Polarized DC as Melanoma Vaccine: Phase 1 Evaluation

描述(申请人提供)：Th1、CTL和NK细胞驱动的细胞介导免疫是对抗癌症的最有效的反应形式。基于树突状细胞(DC)极化的新范式，以及我们最近观察到的IFNα的存在允许在无血清条件下产生1型极化DC(DC)，我们最近开发了第一个临床适用的DC产生方案。这种树突状细胞是第一种临床可应用的树突状细胞，它结合了对其体内活性至关重要的所有三种特性，作为抗癌免疫的诱导剂。它们是：1)完全成熟状态；2)对CCR7结扎的高迁移反应性；3)高IL-12p70产生功能。与目前临床使用的树突状细胞的“黄金标准”相比，α-DC 1显示出选择性增强的诱导1型抗癌反应的能力。在黑色素瘤患者外周血T细胞的体外致敏过程中，多肽冲击的αDC1s诱导的针对Mart-1、酪氨酸酶和gp100的CTL数量高达40倍。它们还能诱导强大的CD4+Th1细胞和NK细胞的抗肿瘤活性。我们假设，在一项新的I期临床试验中，通过淋巴内途径接种基于AlphaDC1的疫苗将是安全的，并将在AlphaDC1治疗的黑色素瘤患者中作为肿瘤特异性反应的优越诱导剂。我们将追求一个特定的目标：特定的目标1.证明基于AlphaDC1的疫苗在III/IV期黑色素瘤患者中的安全性和免疫学有效性。我们将进行一项随机的I期临床试验(UPCI03-118；IND#：11,754)，涉及28名患者，比较淋巴内接种aDC和标准(IL-1β/TNFpha/IL-6/PGE2成熟)DC的安全性和免疫学(以及潜在的临床)有效性。作为这一目标的一部分，进行的免疫监测将使我们能够分析接种疫苗后循环和DTH活检中黑色素瘤特异性反应的免疫变化。这项研究的积极结果将使我们能够获得利用DC极化现象的疫苗在体内免疫有效性的原则性证明，并将有助于我们设计一项针对基于αDC1的疫苗的免疫学和临床有效性的扩展后续研究。对αDC1s体内有效性的验证，也将导致对这些细胞在诱导1型抗癌免疫中的高活性机制的后续研究，并对涉及的关键介质进行前瞻性的识别。

DESCRIPTION (provided by applicant): Th1-, CTL-, and NK cell-driven cell-mediated immunity is the most effective form of response against cancer. Based on the novel paradigm of polarization of dendritic cells (DCs), and on our recent observations that the presence of IFNalpha allows for the generation of type-1 polarized DCs (DC1s) in serum-free conditions, we have recently developed the first clinically-applicable protocol to generate DC1s. Such alphaDC1s are the first clinically-applicable type of DCs that combine all 3 properties important for their in vivo activity as inducers of anti-cancer immunity. These are: 1) fully mature status; 2) high migratory responsiveness to CCR7 ligation; and 3) high IL-12p70-producing function. alphaDC1s show selectively enhanced ability to induce type-1 anti-cancer responses, when compared to the current "gold standard" of clinically-used DCs. Peptide-pulsed alphaDC1s induce up to 40-fold higher numbers of CTLs against MART- 1, tyrosinase, and gp100, during in vitro sensitization of peripheral blood T cells from melanoma patients. They also induce strong antitumor activity of CD4+ Th1 cells and NK cells. We hypothesize that alphaDC1-based vaccines administered by intralymphatic route will be safe and will act as superior inducers of tumor-specific responses in alphaDC1- treated melanoma patients in a novel phase I clinical trial. We will pursue one Specific Aim: Specific Aim 1. Demonstrate the safety and immunologic effectiveness of alphaDC1-based vaccines in patients with stage III/IV melanoma. We will perform a randomized phase I clinical trial (UPCI 03-118; IND#: 11,754) involving 28 patients, comparing the safety and the immunologic (and potentially clinical) efficacy of intralymphatic vaccination with aDC1s versus standard (IL-1beta/TNFalpha/IL-6/PGE2-matured) DCs. The immunomonitoring performed as a part of this aim will allow us to analyze the vaccination induced immunologic changes of melanoma-specific responses in circulation and DTH biopsies. The positive outcome of this study will allow us to obtain a proof of principle for the in vivo immunologic effectiveness of vaccines utilizing the phenomenon of DC polarization, and will help us to design an extended follow-up study of the immunologic and clinical effectiveness of alphaDC1-based vaccines. Verification of the in vivo efficacy of alphaDC1s, will also lead to follow-up studies of the mechanism of high activity of these cells in the induction of type-1 anticancer immunity and the prospective identification of the key mediators involved.