In vitro induction of neoantigen-specific T cells in myelodysplastic syndrome, a disease with low mutational burden
In vitro induction of neoantigen-specific T cells in myelodysplastic syndrome, a disease with low mutational burden
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DOI：
10.1016/j.jcyt.2020.10.003
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发表时间：
2021-03-18
期刊：
影响因子：
4.5
通讯作者：
Vitiello, Antonella
中科院分区：
文献类型：
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作者：
Ferrari, Valentina;Tarke, Alison;Vitiello, Antonella
利用免疫检查点抑制的疗法通过利用突变衍生的新抗原起作用，并在具有较高突变负担的肿瘤中显示出更大的临床疗效。具有低突变负担的肿瘤是否对新抗原靶向治疗敏感尚未得到充分解决。为了检验新抗原特异性过继t细胞治疗的可行性，作者研究了5例骨髓增生异常综合征（MDS）患者的t细胞对体细胞变异的反应，MDS是一种肿瘤突变负担非常低的恶性肿瘤。从患者身上分离的肿瘤细胞（CD34(+)）和正常细胞（CD3(+)）的DNA和RNA ？对血液进行测序以预测患者特异性MDS新肽。代表体细胞变体的新肽被用于体外诱导和扩增自体T细胞，并在杀伤试验中系统地测试这些新肽，以确定产生新抗原特异性T细胞的比例。作者共鉴定出32种体细胞变异（每个患者4到8种），发现21种（66%）诱导肽特异性t细胞反应，19种（59%）诱导能够杀死自体肿瘤细胞的t细胞反应。在32个体细胞变异中，11个（34%）诱导CD4（+）应答，11个（34%）诱导CD8（+）应答，杀死肿瘤。这些结果表明，在体外诱导新抗原特异性T细胞对于突变负担非常低的肿瘤是可行的，并且这种方法值得研究作为这类患者的治疗选择。(C) 2020国际细胞与基因治疗学会。Elsevier Inc.出版。这是一篇开放获取的文章
Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34(+)) and normal (CD3(+)) cells isolated from the patients? blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4(+) response and 11 (34%) induced a CD8(+) response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients. (C) 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. This is an open access article