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.

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 both surfivors and non-survivors initially following 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 miller 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.在使用硅方法中，我们确定了可以分为3个广泛类别的多个潜在的T细胞表位：1）与原始SARS病毒同源的表位2）与其他病毒/细菌具有同源性的表位3）与自我抗原同源的表位。我们已经开发了AAPC构建体，分别询问HLA I类和HLA II类CD8+和CD4+ T细胞响应。因此，我们将能够对这三种不同类型的病毒特异性表位在CoVID19特定反应的发展中的作用有广泛的了解。更好地理解T细胞如何促进疾病严重程度的进展，特别与因恶性，骨髓移植或器官移植而进行长期免疫抑制疗法的患者。 Patients with cancer were found to have higher possibilities of having more severe disease and worse outcomes in China than both patients Without cancer and cancer survivals.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天的时间范围。6-12康复这两种方法，我们将确定临床上重要的T细胞表位，并证明在其他健康的供体和癌症患者中，可以在短时间内将功能性T细胞扩展到大量。

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