Potentiating Anti-WT1 responses by Targeting Peptide/MHC Complexes with T

该项目汇集了三项重要的、专门针对WT1的免疫治疗技术， 一种经过广泛验证的、通常表达的肿瘤抗原，在细胞上加工和呈递 在MHC分子的背景下，表面作为多肽被T细胞受体(TCR)识别。我们的 目标是通过使用类似TCR的单抗，TCR工程化的TCR，将T细胞或其他效应细胞集中在这个靶点上 细胞和WT1疫苗，目标也是延长这些方法的持久性和效力 因为该方法适用于多种人类白细胞抗原分型的患者。我们现在已经产生了一种高度亲和力的 “TCR样”单抗“ESK1”对来自该婚姻的多肽/MHC复合体的新表位具有特异性 这两种方法的优点。我们和其他人已经确定了来自WT1的多肽 诱导人类白细胞抗原限制的细胞毒性CDS T细胞的蛋白质，能够杀死肿瘤细胞。我们假设 这种基于单抗的结构针对多肽/人类白细胞抗原复合体中的WT1(模拟TCR)和TCR 同样针对WT1表位的工程化EBV T细胞将成为新的有效治疗药物 增加了传统的基于WT1多肽的疫苗。此外，使用自然表位 由O‘Reilly实验室在上一个资金周期中定义的，我们将为更广泛的 疫苗组，以及更好的T细胞供人类输注。在此背景下，这一行动的长期目标 项目是通过安全地增加血液肿瘤的SCT来提高SCT的有效性 TCR样单抗TCR对残留白血病和癌细胞的特异性免疫应答 将细胞和疫苗定向到最初由T细胞识别的抗原。因此，具体目标是：1)。至 新型TCR样人IGGI单抗与WT1反应的效应机制探讨 多肽(RMF)-MHC复合体。2)。评估EBV特异性T细胞转导至 表达高亲和力T细胞受体为WT1多肽/人类白细胞抗原复合体提供长寿 用于根除WT1*白血病细胞的效应细胞。3)。评估这些药物的治疗活性 在NOD/SCID muc-/-(NSG)小鼠体内抗人WTI*白血病移植瘤。4).从评估中发现 人类对重叠的天然WTI五聚体的天然免疫反应，新的突变类似物 多肽，包括CD4表位中隐含的CDS表位，并探索其在人类临床上的应用 审判。成功将对一些尚未满足需求的重要癌症产生立竿见影的影响 有效和安全的治疗，从急性白血病开始。

This project brings together three important, specific immunotherapeutic technologies focused on WT1, an extensively validated, commonly expressed tumor antigen that is processed and presented on the cell surface as peptides within the context of MHC molecules for recognition by T cell receptors (TCR). Our goal is to focus the T cell or other effector cells on this target by use of TCR like mAb, TCR engineered cells and WT1 vaccines, with a goal of extending the persistence and potency of the approaches as well as the reach of the approach to patients with multiple HLA types. We have now produced a high-affinity "TCR-like'' mAb "ESK1" specific to the neo-epitopes of peptide/MHC complexes derived from that marries the advantages of both approaches. We and others have identified peptides derived from the WT1 protein that induce HLA-restricted cytotoxic CDS T cells, capable of killing tumor cells. We hypothesize that mAb-based constructs specific for WT1 in the peptide/HLA complex (mimicking a TCR), and TCR engineered EBV T cells also directed to WT1 epitopes would be novel and effective therapeutic agents to add to the repertoire of traditional WT1 peptide-based vaccines. In addition, using the natural epitopes defined by the O'Reilly lab in the last funding cycle, we will develop new analog epitopes for a broader group of vaccines, and better T cells for human infusion. In this context, the long-term goals of this project are to improve the effectiveness of SCT of hematopoietic neoplasms by safely increasing the immune response specifically directed at residual leukemia and cancer cells using TCR-like mAb, TCR directed cells, and vaccines to antigens initially identified by T-cells. Thus, the specific aims are: 1). To explore the mechanisms of effector functions of our new "TCR-like" human IgGI mAb reactive with WT1 peptide (RMF)-MHC complexes. 2). To assess the potential of EBV-specific T-cells transduced to express higher affinity T-cell receptors specific for WT1 peptide/HLA complexes to provide long-lived effector cells for eradication of WT1* leukemia cells. 3). To assess the therapeutic activity of the agents against human WTI* leukemia xenografts in NOD/SCID mu c-/- (NSG) mice. 4).To discover from evaluation of natural human immune responses to overlapping native WTI penta-decamers, new mutated analog peptides, including cryptic CDS epitopes within CD4 epitopes, and explore their use in human clinical trials. Success would have immediate impact on a number of important cancers that have unmet needs for effective and safe therapy, beginning with acute leukemias.