Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.
Eradication of Large Solid Tumors by Gene Therapy with a T-Cell Receptor Targeting a Single Cancer-Specific Point Mutation.
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DOI：
10.1158/1078-0432.ccr-15-2361
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发表时间：
2016-06-01
期刊：
影响因子：
--
通讯作者：
Schreiber H
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文献类型：
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作者：
Leisegang M;Engels B;Schreiber K;Yew PY;Kiyotani K;Idel C;Arina A;Duraiswamy J;Weichselbaum RR;Uckert W;Nakamura Y;Schreiber H
癌症通常含有多个独特的肿瘤特异性抗原，由单氨基酸取代（AAS）产生，并由体细胞非同义单核苷酸取代编码。我们确定了过继性转移的T细胞在表达单一AAS特异性的单一类型T细胞受体（TCR）时，是否可以排斥大型、成熟的实体肿瘤。通过紫外线诱导肿瘤的外显子组和RNA测序，我们在p53的共同激活因子p68 （mp68）中发现了一个AAS。这个AAS似乎是一个理想的肿瘤特异性新表位，因为它是由原发性原位癌的主干突变编码的，并且与MHC结合具有最高的亲和力。高亲和性mp68特异性TCR被用于基因工程T细胞，并产生用于过继治疗的TCR转基因小鼠。当新表位在所有癌细胞中高水平表达时，它们的直接识别足以破坏肿瘤内血管并根除长期存在的大实体瘤。当新表位作为自体抗原靶向时，T细胞引起癌症消退，随后抗原阴性变体逃逸。通过在所有癌细胞中表达更高水平的抗原或将T细胞治疗与局部照射相结合，可以阻止逃逸。tcr转导T细胞和tcr转基因T细胞的治疗效果相似。用单个TCR靶向单个AAS的基因治疗可以根除大的已建立的癌症，但需要统一表达和/或足够水平的靶向新表位或额外的治疗来克服肿瘤逃逸。
Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic non-synonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T cell receptor (TCR) that is specific for a single AAS. By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intra-tumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape.