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: 8625606
• 负责人: JOHN R. YANNELLI
• 金额: $ 7.5万
• 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 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8625606
• 关键词: Accounting; Address; Adjuvant; Advocate; Allogenic; Anatomic Sites; 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; 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; public health relevance; research clinical testing; tumor; vaccine development; vaccine evaluation

Abstract: 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.

摘要：非小细胞肺癌（NSCLC）是世界各地男性和女性的主要杀手。最多 在无法选择手术的时候，诊所中出现患有晚期疾病的患者 常规的化学疗法和放射治疗的有效性受到限制。需要新颖的疗法 对于这个患者人群。继续未能显着影响常规治疗的NSCLC患者 将对卫生保健系统征税，并为家庭和社会承担财务负担。有趣的是， NSCLC对化学治疗剂（例如顺铂）有反应，通常观察到肿瘤复发或 在其他解剖站点中进展。众所周知，NSCLC以及其他实体瘤发展 耐药性机制。因此，持续暴露于顺铂仍然无效。在当前的研究中， 我们建议调查免疫疗法，该免疫疗法是否利用患者的免疫系统识别 应考虑消除癌症，以解决化学抗性问题。我们在问 在NSCLC患者中顺铂治疗后，免疫疗法在防止中可以发挥什么作用 化学抗性肿瘤细胞克隆的生长可能导致肿瘤复发和进展？我们的 假设是疫苗可以靶向以顺铂化学抗性的蛋白质 治疗。为了解决这一假设，我们将基于我们小组的专业知识发展和交付 肺癌中的疫苗。当前的建议是主要研究的证明，该证明将调查存在 新型肿瘤相关的抗原，这些抗原具有免疫原性并定义了化学抗性表型。 提出了一种独特的方法来识别基于正常供体的HLA-A2限制以顺铂的抗性CTL 关于特定的抗原刺激和TCR-VBETA分析。了解正常的VBETA的优先使用 捐助者将应用于源自NSCLC -A2+患者的存档PBMC分析。使用此 方法论，我们将确定CTL的前体频率是否特异 先前暴露于顺铂的患者的顺铂耐药性状态将更高。如果是真的，在将来的临床上 研究，我们假设NSCLC患者可以在顺铂治疗之前针对这些肽免疫。 经过适当的休息后，NSCLC患者对肽的增强疫苗注射 源自化学抗性蛋白的源自 识别和破坏化学抗性肿瘤细胞；从而防止复发和进展。全部 申请人可以使用此原理分析证明所需的试剂。