A high-throughput nanoparticle assay to characterize cancer neoepitope-specific T cells

用于表征癌症新表位特异性 T 细胞的高通量纳米颗粒测定

基本信息

批准号：
10167008
负责人：
JONATHAN P SCHNECK
金额：
$ 16.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10167008
关键词：
2019-nCoV Address Adult Adult Respiratory Distress Syndrome Antibodies Antigen-Presenting Cells Antigens Autoantigens Award Bacteria Biological Assay Blood Blood Cells Blood Volume Blood specimen Bone Marrow Transplantation CD4 Positive T Lymphocytes CD8B1 gene COVID-19 COVID-19 pandemic Cancer Patient Cancer Survivor Categories Cellular Immunity Cessation of life Childhood China Clinical Convalescence Detection Development Diagnosis Diagnostic Diagnostic tests Disease Disease Outcome Disease Progression Enzyme-Linked Immunosorbent Assay Epitopes Failure Generations Goals Grant Hour Human Immunity In Vitro Individual Infection Laboratories Lead Malignant Neoplasms Methods Modality Morbidity - disease rate Mus Nature Oncology Organ Transplantation Outcome Patients Peptides Peripheral Blood Mononuclear Cell Phenotype Play Population Probability Proteins Publishing Reagent Retrospective cohort study Reverse Transcriptase Polymerase Chain Reaction Risk Role SARS coronavirus Sepsis Severity of illness Survivors T cell response T-Lymphocyte T-Lymphocyte Epitopes Techniques Technology Testing Therapeutic immunosuppression Time Variant Viral Viral Antigens Virus Whole Blood Work base cancer diagnosis chemotherapy cohort cytokine cytotoxic CD8 T cells design high throughput analysis immune checkpoint blockade in silico melanoma mortality nanoparticle neoantigens novel pandemic disease parent grant patient screening peripheral blood predictive panel prognostic response screening secondary infection tumor

项目摘要

As of early May 2020, there have been approximately 3.7 million confirmed cases of COVID-19 infection worldwide, and approximately 260,000 deaths.1 A retrospective cohort study of patients from Wuhan, China demonstrated that although both survivors and non-survivors initially follow similar clinical courses, developing sepsis and acute respiratory distress syndrome (ARDS) at similar time points, non-survivors progress on to multi-organ failure (MOF), secondary infection, and death.2 Additionally, pediatric cases have been shown to have a much milder disease course than adults, and the reasons for this are not clear.3These differences in clinical courses could in part be explained by the patients’ pre-existing T cell repertoire, phenotype, and HLAspecificity, which may influence downstream T cell phenotype and cytokine responses. Using in silico approaches, we identified multiple potential T cell epitopes which can be divided into 3 broad categories: 1) Epitopes with homology to the original SARS virus 2) Epitopes with homology to other viruses/bacteria 3) Epitopes with homology to self-antigens. We have developed aAPC constructs to interrogate both HLA class I and HLA class II CD8+ and CD4+ T cell responses, respectively. As such, we will be able to obtain a broad understanding of the role these 3 different types of virus-specific epitopes play in the development of COVID19 specific responses. A better understanding of how T cells contribute to progression of disease severity is especially pertinent to patients who are on long-term immunosuppressive therapies because of malignancies, bone marrow transplant, or organ transplant. Patients with cancer were found to have higher probabilities of having more severe disease and worse outcomes in China than both patients without cancer and cancer survivors.4This proposal builds upon previously published work to screen patients for virus-specific T cells using only 100 L of whole blood, and with a turn-around time of less than 24 hours.5 In addition, we have also developed an enrichment and expansion (E+E) technology to rapidly expand virus and tumor-specific T cells within a 7 day time frame.6–12Combining these two approaches, we will identify clinically important T cell epitopes and demonstrate that functional T cells can be expanded to large numbers over a brief period-of-time in otherwise healthy donors and patients with cancer.

