Personalized, antigen-directed immunotherapy delivered to lymph nodes

项目摘要 T细胞启动是在淋巴结（LN）的隔离环境中精心策划的，在淋巴结中， 来自细胞类型集合的抑制和共刺激信号决定了系统性、免疫显性 对区域呈递抗原（Ag）的反应。然而，肿瘤引流淋巴结（tdLN）通常耐受抗 肿瘤抗原（tAgs），使原本不适宜的环境允许局部LN转移， 最终扩散到全身。虽然检查点阻断免疫疗法（CBI）癌症治疗 意在重新激活针对tAg的T细胞引发和效应子功能，这些疗法是静脉内施用的。 而不考虑身体中存在的所有其他非tAg。由于这种Ag不加选择的 然而，CBI可能导致免疫相关不良事件（irAE），限制了当前和新出现的CBI的使用。 此外，由于tdLN在癌症检测时已经对tAg耐受，因此， CBI有效地引发tAg特异性T细胞应答可能是有限的。虽然CBI确实会导致持久的癌症 治愈，大多数癌症类型是无反应的，大多数癌症患者已知是有反应的 未从CBI治疗中获益或发生复发和irAE。 在这个应用程序中，来自德克萨斯大学和伯尔尼大学的多学科团队合作， 向非tdLN提供tAg和CBI，以便在没有irAE的情况下安装有效的、tAg导向的CBI， 影响其他CBI组合疗法。具体来说，该团队建议开发和使用一个可翻译的， 基于植物的病毒样颗粒（VLP）平台呈递特异性肿瘤新抗原（tNeoAg），并将其联合收割机 在三阴性乳腺癌的同基因小鼠模型中， （TNBC）。强有力的初步数据证明了该方法的有效性，显示出增强的抗肿瘤作用。 免疫应答伴随细胞溶解性、tAg特异性肿瘤浸润淋巴细胞的克隆扩增， 单细胞RNA测序的生物信息学分析。研究小组进一步建议， VLP-tNeoAg与CBI一起分散淋巴流域，以产生对 对抗肿瘤免疫逃逸和再生。该团队还将在转基因动物中测试该方法的安全性。 在正常组织中对诱导淋巴浸润敏感的小鼠作为CBI后irAE的临床读数 剂量。由于这些团队已经将各自的技术转化为临床研究， 在此进行的开发可以被快速实施以提高当前和新兴的CBI的功效， 建立个性化癌症疫苗的概念，并扩大CBI在患有TNBC的患者中的使用 有限的治疗选择。

Project Summary T-cell priming is orchestrated in the sequestered environment of lymph nodes (LNs) where a cascade of co- inhibitory and co-stimulatory signals from an assembly of cell types determines systemic, immunodominant responses to regionally presented antigens (Ag). Yet tumor draining LNs (tdLNs) are often tolerized against tumor Ags (tAgs), rendering an otherwise inhospitable environment permissive to regional LN metastases and eventual dissemination throughout the body. While checkpoint blockade immunotherapy (CBI) cancer therapy is meant to re-invigorate T-cell priming and effector function against tAgs, these therapies are administered i.v. without regard to all the other non-tAgs that are present in the body. As a result of this Ag-indiscriminate activity, CBI can cause immune related adverse events (irAEs) that limit the use of current and emerging CBI. In addition, because tdLNs are already tolerized to tAgs by the time of cancer detection, the effectiveness of CBI to potently prime tAg-specific T-cell responses may be limited. While CBI does result in durable cancer cures, most cancer types are non-responsive and the majority of patients with cancers known to be responsive either do not benefit from CBI treatment or experience relapse and irAEs. In this application, multi-disciplinary teams from the University of Texas and University of Bern collaborate to deliver both tAg and CBI to non-tdLNs in order to mount efficient, tAg-directed CBI without the irAEs that impact other CBI combinational therapies. Specifically, the team proposes to develop and use a translatable, plant-based, virus-like-particle (VLP) platform presenting private tumor neoantigens (tNeoAgs) and to combine it with CBI delivered to lymphatic watersheds in syngeneic mouse models of triple negative breast cancer (TNBC). Effectiveness of the approach is evidenced by strong preliminary data showing enhanced anti-tumor responses accompanied by clonal expansion of cytolytic, tAg-specific tumor infiltrating lymphocytes from bioinformatic analyses of single cell RNA sequencing. The team further proposes to separately dose different VLP-tNeoAgs with CBI to discrete lymphatic watersheds to mount multiple, immunodominant responses to combat tumor immune escape and regrowth. The team will also test safety of the approach in a transgenic mouse susceptible to induced lymphatic infiltration in normal tissues as a clinical readout of irAEs following CBI dosing. Because the teams have translated their respective technologies into clinical studies, the developments made herein could be rapidly implemented to improve the efficacy of current and emerging CBI, establish the concept of personalized cancer vaccines, and expand the use of CBI in TNBC patients who have limited treatment options.