Cell-based tumor vaccines targeting CD4+ T lymphocytes

描述(申请人提供)：我们的长期目标是开发治疗和预防疫苗，以诱导消退和防止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。为了实现这一目标，我们设计了基于细胞的疫苗，激活肿瘤特异性的CD4+T细胞，这是一种关键的细胞群，有助于CD8+T细胞介导的细胞毒性和记忆。眼部黑色素瘤“MHC II疫苗”由肿瘤细胞组成，这些细胞经过基因改造，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的基因相同。如果疫苗细胞和宿主共享MHC I等位基因，疫苗也会激活CD8+T细胞。以前在小鼠身上的研究表明，对已确定的原发和自发转移癌症有显著的治疗效果。由于疫苗缺乏在所有专业抗原提呈细胞(APC)中表达的MHC 11辅助分子不变链(LI)，我们推测疫苗提供了不是由专业APC产生的新的MHC 11限制性多肽。我们花了这笔赠款的1-4年将疫苗转化为人类使用，并制作了一系列眼部黑色素瘤疫苗，在缺乏LI的情况下表达CD80和各种HLA-DR等位基因。这些疫苗在体外激活人PBMC以内源性合成肿瘤抗原。在下一个授权期，我们将确定MHC II疫苗的基本概念是否对人类系统具有治疗效果，并将利用我们在前一个授权期获得的机制洞察力来改进疫苗设计。我们提出了四个具体目标。目的1：确定MHC II“鸡尾酒”疫苗是否激活患者的T细胞对自体肿瘤，以及患者在整个疾病过程中是否对疫苗有反应。目的2：确定位于眼部免疫优势部位的原发黑色素瘤MHC II疫苗是否比位于非免疫优势部位肝脏的转移性肿瘤细胞制备的疫苗更有效。目的：检测转导MHC-II类反式激活剂(CIITA)CD80的眼黑色素瘤细胞是否能激活肿瘤特异性T细胞。目的4：确定MHC 11+Li疫苗是否产生了一系列新的多肽，以及眼部黑色素瘤患者的反应是否偏向于这些新的多肽。

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.