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T-cell receptor mimic antibodies in hematological and solid malignancies: Identification of novel targets and implications for combined immunochemotherapy

T 细胞受体抗体在血液学和实体恶性肿瘤中的模拟：新靶标的鉴定及其对联合免疫化疗的影响

基本信息

批准号：
358467622
负责人：
Dr. Martin Klatt
金额：
--
依托单位：
Memorial Sloan Kettering Cancer Center
依托单位国家：
德国
项目类别：
Research Fellowships
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2019-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/358467622?language=en
关键词：
cell receptor mimic antibodies hematological

项目摘要

Over the last years immunotherapies had a huge positive impact on cancer therapy. T-cell receptor mimic antibodies represent a novel, innovative and promising approach to expand the repertoire of these immunotherapies. By combining the specificity of a T-cell receptor to target a unique peptide presented on a distinct MHC with the therapeutic potency of regular monoclonal antibodies as well as BiTEs, such as Rituximab or Blinatumomab, TCRms have the potential to form a new class of highly specific, effective and hardly toxic immunotherapy. Recent publications by the Scheinberg Lab at the MSKCC demonstrated the immense potential of this approach in nude mouse xenograft models of different kind of malignancies. Therefore the Scheinberg lab established a perfect model for further investigations on these new therapeutics.One of the main goals in this research project will be the identification of more specifically selected target epitopes for TCRm therapy. Therefore, we want to isolate HLA-ligands directly from primary cancer tissues, tumor cell lines and peripheral blood mononuclear cells (PBMCs) from healthy donors. After the identification of the peptide sequence of the ligands by mass spectrometry we are able to appoint novel and hopefully truly tumor specific epitopes. By using this approach we aim to minimize potential side effects of TCRm treatment through cross reactions with healthy tissue cells and to facilitate the use of TCRms for early translational therapy. Considering epitope selection network analysis of HLA ligands will be performed in order to lighten identification of relevant T cell epitopes as recently published by Klatt et al.. Preliminary work of the Rammensee and Stevanovic Lab by colleagues and myself already showed encouraging results for detection of possible HLA ligands derived from AML, prostate cancer or renal cell carcinoma.A similar approach will be used for the identification of non HLA-A*02 restricted T cell epitopes from the well established tumor associated antigen WT1 to enlarge the potential therapeutic use of TCRms directed against this antigen which showed impressive results so far.All epitopes detected by aforementioned experiments will form the basis for the design of novel TCRms. Afterwards their efficacy will be analyzed in pre-established NSG-mouse xenograft tumor models.Additionally, combination therapies of e.g. TCRms with chemotherapeutics or tyrosine kinase inhibitors used at non-cytotoxic doses will be performed to check for improved potency by the TCRms through upregulation of MHC-molecules on the cell surface. Altogether, these projects aim to expand the applications of TCRms by establishing novel TCRms against different cancer epitopes and entities as well as to prepare TCRms for translational approaches by improving their specificity.

在过去的几年里，免疫疗法对癌症治疗产生了巨大的积极影响。t细胞受体模拟抗体代表了一种新颖，创新和有前途的方法来扩大这些免疫疗法的曲目。通过将t细胞受体的特异性与常规单克隆抗体和bite（如利妥昔单抗或布利纳单抗）的治疗效力相结合，TCRms有可能形成一类新的高度特异性、有效且几乎没有毒性的免疫疗法。MSKCC的Scheinberg实验室最近发表的文章表明，这种方法在不同类型恶性肿瘤的裸鼠异种移植模型中具有巨大的潜力。因此，舍恩伯格实验室为进一步研究这些新疗法建立了一个完美的模型。该研究项目的主要目标之一将是确定更具体地选择TCRm治疗的靶表位。因此，我们希望直接从健康供体的原发癌组织、肿瘤细胞系和外周血单个核细胞（PBMCs）中分离hla配体。在通过质谱鉴定配体的肽序列后，我们能够指定新的和有希望真正的肿瘤特异性表位。通过使用这种方法，我们的目标是通过与健康组织细胞的交叉反应，最大限度地减少TCRm治疗的潜在副作用，并促进TCRm用于早期转化治疗。考虑到表位选择，HLA配体的网络分析将进行，以减轻相关T细胞表位的鉴定，最近由Klatt等人发表。Rammensee和Stevanovic实验室的同事和我的初步工作已经在检测AML、前列腺癌或肾细胞癌可能的HLA配体方面显示出令人鼓舞的结果。类似的方法将用于从已建立的肿瘤相关抗原WT1中鉴定非HLA-A*02限制性T细胞表位，以扩大针对该抗原的TCRms的潜在治疗用途，迄今为止已显示出令人印象深刻的结果。上述实验检测到的所有表位都将成为设计新型TCRms的基础。然后在预先建立的nsg -小鼠异种移植瘤模型中分析其疗效。此外，将TCRms与非细胞毒性剂量的化疗药物或酪氨酸激酶抑制剂联合使用，以检查TCRms是否通过上调细胞表面mhc分子来提高效力。总之，这些项目旨在通过建立针对不同癌症表位和实体的新型TCRms来扩大TCRms的应用范围，并通过提高TCRms的特异性为TCRms的转化途径做准备。