T-cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade

T 细胞抵抗 PD-1 检查点阻断的内在机制

• 批准号: 10171108
• 负责人: MICHELLE KROGSGAARD
• 金额: $ 16.95万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171108
• 关键词: 2019-nCoV; Adaptive Immune System; Address; Adjuvant; Affect; Animals; Antibodies; Antigens; Bacteria; Biological Assay; Blood; CD8-Positive T-Lymphocytes; COVID-19; COVID-19 pandemic; Cancer Patient; Cellular Immunity; Cholera Toxin; Clinical Data; Clinical Research; Communicable Diseases; Coronavirus; Coronavirus Infections; Crystallization; Data; Data Reporting; Dendritic Cells; Development; Engineering; Enzyme-Linked Immunosorbent Assay; Epitopes; Evaluation; Flow Cytometry; Goals; HLA A*0201 antigen; Human; Immune response; Immunity; Immunization; Immunocompromised Host; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunology; Immunosuppression; Individual; Infection; Intramuscular; Lead; Libraries; Lung; Malignant Neoplasms; Mass Spectrum Analysis; Memory B-Lymphocyte; Modeling; Molecular; Mucous Membrane; Mus; PD-1 blockade; Parents; Patients; Peptides; Play; Population; Prevention; Probability; Production; Protein Biochemistry; Proteins; Protocols documentation; Recombinant Vaccines; Recombinants; Reporting; Research; Resistance; Respiratory Mucosa; Respiratory Tract Infections; Role; SARS coronavirus; Serum; Severe Acute Respiratory Syndrome; Structure; Structure of parenchyma of lung; T cell response; T memory cell; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; Testing; Therapeutic; Transgenic Mice; Vaccination; Vaccines; Variant; Virus; Work; adaptive immunity; anticancer treatment; base; cancer therapy; chemotherapy; cross reactivity; efficacy testing; enzyme linked immunospot assay; experimental study; flu; human subject; immune checkpoint blockade; immunogenic; immunogenicity; improved; in vivo; individual patient; insight; milligram; mouse model; mucosal vaccine; novel; novel therapeutics; novel vaccines; pandemic disease; parent grant; peripheral blood; preclinical study; programmed cell death protein 1; prototype; resistance mechanism; respiratory; response; side effect; targeted delivery; therapeutic vaccine; vaccination strategy; vaccine efficacy

Abstract This Urgent Supplement is addressing the possible effects of cancer therapies, and PD-1 blockade in particular, on immune responses to COVID-19 infection and vaccination. The primary objective of the parent proposal CA243486 entitled “T cell intrinsic mechanisms of resistance to PD-1 checkpoint blockade” is to determine the function of T cell receptors in the molecular mechanism of resistance to PD-1 checkpoint blockade. The COVID-19 pandemic underscores the urgent need for effective vaccines and treatments, especially in immunocompromised individuals including majority of cancer patients. Previously reported data on animal vaccination against coronaviruses (CoV), including SARS-CoV, demonstrated that parenteral or intramuscular immunization, which predominantly activates systemic immunity, may be inadequate in prevention of these and other respiratory tract infections. Since respiratory mucosa is a primary target for CoV, it has been demonstrated that targeted mucosal immunization could be a much more effective strategy as it involves activation of all types of adaptive immunity: systemic, mucosal and cellular. It has been shown that resistance to SARS-CoV infection in mice is primarily driven by cellular immunity represented by the resident memory T cells. In humans, SARS-CoV-specific memory T cells have been detected in the peripheral blood of SARS patients six or more years post-infection despite the lack of virus-specific memory B cells. We hypothesize that (1) the long-term protection against CoV including SARS-CoV2 can be achieved by a mucosal vaccine eliciting long-lasting cellular immunity and (2) checkpoint blockade can elevate the T cell response during COVID-19 vaccination. In this supplement to our parent grant we propose to identify SARS-CoV2 specific T cell epitopes in cancer patients and healthy individuals (Aim 1) and utilize the most immunogenic epitopes in engineering of a recombinant vaccine library (Aim 2). Since short peptide epitopes are poor immunogens, we will utilize a non-toxic cholera toxin B (CTB) protein as a mucosal adjuvant and as a carrier for targeted delivery of immunogens to the lung dendritic cells (Aim 2). Next, the vaccine library will be tested for immunogenicity using mouse models with and without PD-1 blockade to evaluate the effect of checkpoint blockade on T cell activation during vaccination. The most efficient vaccine prototype will be further validated using a SARS-CoV2 mouse model (Aim 3). This project will help to evaluate the role of T cells in immunity to COVID-19 in healthy individuals and cancer patients, test the efficacy of a novel vaccine using in in vivo mouse model and determine the role of PD-1 blockade in T cell response to immunization.

摘要 这个紧急补充是解决癌症治疗的可能影响，和PD-1阻断， 特别是对COVID-19感染和疫苗接种的免疫反应。家长的主要目标 标题为“T细胞对PD-1检查点阻断的抵抗的内在机制”的提案CA 243486是 确定T细胞受体在PD-1检查点抗性的分子机制中的功能 封锁 COVID-19大流行强调了对有效疫苗和治疗的迫切需要，特别是在 免疫功能低下的个体，包括大多数癌症患者。以前报告的动物数据 针对冠状病毒（CoV）（包括SARS-CoV）的疫苗接种表明， 免疫接种主要激活全身免疫，可能不足以预防这些疾病， 其他呼吸道感染。由于呼吸道粘膜是CoV的主要靶点， 表明靶向粘膜免疫可能是一种更有效的策略，因为它涉及 激活所有类型的适应性免疫：全身性、粘膜和细胞免疫。研究表明， 小鼠对SARS-CoV感染的免疫应答主要是由常驻记忆T 细胞在人类中，在SARS患者的外周血中检测到SARS-CoV特异性记忆T细胞 尽管缺乏病毒特异性记忆B细胞，但患者感染后6年或更长时间。我们假设 (1)针对包括SARS-CoV 2在内的CoV的长期保护可以通过粘膜疫苗来实现， 持久的细胞免疫和（2）检查点阻断可以提高COVID-19期间的T细胞反应 预防针在我们的母基金的补充中，我们建议鉴定SARS-CoV 2特异性T细胞表位 在癌症患者和健康个体中（目的1），并在工程化中利用最具免疫原性的表位， 重组疫苗文库（Aim 2）。由于短肽表位是较差的免疫原，我们将利用一种 无毒霍乱毒素B（CT B）蛋白作为粘膜佐剂和作为靶向递送 肺树突状细胞的免疫原（目的2）。接下来，将对疫苗库进行免疫原性检测 使用具有和不具有PD-1阻断的小鼠模型来评估检查点阻断对T细胞的影响 在接种疫苗期间激活。最有效的疫苗原型将使用SARS-CoV 2进一步验证。 小鼠模型（Aim 3）。该项目将有助于评估T细胞在健康人群中对COVID-19免疫的作用。 个体和癌症患者，使用体内小鼠模型测试新型疫苗的功效， 确定PD-1阻断在T细胞免疫应答中的作用。