Evaluation of T Cell Response to Cisplatin Resistant NSCLC

摘要：非小细胞肺癌(NSCLC)是全球男性和女性的头号杀手。多数 在临床上患有晚期疾病的患者不能选择手术， 常规化疗和放射治疗的效果有限。需要新的治疗方法 对于这群病人来说。继续未能显著影响常规治疗的非小细胞肺癌患者 将对医疗保健系统征税，并仍然是家庭和社会的经济负担。有趣的是，虽然 非小细胞肺癌对化疗药物如顺铂有反应，肿瘤经常复发或 其他解剖部位的研究进展。众所周知，非小细胞肺癌和其他实体肿瘤一样， 耐药机制。因此，继续接触顺铂仍然无效。在目前的研究中， 我们建议调查免疫疗法，它利用患者的免疫系统识别 并消除癌症，应考虑解决化疗耐药问题。我们正在询问 问题：在非小细胞肺癌患者接受顺铂治疗后，免疫治疗在预防 化疗耐药肿瘤细胞克隆的生长可能导致肿瘤的复发和进展？我们的 假说是表征顺铂耐药的蛋白质可以成为疫苗的靶点。 心理治疗。为了解决这一假设，我们将以我们团队在开发和交付方面的专业知识为基础 肺癌疫苗。目前的提议是一项原则性研究的证明，该研究将调查 新的共享肿瘤相关抗原是免疫原性的，并定义了化疗耐药表型。 提出了一种独特的方法来鉴定正常供者的人类白细胞抗原A2限制性顺铂耐药CTL。 关于特异性抗原刺激和TCR-Vbeta分析。了解Vbetas在正常情况下的优先使用 供者将用于分析来自-A2+非小细胞肺癌患者的存档PBMC。使用这个 方法，我们将确定CTL的前体频率是否针对多肽的特性 以前接触过顺铂的患者对顺铂的耐药状态会更高。如果是真的，在未来的临床中 研究表明，我们假设非小细胞肺癌患者在接受顺铂治疗前可以针对这些多肽进行免疫。 在适当的休息时间后，非小细胞肺癌患者用这些多肽进行加强疫苗注射。 从耐化疗蛋白中提取的预计会产生强大的免疫反应，从而使 识别和破坏耐化疗的肿瘤细胞；从而防止复发和进展。全 申请人可获得此原则证明分析所需的试剂。

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.