苷酸间隔。引人注目的是，当这些脂质-极性嵌段疫苗两亲物用（i）对白蛋白表现出高亲和力的亲脂性尾部和（ii）长极性间隔区/货物合成时，它们在肠胃外注射后相对于可溶性肽/CpG在LN中表现出显著增强的（>10倍）积累。与病毒载体相比，这种增强的抗原和分子佐剂的LN靶向引起显著增强的CD 8 + T细胞应答。基于这个有希望的初步数据，我们建议建立这些“白蛋白搭便车”两亲疫苗的功能机制，并测试这种方法的可扩展性，以其他佐剂和免疫调节因子。此外，我们已经发现，amph疫苗有效地通过气道粘膜，我们将测试肺两亲物的能力，作为同时疫苗引发新的T细胞反应，在引流淋巴结和直接调节剂的肺肿瘤微环境中的肺转移和原发性GEM肺腺癌的模型。

 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.