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

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的、创新的和有前途的方法来扩展这些免疫疗法的库。通过将T细胞受体靶向不同MHC上呈现的独特肽的特异性与常规单克隆抗体以及BiTE（如利妥昔单抗或Blinatumomab）的治疗效力相结合，TCR具有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的潜力。MSKCC的Scheinberg实验室最近的出版物证明了这种方法在不同类型恶性肿瘤的裸鼠异种移植模型中的巨大潜力。因此，Scheinberg实验室为进一步研究这些新疗法建立了一个完美的模型。本研究项目的主要目标之一将是鉴定更特异性选择的TCRm治疗靶表位。因此，我们希望直接从健康供体的原发性癌组织、肿瘤细胞系和外周血单核细胞（PBMC）中分离HLA配体。在通过质谱鉴定配体的肽序列之后，我们能够指定新的并且有希望是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小化TCRm治疗的潜在副作用，并促进TCRm用于早期转化治疗。考虑到HLA配体的表位选择网络分析，将进行HLA配体的表位选择网络分析，以减轻相关T细胞表位的鉴定，如Klatt等人最近发表的。Rammensee和Stevanovic实验室的同事和我自己的初步工作已经显示了令人鼓舞的结果，用于检测可能来自AML的HLA配体，前列腺癌或肾细胞癌。类似的方法将用于鉴定非HLA-A* 02限制性T细胞表位，以扩大针对该抗原的TCR m的潜在治疗用途，其显示通过上述实验检测到的所有表位将形成设计新型TCR m的基础。此外，将进行例如TCR m与以非细胞毒性剂量使用的化疗剂或酪氨酸激酶抑制剂的组合疗法，以检查TCR m通过上调细胞表面上的MHC分子而提高的效力。总而言之，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，并通过提高其特异性来为翻译方法做好准备。

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.