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.

翻译后摘要：非小细胞肺癌（NSCLC）是世界各地的男性和女性的主要杀手。最 在临床上晚期疾病的患者在手术不是一种选择的时候， 常规的化疗和放疗的有效性有限。需要新的治疗方法 对于这个病人群体。持续未能显著影响接受常规治疗的NSCLC患者 将对医疗保健系统征税，并仍然是家庭和社会的财政负担。有趣的是， NSCLC对化疗剂如顺铂有反应，经常观察到肿瘤复发或复发。 其他解剖部位的进展。众所周知，NSCLC以及其他实体瘤， 耐药机制。因此，继续暴露于顺铂仍然无效。在目前的研究中， 我们建议研究免疫疗法，它利用病人的免疫系统来识别 和消除癌症，应该考虑解决化疗耐药性的问题。我们要求 在NSCLC患者接受顺铂治疗后， 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？我们 假设是表征顺铂化学抗性的蛋白质可以被疫苗靶向 疗法为了解决这一假设，我们将利用我们团队的专业知识， 肺癌的疫苗目前的建议是一项原则性研究的证明， 具有免疫原性并定义了化疗耐药表型的新型共享肿瘤相关抗原。 提出了一种独特的方法来鉴定正常供体中HLA-A2限制性顺铂耐药CTL， 特异性抗原刺激和TCR-V β分析。了解Vbetas在正常情况下的优先使用 供体将被应用于来自NSCLC的-A2+患者的存档PBMC的分析。使用此 方法，我们将确定是否前体频率特异性CTL的肽的特征， 顺铂耐药状态在先前暴露于顺铂的患者中将更高。如果是真的，在未来的临床 研究中，我们假设NSCLC患者可以在顺铂治疗前免疫这些肽。 在适当的休息期后，NSCLC患者给予用肽的加强疫苗注射。 源自化学抗性蛋白的免疫抑制剂预期产生有效的免疫应答， 识别和破坏化疗耐药肿瘤细胞;从而防止复发和进展。所有 申请人可获得用于该原理验证分析的所需试剂。