Developing newly combined therapeutic strategies for mature B cell lymphoma

开发成熟 B 细胞淋巴瘤的新联合治疗策略

• 批准号: 10196434
• 负责人: Jing Hong Wang
• 金额: $ 15.48万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196434
• 关键词: 2019-nCoV; Administrative Supplement; Admission activity; American; Antigen-Presenting Cells; Antigens; B-Cell Lymphomas; B-Lymphocytes; COVID-19; Cancer Patient; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); Chronic; Data; Development; Fatality rate; General Population; Goals; Host Defense; Immune response; Immune system; Immunity; Immunocompetent; Immunotherapy; Infection; Infectious Agent; Lead; Malignant Neoplasms; Mature B-Lymphocyte; Mechanical ventilation; Methods; Modeling; Multiple Organ Failure; Mus; Normal Cell; PD-1 inhibitors; Pathogenesis; Patients; Production; Proteins; Reporting; Research; Risk; Risk Factors; Squamous cell carcinoma; System; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Tumor Burden; Vaccination; Viral; Viral Antigens; Viral Proteins; Virus; Virus Diseases; Virus Replication; anti-PD1 therapy; antigen challenge; cancer cell; cancer therapy; chemotherapy; cytokine release syndrome; exhaustion; high risk; immune activation; improved; indicated prevention; innovation; insight; mortality; neutralizing antibody; novel; patient response; programmed cell death protein 1; response; tumor; tumorigenesis; vaccination strategy; vaccine effectiveness

Cancer patients inflicted with COVID-19 are at 3.5 times the risk of requiring mechanical ventilation or ICU admission, compared to the general population. Infection of SARS-CoV-2, the causative agent of COVID-19, elicits both T and B cell responses against the virus and the successful coordination of these systems working in concert would normally lead to the control of the viral infection. However, if the immune system is compromised or defective, SARS-CoV-2 may undergo unchecked viral replication triggering cytokine storm, multiple organ failure and ultimately lethality. Conventional wisdom would suggest that fatality rate should be higher in COVID-19 infected cancer patients. While many cancer therapeutics such as chemotherapies preferentially target cancer cells, they also hurt normal cells to a degree, particularly the very cells that are involved in immune responses to infectious agents. Consequently, chemotherapies may weaken the host defense system to allow viral spreading. Other cancer treatments such as immunotherapies or CAR-T, which seek to enhance immune responses of patients to tumors, could be a double-edged sword as these treatments may also enhance the cytokine storm responses. The high mortality rate of cancer patients infected with SARS-CoV-2 begs the question whether vaccination should be prioritized. However, the effectiveness of vaccine in patients with cancer and the presence of tumors with or without anti-PD1 treatment on the development of SARS-CoV-2 immunity remains largely unknown. The goal of this administrative supplement is to investigate the effects of tumors or anti-PD-1 treatment on T and B cell responses against SARS-CoV-2 antigen in a unique syngeneic mouse tumor model we developed. We hypothesize that the presence of tumor compromises mounting of an adequate immune response to viral antigens and impedes production of neutralizing antibodies. Anti-PD1 treatment may enhance SARS-CoV-2 immunity. Two aims are proposed. In SA1, we will characterize T and B cell immune responses to SARS-CoV-2 in wild type (WT) and tumor-bearing mice. In SA2, we will determine the effect of anti-PD1 treatment on T and B cell immune responses to SARSCoV-2 in WT or tumor-bearing mice. The result may provide novel insights into the observed high mortality rate of SARS-CoV-2 inflicted cancer patients, and inform the vaccination strategy for cancer patients.

与普通人群相比，感染COVID-19的癌症患者需要机械通气或入住ICU的风险是其3.5倍。感染SARS-CoV-2 （COVID-19的病原体）会引发T细胞和B细胞对病毒的反应，这些系统的成功协调通常会导致病毒感染的控制。然而，如果免疫系统受损或有缺陷，SARS-CoV-2可能会进行不受控制的病毒复制，引发细胞因子风暴、多器官衰竭，最终导致死亡。传统观点认为，COVID-19感染的癌症患者的死亡率应该更高。虽然许多癌症治疗方法，如化疗，优先针对癌细胞，但它们也会在一定程度上伤害正常细胞，特别是那些参与对传染性病原体的免疫反应的细胞。因此，化疗可能会削弱宿主防御系统，使病毒传播。其他癌症治疗方法，如免疫疗法或CAR-T，旨在增强患者对肿瘤的免疫反应，可能是一把双刃剑，因为这些治疗方法也可能增强细胞因子风暴反应。感染SARS-CoV-2的癌症患者的高死亡率引发了是否应该优先接种疫苗的问题。然而，在癌症患者中接种疫苗的有效性以及肿瘤存在与否抗pd1治疗对SARS-CoV-2免疫发展的影响在很大程度上仍然未知。本行政补充的目的是在我们开发的独特的同基因小鼠肿瘤模型中研究肿瘤或抗pd -1治疗对T细胞和B细胞对SARS-CoV-2抗原反应的影响。我们假设肿瘤的存在损害了对病毒抗原的充分免疫反应的建立，并阻碍了中和抗体的产生。抗pd1治疗可增强SARS-CoV-2免疫。提出了两个目标。在SA1中，我们将描述野生型（WT）和荷瘤小鼠对SARS-CoV-2的T细胞和B细胞免疫反应。在SA2中，我们将确定抗pd1治疗对WT或荷瘤小鼠对SARSCoV-2的T和B细胞免疫反应的影响。该结果可能为观察到的SARS-CoV-2感染的癌症患者的高死亡率提供新的见解，并为癌症患者的疫苗接种策略提供信息。