Personalized, antigen-directed immunotherapy delivered to lymph nodes

递送至淋巴结的个性化抗原导向免疫疗法

基本信息

批准号：
10744599
负责人：
Mona Mohsen
金额：
$ 60.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10744599
关键词：
4T1 Affect Age Animals Antigen Presentation Antigens Antitumor Response Autoantigens Autoimmune Diseases Bacteriophages Binding Bioinformatics Breast Cancer Patient Breast Carcinoma Cancer Center Cancer Detection Cancer Patient Cancer Vaccines Cells Clinical Clinical Research Clonal Expansion Collaborations Combination immunotherapy Combined Modality Therapy Communicable Diseases Cross Presentation Cucumber mosaic virus Data Dendritic Cells Development Disease Dose Drug Delivery Systems Educational process of instructing Effectiveness Environment Growth Health Sciences Imaging technology Immune response Immunity Immunofluorescence Immunologic Immunologic Tests Immunologics Immunology Immunotherapy Infiltration Intervention Intravenous Ligands Link Lymphatic Malignant Neoplasms Mass Spectrum Analysis Metastatic Neoplasm to Lymph Nodes Modeling Mus Neoplasm Circulating Cells Normal tissue morphology Pathology Patients Phenotype Plants Predisposition Privatization Regulatory T-Lymphocyte Relapse Research Research Proposals Signal Transduction Site Switzerland T cell response T-Lymphocyte T-cell receptor repertoire TLR9 gene Technology Texas Time Transgenic Mice Translating Tumor Antigens Tumor Escape Tumor-Infiltrating Lymphocytes Universities Vaccinated Vaccination Vaccine Design Vaccine Production Vaccines Virus-like particle Woman Work anti-tumor immune response cancer immunotherapy cancer therapy cancer type cancer vaccination cell assembly cell type central tolerance clinical translation combat draining lymph node exhaust exome sequencing experience image guided immune checkpoint blockade immune-related adverse events immunoregulation improved intravenous administration lymph nodes lymphatic imaging man mouse model multidisciplinary neoantigen vaccination neoantigens peripheral tolerance permissiveness prevent response safety testing single cell analysis single-cell RNA sequencing transcriptomics triple-negative invasive breast carcinoma tumor tumor growth

项目摘要

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.

项目概要 T 细胞启动是在淋巴结 (LN) 的隔离环境中精心策划的，其中一系列共- 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) 经常被耐受肿瘤抗原（tAg），使原本不适宜的环境有利于局部淋巴结转移，最终扩散到全身。检查点阻断免疫疗法 (CBI) 癌症治疗旨在重新激活针对 tAg 的 T 细胞启动和效应功能，这些疗法通过静脉注射进行。不考虑体内存在的所有其他非标签。由于这种 Ag-不分青红皂白活性，CBI 可能会导致免疫相关不良事件 (irAE)，从而限制当前和新兴 CBI 的使用。此外，由于在癌症检测时 tdLN 已经对 tAg 具有耐受性，因此 CBI 有效引发 tAg 特异性 T 细胞反应可能有限。虽然 CBI 确实会导致持久性癌症治愈后，大多数癌症类型都没有反应，而大多数癌症患者已知有反应要么无法从 CBI 治疗中获益，要么出现复发和 irAE。在此应用中，来自德克萨斯大学和伯尔尼大学的多学科团队合作将 tAg 和 CBI 递送至非 tdLN，以便安装有效的、以 tAg 为导向的 CBI，而无需 irAE 影响其他 CBI 联合疗法。具体来说，该团队建议开发和使用可翻译的、基于植物的病毒样颗粒（VLP）平台呈现私有肿瘤新抗原（tNeoAgs）并结合将其与 CBI 一起递送至三阴性乳腺癌同基因小鼠模型的淋巴分水岭（TNBC）。强有力的初步数据证明了该方法的有效性，显示其抗肿瘤能力增强伴随着溶细胞性、tAg 特异性肿瘤浸润淋巴细胞的克隆扩增的反应单细胞RNA测序的生物信息分析。该团队进一步建议分别服用不同的剂量 VLP-tNeoAgs 与 CBI 分离淋巴分水岭，以产生多种免疫显性反应对抗肿瘤免疫逃逸和再生。该团队还将测试该方法在转基因中的安全性小鼠对正常组织中诱导的淋巴浸润敏感，作为 CBI 后 irAE 的临床读数剂量。由于这些团队已将各自的技术转化为临床研究，本文取得的进展可以迅速实施，以提高当前和新兴 CBI 的效率，确立个性化癌症疫苗的概念，扩大CBI在TNBC患者中的应用治疗选择有限。