Medigene Immunotherapies GmbH, Planegg-Martinsried, Germany.
bluebird bio Inc, Cambridge, Massachusetts, USA.
J Immunother Cancer. 2021 Mar;9(3). doi: 10.1136/jitc-2020-002035.
The cancer-testis antigen MAGE-A4 is an attractive target for T-cell-based immunotherapy, especially for indications with unmet clinical need like non-small cell lung or triple-negative breast cancer.
An unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived epitope (GVYDGREHTV) that was properly processed and presented on human leukocyte antigen (HLA)-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high-avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies.
A MAGE-A4-reactive, HLA-A2-restricted T-cell receptor (TCR) was isolated from primed T cells of an HLA-A2-negative donor. The respective TCR-T-cell (TCR-T) product bbT485 was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared with TCR-Ts expressing a TCR derived from a tolerized T-cell repertoire to self-antigens. This natural high-avidity TCR was found to be CD8 co-receptor independent, allowing effector functions to be elicited in transgenic CD4 T helper cells. These CD4 TCR-Ts supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells and upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines on tumor-specific stimulation.
The extensive pre-clinical assessment of safety and in vivo potency of bbT485 provide the basis for its use in TCR-T immunotherapy studies. The ability of this non-mutated high-avidity, co-receptor-independent TCR to activate CD8 and CD4 T cells could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T-cell subsets that goes beyond what is currently tested in the clinic.
癌症睾丸抗原 MAGE-A4 是一种有吸引力的 T 细胞为基础的免疫治疗靶点，特别是对于那些有未满足临床需求的适应症，如非小细胞肺癌或三阴性乳腺癌。
首先使用无偏见的 CD137 为基础的分选方法来鉴定一个免疫原性的 MAGE-A4 衍生的表位（GVYDGREHTV），该表位在人类白细胞抗原（HLA）-A2 分子上被正确加工和呈递，这些 HLA-A2 分子由 HLA-A*02:01 等位基因编码。为了通过随后的多聚体分选分离高亲和力 T 细胞，通过使用 HLA-A2 阴性供体进行体外初始处理来绕过对这种自身抗原的中枢耐受。在一系列全面的体外和体内研究中评估了安全性和活性的临床前参数。
从 HLA-A2 阴性供体的初始 T 细胞中分离出一种对 MAGE-A4 有反应的 HLA-A2 限制性 T 细胞受体（TCR）。该 TCR-T 细胞（TCR-T）产物 bbT485 在临床前研究中被证明具有良好的安全性特征和优于表达源自自身抗原耐受 T 细胞 repertoire 的 TCR 的 TCR-Ts 的体内效力。这种天然的高亲和力 TCR 被发现不依赖于 CD8 共受体，允许在转基因 CD4 T 辅助细胞中引发效应功能。这些 CD4 TCR-Ts 通过直接杀伤 MAGE-A4 阳性肿瘤细胞和上调与辅助功能相关的标志物，如 CD154 的表达和关键细胞因子的释放，支持抗肿瘤反应。
对 bbT485 的广泛临床前安全性和体内效力评估为其在 TCR-T 免疫治疗研究中的应用提供了基础。这种非突变的高亲和力、不依赖共受体的 TCR 激活 CD8 和 CD4 T 细胞的能力可能通过诱导功能多样化的 T 细胞亚群在临床环境中提供增强的细胞反应，这种反应超出了目前在临床上测试的范围。
