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

描述(申请人提供)：我们对人类树突状细胞的了解的进步已经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数。肿瘤抗原本身就是弱免疫原，因为它们要么是自身抗原，要么是改变的自身抗原。因此，克服对癌症自身抗原的耐受性的门槛虽然是可以达到的，但也是相当高的。树突状细胞可以通过递呈肿瘤抗原和所有其他诱导免疫反应的必需分子来绕过许多这些障碍。基因策略在将肿瘤抗原与树突状细胞偶联方面提供了潜在的优势。与标准的多肽脉冲相比，转基因树突状细胞可以表达多个表位，并且可以加工和定制各种MHC等位基因。持续的抗原提呈更有可能，而且可以随着时间的推移进行监测。我们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，产生了大量的临床前数据。然而，我们已经成功地将CD34+祖细胞转化为朗格汉斯型树突状细胞并表达全长的人酪氨酸酶，这是一种重要的黑色素瘤抗原。我们现在建议对晚期黑色素瘤(III-IV期)患者进行一项人类临床试验。我们将比较通过逆转录病毒转导基因修饰的表达全长人酪氨酸酶的朗格汉斯型树突状细胞与冲击了人类白细胞抗原-A*0201限制性酪氨酸酶多肽的朗格汉斯细胞。安全性和毒性将在这一阶段的试验中进行评估。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分析，比较疫苗后和治疗前的基线反应。这些研究将为持续呈现多个I类和II类MHC表位而不是呈现单一I类MHC多肽以刺激适应性肿瘤特异性免疫的任何优势提供原则证据。(LAY摘要：针对晚期III-IV期黑色素瘤患者，将测试特化朗格汉斯型树突状细胞的基因改变的安全性、毒性和对肿瘤特异性免疫的刺激作用。)

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.)