Evaluation of T Cell Response to Cisplatin Resistant NSCLC

描述（由申请人提供）：非小细胞肺癌（NSCLC）是世界各地男性和女性的主要杀手。大多数患者在临床上表现为晚期疾病，此时手术不是一种选择，常规化疗和放疗的有效性有限。这一患者群体需要新的治疗方法。 常规治疗继续未能对非小细胞肺癌患者产生显着影响，将给医疗保健系统带来负担，并仍然是家庭和社会的经济负担。有趣的是，虽然NSCLC对化疗药物如顺铂有反应，但经常观察到肿瘤在其他解剖部位复发或进展。众所周知，NSCLC以及其他实体瘤会产生耐药性机制。因此，继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。我们提出的问题是，NSCLC患者接受顺铂治疗后，免疫治疗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生长方面可以发挥什么作用？我们的假设是，蛋白质的特点顺铂化疗耐药性可以通过疫苗治疗的目标。为了解决这一假设，我们将建立在我们小组在开发和提供肺癌疫苗方面的专业知识的基础上。目前的提议是一项原则性研究的证明，该研究将研究具有免疫原性的新型共享肿瘤相关抗原的存在，并定义化疗耐药表型。提出了一种基于特异性抗原刺激和TCR-V β分析来鉴定正常供体中HLA-A2限制性顺铂抗性CTL的独特方法。了解Vbetas在正常供体中的优先使用将适用于分析来自-A2+ NSCLC患者的存档PBMC。使用这种方法，我们将确定是否前体频率的特异性肽的顺铂耐药状态的CTL将在以前暴露于顺铂的患者更高。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对这些肽进行免疫。经过适当的休息时间后，非小细胞肺癌患者接受来自化疗耐药蛋白的肽的加强疫苗注射，预计将产生强效的免疫反应，从而识别和破坏化疗耐药肿瘤细胞;从而预防复发和进展。申请人可获得本原理验证分析所需的所有试剂。

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.