Immune responses to gene-modified, autologous dendritic cell vaccines in melanoma

描述（由申请人提供）：我们对人类树突状细胞的理解取得了进展，解决了许多关于免疫启动以及树突状细胞如何控制这些抗癌反应的重要未知因素。肿瘤抗原本身是弱免疫原，因为它们是自身抗原或改变自身的抗原。因此，克服对癌症自身抗原的耐受性的障碍虽然是可以实现的，但却相当高。树突状细胞可以通过呈递肿瘤抗原以及引发免疫反应的所有其他必需分子来绕过许多这些屏障。遗传策略在将肿瘤抗原偶联至树突状细胞方面提供了潜在的优势。与标准肽脉冲相比，多个表位可以由遗传修饰的树突状细胞表达，其可以被加工并定制为各种MHC等位基因。持续的抗原呈递更有可能，并且可以随着时间的推移进行监测。我们使用常见病毒抗原（流感病毒、CMV）代替肿瘤抗原作为模型，生成了大量的临床前数据。然而，我们已经成功地转导了CD 34+祖细胞，其分化为朗格汉斯型树突细胞并表达全长人酪氨酸酶，一种重要的黑色素瘤抗原。我们现在提出在晚期黑色素瘤（III-IV期）患者中进行人体临床试验。我们将比较通过逆转录病毒转导进行遗传修饰以表达全长人酪氨酸酶的朗格汉斯型树突状细胞与用HLA-A*0201限制性酪氨酸酶肽脉冲的朗格汉斯细胞。将在本I期试验中评估安全性和毒性。其他应答评估包括通过ELISpot进行的详细免疫监测。四聚体反应性和基于流式细胞术的细胞因子分泌测定，比较疫苗后应答与治疗前基线。这些研究将为持续呈递多个I类和II类MHC表位优于呈递单个I类MHC肽以刺激适应性肿瘤特异性免疫的任何优势提供原理证明。(LAY总结：将在晚期III-IV期黑色素瘤患者中测试特化朗格汉斯型树突细胞的遗传改变的安全性、毒性和肿瘤特异性免疫刺激。

DESCRIPTION (provided by applicant): Advances in our understanding of human dendritic cells have resolved many important unknowns about the onset of immunity and how dendritic cells could control these responses against cancer. Tumor antigens are poor immunogens by themselves, because they are either self or altered-self antigens. Hence the bar to overcoming tolerance toward cancer-self antigens, while attainable, is quite high. Dendritic cells can circumvent many of these barriers by presenting tumor antigens in association with all the other requisite molecules that elicit immune reactivity. Genetic strategies offer potential advantages in coupling tumor antigens to dendritic cells. Compared with standard peptide-pulsing, multiple epitopes can be expressed by genetically modified dendritic cells, which can be processed and tailored to a variety of MHC alleles. Sustained antigen-presentation is more likely and can be monitored over time. We have generated substantial preclinical data using common viral antigens (influenza, CMV) as models, in lieu of tumor antigens. We have successfully transduced CD34+ progenitors, however, that differentiate into Langerhans- type dendritic cells and express full-length human tyrosinase, an important melanoma antigen. We now propose a human clinical trial in patients with advanced melanoma (stages III-IV). We will compare Langerhans-type dendritic cells genetically modified by retroviral transduction to express full-length human tyrosinase with Langerhans cells pulsed with the HLA-A*0201 -restricted tyrosinase peptide. Safety and toxicity will be assessed in this phase I trial. Additional response assessments include detailed immune monitoring by ELISpot. tetramer reactivity, and flow cytometry-based cytokine secretion assays, comparing post-vaccine responses with pre-treatment baselines. These studies will provide proof of principle for any advantage to sustained presentation of multiple class I and II MHC epitopes over presentation of a single class I MHC peptide to stimulate adaptive tumor-specific immunity. (LAY SUMMARY: Genetic alterations of specialized Langerhans-type dendritic cells will be tested for safety, toxicity, and the stimulation of tumor- specific immunity in patients with advanced stage III-IV melanoma.)