Cell-based tumor vaccines targeting CD4+ T lymphocytes

我们的长期目标是开发治疗和预防疫苗，以诱导退化和预防 转移性眼部黑色素瘤的进展，这种疾病目前还没有治疗方法。要实现 为了实现这一目标，我们设计了基于细胞的疫苗，可以激活肿瘤特异性的CD4+T细胞，这是一种关键细胞 具有CD8+T细胞介导的细胞毒作用和记忆力的人群。眼部黑色素瘤“MHC II” 疫苗由经过基因改造的肿瘤细胞组成，可以表达共刺激分子CD80 和MHC II类等位基因，这些等位基因与荷瘤宿主是同基因的。如果疫苗细胞和宿主 这些疫苗具有相同的MHC I等位基因，也可以激活CD8+T细胞。之前在小鼠身上的研究表明 对已确定的原发癌和自发转移性癌症有显著疗效。因为 疫苗缺乏MHC 11辅助分子不变链(Li)，这种分子在所有专业人士中都有表达。 抗原提呈细胞(ARC)，我们假设疫苗呈现新的MHC 11型限制性 不是由专业ARC生产的多肽。我们已经花了这笔赠款的1-4年来翻译 用于人类的疫苗，并已经制造了一系列表达C080+A的眼部黑色素瘤疫苗 LI缺失时的人类白细胞抗原-DR等位基因多样性。这些疫苗通过内源性激活人PBMC 体外合成肿瘤抗原。在下一个授权期内，我们将决定是否将基本概念 MHC II疫苗在人体系统中具有治疗效果，并将利用我们已有的机制洞察力 在上一次赠款期间获得的资金，用于改进疫苗设计。我们提出了四个具体目标。目标1： 确定MHC II“鸡尾酒”疫苗是否激活患者的T细胞至自体肿瘤，以及患者是否 在他们疾病的整个过程中对疫苗有反应。目的2.确定眼部黑色素瘤 从原发肿瘤中制备的MHC II疫苗，位于眼睛的免疫特权部位，是 比由驻留在肝脏的转移肿瘤细胞制备的疫苗更有效，这是一种非特权的 地点。目的3：确定转导MHC-II类反式激活剂CD80的眼黑色素瘤细胞 (CIITA)，并下调Li激活肿瘤特异性T细胞。目标4：确定MHC 11+LiV疫苗 产生一系列新的多肽，如果眼部黑色素瘤患者的反应扭曲 朝向新奇的多肽。

Our long-term goal is to develop therapeutic and prophylactic vaccines that induce regression and prevent progression of metastatic ocular melanoma, a disease for which there is no current treatment. To achieve this goal we have designed cell-based vaccines that activate tumor-specific CD4+ T cells, a key cell population that facilities CD8+ T cell-mediated cytotoxicity and memory. The ocular melanoma "MHC II vaccines" consist of tumor cells that are genetically modified to express the costimulatory molecule CD80 and MHC class II alleles that are syngeneic to the tumor-bearing host. If the vaccine cells and the host share MHC I alleles, the vaccines also activate CD8+ T cells. Previous studies in mice demonstrated significant therapeutic efficacy against established primary and spontaneously metastatic cancers. Because the vaccines lack the MHC ll-accessory molecule, Invariant chain (li), which is expressed in all professional antigen presenting cells (ARC), we have hypothesized that the vaccines present novel MHC ll-restricted peptides which are not produced by professional ARC. We have spent years 1-4 of this grant translating the vaccines for human use and have made a series of ocular melanoma vaccines that express C080 plus a variety of HLA-DR alleles in the absence of li. These vaccines activate human PBMC to endogenously synthesized tumor antigens in vitro. During the next grant period we will determine if the basic concept of MHC II vaccines has therapeutic efficacy in human systems and will exploit the mechanistic insight we have gained during the previous grant period to improve vaccine design. We propose four Specific Aims. Aim 1: Determine if MHC II "cocktail" vaccines activate patients' T cells to autologous tumor and if patients are responsive to the vaccines throughout the course of their disease. Aim 2. Determine if ocular melanoma MHC II vaccines prepared from primary tumors, which reside in the immune privileged site of the eye, are more efficacious than vaccines prepared from metastatic tumor cells that reside in the liver, a non-privileged site. Aim 3: Determine if ocular melanoma cells transduced with CD80, the MHC class II transactivator (CIITA), and down-regulated for li activate tumor-specific T cells. Aim 4: Determine if the MHC ll+livaccines produce a novel repertoire of peptides and if ocular melanoma patients' responses are skewed towards the novel peptides.