截至 2020 年 5 月上旬，全球已确诊约 370 万例 COVID-19 感染病例，约 26 万人死亡。1 对中国武汉患者进行的一项回顾性队列研究表明，幸存者和非幸存者最初都遵循相似的临床表现病程、在相似时间点出现败血症和急性呼吸窘迫综合征 (ARDS)、非幸存者进展为多器官衰竭 (MOF)、继发感染和死亡。2 此外，儿科病例已研究显示，T 细胞的病程比成人轻得多，其原因尚不清楚。 3 临床病程的这些差异部分可以通过患者预先存在的 T 细胞库、表型和 HLA 特异性来解释，这可能会影响下游T 细胞表型和细胞因子反应。使用计算机方法，我们鉴定了多个潜在的 T 细胞表位，这些表位可分为 3 大类：1) 与原始 SARS 病毒同源的表位 2) 与其他病毒同源的表位病毒/细菌 3) 与自身抗原同源的表位我们开发了 aAPC 构建体来分别询问 HLA I 类和 HLA II 类 CD8+ 和 CD4+ T 细胞反应。这 3 种不同类型的病毒特异性表位在 COVID19 特异性反应的发展中所发挥的作用，更好地了解 T 细胞如何促进疾病严重程度的进展对于正在接受治疗的患者尤其重要。研究发现，在中国，由于恶性肿瘤、骨髓移植或器官移植而接受长期免疫抑制治疗的患者，与非癌症患者和癌症幸存者相比，患上更严重疾病和更差结果的可能性更高。4该提议建立在先前的基础上。已发表的工作仅使用 100 µL 全血筛查患者的病毒特异性 T 细胞，周转时间不到 24 小时。5 此外，我们还开发了一种富集和扩增方法(E+E) 技术可在 7 天的时间内快速扩增病毒和肿瘤特异性 T 细胞。6-12结合这两种方法，我们将识别临床上重要的 T 细胞表位，并证明功能性 T 细胞可以大量扩增在短时间内对其他健康的捐赠者和癌症患者进行研究。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Artificial Antigen-Presenting Cell Fabrication for Murine T Cell Expansion.

用于鼠 T 细胞扩增的人工抗原呈递细胞制造。

DOI：
发表时间：
2024-02
期刊：
影响因子：
0
作者：
Omotoso, Mary O;Lanis, Mara R;Schneck, Jonathan P
通讯作者：
Schneck, Jonathan P

SARS-CoV-2 as a superantigen in multisystem inflammatory syndrome in children.

SARS-CoV-2 作为儿童多系统炎症综合征的超抗原。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Kouo, Theodore;Chaisawangwong, Worarat
通讯作者：
Chaisawangwong, Worarat

Rapid Expansion of Highly Functional Antigen-Specific T Cells from Patients with Melanoma by Nanoscale Artificial Antigen-Presenting Cells.

通过纳米级人工抗原呈递细胞快速扩增黑色素瘤患者的高功能抗原特异性 T 细胞。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Ichikawa, Junya;Yoshida, Tatsuya;Isser, Ariel;Laino, Andressa S;Vassallo, Melinda;Woods, David;Kim, Sojung;Oelke, Mathias;Jones, Kristi;Schneck, Jonathan P;Weber, Jeffrey S
通讯作者：
Weber, Jeffrey S

Wnt activation promotes memory T cell polyfunctionality via epigenetic regulator PRMT1.

Wnt 激活通过表观遗传调节因子 PRMT1 促进记忆 T 细胞的多功能性。

DOI：
发表时间：
2022-01-18
期刊：
影响因子：
0
作者：
Sung, Bo;Lin, Yi;Kong, Qiongman;Shah, Pali D;Glick Bieler, Joan;Palmer, Scott;Weinhold, Kent J;Chang, Hong;Huang, Hailiang;Avery, Robin K;Schneck, Jonathan;Chiu, Yen
通讯作者：
Chiu, Yen

Adaptive Nanoparticle Platforms for High Throughput Expansion and Detection of Antigen-Specific T cells.

用于高通量扩增和检测抗原特异性 T 细胞的自适应纳米颗粒平台。

DOI：
10.1021/acs.nanolett.0c01511
发表时间：
2020-09-09
期刊：
Nano letters
影响因子：
10.8
作者：
Hickey JW;Isser A;Salathe SF;Gee KM;Hsiao MH;Shaikh W;Uzoukwu NC;Bieler JG;Mao HQ;Schneck JP
通讯作者：
Schneck JP