A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer.
A TCR targeting the HLA-A*0201-restricted epitope of MAGE-A3 recognizes multiple epitopes of the MAGE-A antigen superfamily in several types of cancer.
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DOI：
10.4049/jimmunol.1001775
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发表时间：
2011-01-15
期刊：
影响因子：
--
通讯作者：
Morgan RA
中科院分区：
文献类型：
--
作者：
Chinnasamy N;Wargo JA;Yu Z;Rao M;Frankel TL;Riley JP;Hong JJ;Parkhurst MR;Feldman SA;Schrump DS;Restifo NP;Robbins PF;Rosenberg SA;Morgan RA
使用经T细胞受体（TCR）工程改造的外周血淋巴细胞（PBLs）针对黑素细胞分化抗原进行的过继性免疫疗法可介导肿瘤客观消退，但伴有靶向毒性。为避免对正常组织产生毒性，我们将靶点指向癌-睾丸抗原（CTA）MAGE - A3，它在多种上皮恶性肿瘤中广泛表达，但在大多数正常组织中不表达。为了产生针对MAGE - A3的高亲和力TCR，我们采用了一种表达人HLA - A*0201分子的转基因小鼠模型。用MAGE - A3的两种HLA - A*0201限制性肽段：112 - 120（KVAELVHFL）或MAGE - A3：271 - 279（FLWGPRALV）对小鼠进行免疫，并产生T细胞克隆。分离出MAGE - A3特异性TCR的α链和β链，并将其克隆到逆转录病毒载体中。两种TCR在人PBLs中的表达均显示出针对一系列黑素瘤和非黑素瘤肿瘤细胞的抗原特异性反应性。基于对肿瘤靶细胞的优越反应性，选择了针对MAGE - A3：112 - 120的TCR进行进一步开发。有趣的是，经工程改造表达此TCR的PBLs能够识别来自MAGE - A3和MAGE - A12的肽表位（在较小程度上，也能识别来自MAGE - A2和MAGE - A6的肽段）。为了进一步改善TCR功能，构建了CDR3α链的单氨基酸变异体。在TCR的CDR3区域中，α链第118位的丙氨酸替换为苏氨酸提高了其在CD4和CD8细胞中的功能亲和力。基于这些结果，计划开展一项临床试验，患有多种肿瘤组织学类型的患者将接受经此优化的抗MAGE - A3 TCR转导的自体PBLs。
Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which is widely expressed in a range of epithelial malignancies but is not expressed in most normal tissues. To generate high-avidity TCRs against MAGE-A3, we employed a transgenic mouse model that expresses the human HLAA*0201 molecule. Mice were immunized with two HLA-A*0201–restricted peptides of MAGE-A3: 112–120 (KVAELVHFL) or MAGE-A3: 271–279 (FLWGPRALV), and T cell clones were generated. MAGE-A3–specific TCR α- and β-chains were isolated and cloned into a retroviral vector. Expression of both TCRs in human PBLs demonstrated Ag-specific reactivity against a range of melanoma and nonmelanoma tumor cells. The TCR against MAGE-A3: 112–120 was selected for further development based on superior reactivity against tumor target cells. Interestingly, peptide epitopes from MAGE-A3 and MAGE-A12 (and to a lesser extent, peptides from MAGE-A2 and MAGE-A6) were recognized by PBLs engineered to express this TCR. To further improve TCR function, single amino acid variants of the CDR3 α-chain were generated. Substitution of alanine to threonine at position 118 of the α-chain in the CDR3 region of the TCR improved its functional avidity in CD4 and CD8 cells. On the basis of these results, a clinical trial is planned in which patients bearing a variety of tumor histologies will receive autologous PBLs that have been transduced with this optimized anti–MAGE-A3 TCR.
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影响因子：
3.9
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Dudley, ME;Wunderlich, JR;Rosenberg, SA
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