Evaluation of T Cell Response to Cisplatin Resistant NSCLC

T 细胞对顺铂耐药 NSCLC 的反应评估

• 批准号: 8788695
• 负责人: JOHN R. YANNELLI
• 金额: $ 7.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8788695
• 关键词: Accounting; Address; Adjuvant; Advocate; Allogenic; Anatomy; Antigens; Apoptotic; Archives; Autologous Dendritic Cells; Brain; Breast; CD8B1 gene; Cancer Patient; Cancer cell line; Cell Line; Cell Survival; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Characteristics; Cisplatin; Clinic; Clinical Research; Colon; Colon Carcinoma; Cytotoxic T-Lymphocytes; Data; Disease; Drug Targeting; Drug resistance; Drug toxicity; Effectiveness; Evaluation; Exposure to; Failure; Family; Flow Cytometry; Frequencies; Funding; Future; Growth; HLA-A2 Antigen; Habits; Health; Healthcare Systems; Household; Immune response; Immune system; Immunity; Immunotherapeutic agent; Immunotherapy; In Vitro; Injection of therapeutic agent; Investigation; Kentucky; Laboratories; Lead; Link; Literature; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Methodology; Necrosis; Non-Small-Cell Lung Carcinoma; Oncologist; Operative Surgical Procedures; Outcome; Patients; Peptides; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Play; Population; Primary Health Care; Prostate; Proteins; Quality of life; Radiation; Radiation therapy; Reagent; Recurrence; Resistance; Rest; Role; Site; Smoke; Smoking; Societies; Solid Neoplasm; Source; Specificity; Staging; Supportive care; Survival Rate; Symptoms; T cell response; T-Lymphocyte; Taxes; Therapeutic; Tumor Antigens; Universities; Vaccine Therapy; Vaccines; Variant; Woman; base; beta-Glucans; bone; chemotherapeutic agent; chemotherapy; conventional therapy; design; disease diagnosis; immunogenic; immunogenicity; improved; lymph nodes; malignant breast neoplasm; men; neoplastic cell; never smoker; novel; novel vaccines; outcome forecast; patient population; prevent; research clinical testing; tumor; vaccine development; vaccine evaluation; vaccine trial

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is a leading killer of men and women around the world. Most patients present in the clinic with advanced stage disease at a point where surgery is not an option and conventional chemotherapy and radiation therapy are limited in their effectiveness. Novel therapies are needed for this patient population. Continued failure to significantly impact NSCLC patients with conventional therapy will tax the health care system and remain a financial burden for families and society. Interestingly, while NSCLC is responsive to chemotherapeutic agents such as cisplatin, tumor is often observed to recur or progress in additional anatomic sites. It is known that NSCLC, as well as other solid tumors, develop mechanisms of drug resistance. Thus, continued exposure to cisplatin remains ineffective. In the current study, we propose to investigate whether Immunotherapy, which exploits the patient's immune system to recognize and eliminate cancer, should be considered to address the issue of chemo-resistance. We are asking the question that following cisplatin therapy in NSCLC patients, what role can immunotherapy play in preventing the growth of chemo-resistant tumor cell clones which likely result in tumor recurrence and progression? Our hypothesis is that proteins which characterize cisplatin chemo-resistance can be targeted by vaccine therapy. To address this hypothesis we will build on the expertise of our group in developing and delivering vaccines in lung cancer. The current proposal is a proof of principle study which will investigate the existence of novel shared tumor associated antigens which are immunogenic and define the chemo-resistant phenotype. A unique methodology is proposed to identify HLA-A2 restricted cisplatin resistant CTL in normal donors based on specific antigen stimulation and TCR-Vbeta analysis. Understanding preferential usage of Vbetas in normal donors will be applied to the analysis of archived PBMC derived from -A2+ patients with NSCLC. Using this methodology, we will determine if the precursor frequency for CTL specific for peptides characteristic of the cisplatin resistant state will be higher in patients previously exposed to cisplatin. If true, in a future clinical study, we hypothesize that NSCLC patients can be immunized against these peptides before cisplatin therapy. Following an appropriate period of rest, NSCLC patients given boost vaccine injections with the peptides derived from the chemo-resistant proteins are expected to generate a potent immune response allowing the recognition and destruction of chemo-resistant tumor cells; thus preventing recurrence and progression. All required reagents for this proof of principle analysis are available to the applicant.

描述（由申请人提供）：非小细胞肺癌（NSCLC）是全世界男性和女性的主要杀手。大多数患者在诊所就诊时已处于晚期疾病，无法进行手术，并且传统化疗和放疗的有效性有限。该患者群体需要新的疗法。 传统疗法持续未能对非小细胞肺癌患者产生显着影响，这将给医疗保健系统带来负担，并继续给家庭和社会带来经济负担。有趣的是，虽然非小细胞肺癌对顺铂等化疗药物有反应，但经常观察到肿瘤在其他解剖部位复发或进展。众所周知，非小细胞肺癌以及其他实体瘤会产生耐药机制。因此，持续暴露于顺铂仍然无效。在当前的研究中，我们建议调查是否应该考虑利用患者的免疫系统来识别和消除癌症的免疫疗法来解决化疗耐药性问题。我们要问的问题是，在非小细胞肺癌患者接受顺铂治疗后，免疫疗法在预防可能导致肿瘤复发和进展的化疗耐药肿瘤细胞克隆的生长方面可以发挥什么作用？我们的假设是，具有顺铂化疗耐药性的蛋白质可以成为疫苗治疗的目标。为了解决这一假设，我们将利用我们团队在开发和提供肺癌疫苗方面的专业知识。目前的提案是一项原理研究证明，它将调查新型共享肿瘤相关抗原的存在，这些抗原具有免疫原性并定义化疗耐药表型。基于特异性抗原刺激和 TCR-Vbeta 分析，提出了一种独特的方法来识别正常供体中 HLA-A2 限制性顺铂耐药性 CTL。了解 Vbeta 在正常供体中的优先使用将应用于分析来自 -A2+ NSCLC 患者的存档 PBMC。使用这种方法，我们将确定对于顺铂耐药状态的肽特征特异的 CTL 前体频率在之前暴露于顺铂的患者中是否会更高。如果属实，在未来的临床研究中，我们假设 NSCLC 患者可以在顺铂治疗前针对这些肽进行免疫接种。经过适当的休息时间后，非小细胞肺癌患者接受来自化疗抗性蛋白的肽的加强疫苗注射，预计会产生有效的免疫反应，从而识别和破坏化疗抗性肿瘤细胞；从而防止复发和进展。申请人可以获得原理分析验证所需的所有试剂。