Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab.
Mobilization of pre-existing polyclonal T cells specific to neoantigens but not self-antigens during treatment of a patient with melanoma with bempegaldesleukin and nivolumab.
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DOI：
10.1136/jitc-2020-001591
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发表时间：
2020-12
影响因子：
10.9
通讯作者：
Riddell SR
中科院分区：
文献类型：
--
作者：
Veatch JR;Singhi N;Jesernig B;Paulson KG;Zalevsky J;Iaccucci E;Tykodi SS;Riddell SR
识别自身抗原和突变的新抗原的T细胞被认为介导黑色素瘤中免疫检查点阻断（ICB）的抗肿瘤活性。很少有研究分析了对ICB有反应的患者的自身和新抗原特异性T细胞反应。在这里，我们报告了一名转移性黑色素瘤患者，他在接受程序性细胞死亡蛋白1抑制剂纳武单抗（nivolumab）联合一流的CD 122优先白细胞介素-2通路激动剂bempegaldesleukin（BEMPEG，NKTR-214）治疗后获得了持久的临床应答。我们使用抗原特异性T细胞扩增和干扰素-γ分泌测量的组合来鉴定治疗前后该患者血液和肿瘤中对新抗原、谱系特异性抗原和癌症睾丸抗原具有特异性的多个CD 4+和CD 8 + T细胞克隆。与外周血相比，治疗前肿瘤中对多种新抗原而非自身抗原特异性的多克隆CD 4+和CD 8 + T细胞高度富集。在成功治疗期间，新抗原而非自身抗原特异性T细胞克隆在血液中频繁扩增。有证据表明，在治疗过程中，免疫细胞显著浸润到肿瘤中，并且肿瘤内新抗原特异性T细胞的相对频率适度增加。这些观察结果表明，在该患者中，与自身抗原特异性T细胞相比，对治疗前肿瘤中存在的新抗原特异性的多种CD 8+和CD 4 + T细胞克隆在免疫肿瘤排斥中具有更大的作用。试验注册号：NCT 02983045。
T cells that recognize self-antigens and mutated neoantigens are thought to mediate antitumor activity of immune checkpoint blockade (ICB) in melanoma. Few studies have analyzed self and neoantigen-specific T cell responses in patients responding to ICB. Here, we report a patient with metastatic melanoma who had a durable clinical response after treatment with the programmed cell death protein 1 inhibitor, nivolumab, combined with the first-in-class CD122-preferential interleukin-2 pathway agonist, bempegaldesleukin (BEMPEG, NKTR-214). We used a combination of antigen-specific T cell expansion and measurement of interferon-γ secretion to identify multiple CD4+ and CD8+ T cell clones specific for neoantigens, lineage-specific antigens and cancer testis antigens in blood and tumor from this patient prior to and after therapy. Polyclonal CD4+ and CD8+ T cells specific to multiple neoantigens but not self-antigens were highly enriched in pretreatment tumor compared with peripheral blood. Neoantigen, but not self-antigen-specific T cell clones expanded in frequency in the blood during successful treatment. There was evidence of dramatic immune infiltration into the tumor on treatment, and a modest increase in the relative frequency of intratumoral neoantigen-specific T cells. These observations suggest that diverse CD8+ and CD4+ T cell clones specific for neoantigens present in tumor before treatment had a greater role in immune tumor rejection as compared with self-antigen-specific T cells in this patient. Trial registration number: NCT02983045.
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影响因子：
82.9
作者：
Gros A;Parkhurst MR;Tran E;Pasetto A;Robbins PF;Ilyas S;Prickett TD;Gartner JJ;Crystal JS;Roberts IM;Trebska-McGowan K;Wunderlich JR;Yang JC;Rosenberg SA
通讯作者：
Rosenberg SA
影响因子：
32.4
作者：
Effern, Maike;Glodde, Nicole;Hoelzel, Michael
通讯作者：
Hoelzel, Michael
影响因子：
10.1
作者：
Veatch, Joshua R.;Jesernig, Brenda L.;Riddell, Stanley R.
通讯作者：
Riddell, Stanley R.
影响因子：
7.2
作者：
Kvistborg P;Shu CJ;Heemskerk B;Fankhauser M;Thrue CA;Toebes M;van Rooij N;Linnemann C;van Buuren MM;Urbanus JH;Beltman JB;Thor Straten P;Li YF;Robbins PF;Besser MJ;Schachter J;Kenter GG;Dudley ME;Rosenberg SA;Haanen JB;Hadrup SR;Schumacher TN
通讯作者：
Schumacher TN
DOI：
10.1126/science.aaf1490
发表时间：
2016-03-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
McGranahan N;Furness AJ;Rosenthal R;Ramskov S;Lyngaa R;Saini SK;Jamal-Hanjani M;Wilson GA;Birkbak NJ;Hiley CT;Watkins TB;Shafi S;Murugaesu N;Mitter R;Akarca AU;Linares J;Marafioti T;Henry JY;Van Allen EM;Miao D;Schilling B;Schadendorf D;Garraway LA;Makarov V;Rizvi NA;Snyder A;Hellmann MD;Merghoub T;Wolchok JD;Shukla SA;Wu CJ;Peggs KS;Chan TA;Hadrup SR;Quezada SA;Swanton C
通讯作者：
Swanton C