MUTANT P53 EPITOPE TARGETING IN SCLC

已发现常见的人类癌症经常与 包括ras在内的显性和隐性癌基因的体细胞突变 和p53基因，并经常产生突变的癌基因蛋白， 唯一存在于患者的癌症中，但不存在于他/她的正常 细胞 这些肿瘤特异性蛋白质可以形成高度免疫调节的基础。 肿瘤特异性细胞免疫疗法，其靶向 存在于每个癌细胞中，是维持癌细胞增殖的基础。 恶性表型 目前已知细胞毒性T淋巴细胞（CTL） 通过识别短肽片段检测用于杀伤的靶细胞 由I类MHC呈递给它们的内源性蛋白质 靶细胞表面的分子。靶蛋白 因此不需要在细胞表面正常表达。 我们 已经开发出有效的方法来诱导突变的癌基因- 在动物中的特异性CTL，并在人类中检测到这种反应， 表明我们可以用肽疫苗来诱导它们。 在这 项目，我们将： 1)测试个体化突变p53- 特异性肽致敏的自体树突状细胞（DC）， IL 12在小细胞肺癌辅助免疫治疗的II期临床试验中的应用 对标准治疗反应良好的肺癌患者 疗法 2)从免疫学和分子学上表征来自患者的成熟DC 在化疗前后进行临床试验。 我们有 初步数据显示，DC在功能上有缺陷， 癌症患者，但在体外培养时功能完全 用于未来临床疫苗试验的DC前体的生长条件， 并将有助于阐明这种DC功能障碍的机制。 3)表征经基因工程改造以表达T细胞的树突状细胞 表位作为自体细胞肽脉冲的替代方案 疫苗。 4)分析来自这些患者的SCLC肿瘤，以确定其在细胞周期中的获得性缺陷。 抗原呈递机制，特别是β 2微球蛋白。 这项工作的最终目标是更好地了解人类细胞 小细胞肺癌癌基因突变产物免疫应答的研究 并开发有效的临床转化疗法， 在微小残留病环境中。

Common human cancers have been found to be frequently associated with somatic mutations in dominant and recessive oncogenes including the ras and p53 genes and often produce mutant oncogene proteins that are uniquely present in the patient's cancer but not in his/her normal cells. These tumor specific proteins could form the basis for highly tumor specific cellular immunotherapy which targets an epitope that is present in each cancer cell and is fundamental to the maintenance of the malignant phenotype. It is now known that cytotoxic T lymphocytes (CTL) detect target cells for killing by recognizing short peptide fragments of endogenous proteins which are presented to them by class I MHC molecules on the surface of the target cell. The target proteins therefore do not have to be normally expressed on the cell surface. We have developed effective methods for induction of mutant oncogene- specific CTL in animals, and have detected such responses in humans, and shown that we can induce them with peptide vaccination. In this project, we will: 1) Test the immunological efficacy of individualized, mutant p53- specific, peptide-pulsed autologous dendritic cells (DC) with concurrent IL12 in a Phase II clinical trial of adjuvant immunotherapy for small cell lung cancer patients who achieve a good response to standard therapy. 2) Immunologically and molecularly characterize mature DC from patients with SCLC on this clinical trial before and after chemotherapy. We have preliminary data which shows that DC are functionally defective in patients with cancer, but are fully functional when grown in vitro growth conditions of DC precursors for future clinical vaccine trials, and will help elucidate the mechanism of this DC dysfunction. 3) Characterize dendritic cells genetically engineered to express T-cell epitopes as an alternative to peptide pulsing for autologous cell vaccines. 4) Analyze SCLC tumors from these patients for acquired defects in the machinery of antigen presentation, particularly beta2 microglobulin. The ultimate goal of this work is to better understand human cellular immune responses to mutant oncogene products in small cell lung cancer and to develop effective clinical translational therapies, particularly in the minimal residual disease setting.