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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.

项目总结