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发生的重要未知问题，以及树突状细胞如何控制这些对抗癌症的反应。肿瘤抗原本身是较差的免疫原，因为它们要么是自体抗原，要么是异自体抗原。因此，克服对癌症自身抗原的耐受性的门槛虽然可以实现，但相当高。树突状细胞可以通过将肿瘤抗原与所有其他引起免疫反应的必要分子结合来绕过许多这些障碍。遗传策略为肿瘤抗原与树突状细胞的偶联提供了潜在的优势。与标准肽脉冲相比，基因修饰的树突状细胞可以表达多个表位，可以针对多种MHC等位基因进行加工和定制。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。我们已经生成了大量的临床前数据，使用常见的病毒抗原（流感，巨细胞病毒）作为模型，代替肿瘤抗原。然而，我们已经成功地将CD34+祖细胞转化为Langerhans型树突状细胞，并表达全长人酪氨酸酶（一种重要的黑色素瘤抗原）。我们现在建议在晚期黑色素瘤（III-IV期）患者中进行人体临床试验。我们将比较逆转录病毒转导基因修饰的表达全长人酪氨酸酶的Langerhans型树突状细胞与HLA-A*0201限制性酪氨酸酶肽脉冲的Langerhans细胞。安全性和毒性将在I期试验中进行评估。其他反应评估包括ELISpot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，比较疫苗后反应与治疗前基线。这些研究将为持续呈递多个I类和II类MHC表位比呈递单一I类MHC肽刺激适应性肿瘤特异性免疫的任何优势提供原理证明。（LAY摘要：特化朗格汉斯型树突状细胞的遗传改变将在晚期III-IV期黑色素瘤患者中进行安全性、毒性和肿瘤特异性免疫刺激的测试。）

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.)