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

• 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
• 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

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月初，全球约有370万确诊COVID-19感染病例，约有260，000人死亡。1一项针对中国武汉患者的回顾性队列研究表明，尽管幸存者和非幸存者最初的临床病程相似，但在相似的时间点发生脓毒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，已显示儿科病例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可以部分地由患者预先存在的T细胞库、表型和HLA特异性解释，其可影响下游T细胞表型和细胞因子应答。使用计算机模拟方法，我们鉴定了多个潜在的T细胞表位，其可以分为3大类：1）与原始SARS病毒同源的表位2）与其他病毒/细菌同源的表位3）与自身抗原同源的表位。我们已经开发了aAPC构建体以分别询问HLA I类和HLA II类CD 8+和CD 4 + T细胞应答。因此，我们将能够广泛了解这3种不同类型的病毒特异性表位在COVID 19特异性反应发展中的作用。更好地了解T细胞如何促进疾病严重程度的进展，对于因恶性肿瘤、骨髓移植或器官移植而接受长期免疫抑制治疗的患者尤其重要。在中国，癌症患者比非癌症患者和癌症幸存者患更严重疾病和更糟糕结局的概率更高。4该提案建立在先前发表的工作基础上，仅使用100 μ L全血筛选患者的病毒特异性T细胞，周转时间不到24小时。5此外，我们还开发了富集和扩增（E+E）技术以在7天的时间范围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，我们将鉴定临床上重要的T细胞表位，并证明功能性T细胞可以在短时间内扩增到大量，其他健康供体和癌症患者的时间。

项目成果

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: 10.1002/cpz1.976
• 发表时间: 2024
• 期刊: Current protocols
• 作者: Omotoso,MaryO;Lanis,MaraR;Schneck,JonathanP
• 通讯作者: Schneck,JonathanP

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

• DOI: 10.1172/jci140508
• 发表时间: 2022-01-18
• 期刊: The Journal of clinical investigation
• 作者: Sung BY;Lin YH;Kong Q;Shah PD;Glick Bieler J;Palmer S;Weinhold KJ;Chang HR;Huang H;Avery RK;Schneck J;Chiu YL
• 通讯作者: Chiu YL

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

• 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