Cell-based tumor vaccines targeting CD4+ T lymphocytes

描述（由申请人提供）：我们的长期目标是开发治疗性和预防性疫苗，诱导转移性眼部黑色素瘤消退并预防其进展，转移性眼部黑色素瘤是一种目前尚无治疗方法的疾病。为了实现这一目标，我们设计了基于细胞的疫苗，其激活肿瘤特异性CD 4 + T细胞，这是一种促进CD 8 + T细胞介导的细胞毒性和记忆的关键细胞群。眼黑色素瘤“MHC II疫苗”由经遗传修饰以表达与携带肿瘤的宿主同基因的共刺激分子CD 80和MHC II类等位基因的肿瘤细胞组成。如果疫苗细胞和宿主共享MHC I等位基因，则疫苗也激活CD 8 + T细胞。先前在小鼠中的研究证明了对已建立的原发性和自发转移性癌症的显著治疗功效。由于疫苗缺乏MHC II辅助分子，不变链（Ii），其在所有专职抗原呈递细胞（APC）中表达，我们假设疫苗呈递不是由专职APC产生的新的MHC II限制性肽。我们花了1-4年的时间将疫苗翻译成人类使用的疫苗，并制备了一系列在缺乏li的情况下表达CD 80和多种HLA-DR等位基因的眼黑色素瘤疫苗。这些疫苗在体外激活人PBMC以产生内源性合成的肿瘤抗原。在下一个资助期间，我们将确定MHC II疫苗的基本概念是否在人类系统中具有治疗效果，并将利用我们在上一个资助期间获得的机制见解来改进疫苗设计。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，使其成为自体肿瘤，以及患者在整个疾病过程中是否对疫苗有反应。目标二：确定从原发性肿瘤（位于眼睛的免疫特权部位）制备的眼黑色素瘤MHC II疫苗是否比从肝脏（非特权部位）转移性肿瘤细胞制备的疫苗更有效。目标3：确定用CD 80（MHC II类反式激活因子（CIITA））转导并下调Ii的眼黑素瘤细胞是否激活肿瘤特异性T细胞。目标4：确定MHCII + Ii-疫苗是否产生新的肽库，以及眼黑素瘤患者的应答是否偏向新的肽。

DESCRIPTION (provided by applicant): 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 (APC), we have hypothesized that the vaccines present novel MHC ll-restricted peptides which are not produced by professional APC. 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 CD80 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+li- vaccines produce a novel repertoire of peptides and if ocular melanoma patients' responses are skewed towards the novel peptides.