Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.
Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors.
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DOI：
10.1111/cas.15009
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发表时间：
2021-08
期刊：
影响因子：
5.7
通讯作者：
Kawakami Y
中科院分区：
文献类型：
--
作者：
Hirai I;Funakoshi T;Kamijuku H;Fukuda K;Mori M;Sakurai M;Koda Y;Kato J;Mori T;Watanabe N;Noji S;Yaguchi T;Iwata T;Ohta S;Fujita T;Tanosaki R;Handa M;Okamoto S;Amagai M;Kawakami Y
为了评价在免疫检查点抑制剂治疗失败的日本黑色素瘤患者中使用离体扩增的肿瘤浸润淋巴细胞（TIL）进行过继细胞治疗（ACT）的可行性，进行了一项开放标签、单臂、初步研究。我们研究了可能与临床反应相关的预处理肿瘤和扩增TIL的免疫学和遗传学因素。治疗方案包括制备TIL培养物、使用环磷酰胺和氟达拉滨进行淋巴细胞清除性非清髓性预处理、TIL输注和低剂量IL-2静脉给药。3例临床亚型粘膜、浅表扩散和肢端黑色素瘤患者接受了TIL-ACT。大多数严重不良事件（包括发热和白细胞减少症）可通过方案中规定的支持性方案进行管理，表明TIL-ACT方案适用于日本黑色素瘤患者。1例患者显示短期部分缓解，1例患者疾病相对长期稳定，1例患者发生疾病进展。在TIL-ACT之前，分离的肿瘤细胞的全外显子组和转录测序以及免疫组织化学分析显示了各种免疫刺激因子，包括高肿瘤突变负荷和免疫细胞募集趋化因子，以及各种免疫抑制因子，包括TGF-β、VEGF、Wnt/β连环蛋白和MAPK信号传导和上皮-间质转化，这可能影响TIL-ACT的疗效。我们的结果暗示了TIL-ACT的抗肿瘤作用和耐药性的机制。需要进一步研究TIL-ACT的免疫耐药机制。本研究已在UMIN 000011431临床试验登记处注册。参与免疫刺激和免疫抑制平衡的各种因素在黑色素瘤患者的TIL-ACT应答中很重要。
To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo‐expanded tumor‐infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune‐checkpoint inhibitor therapy, an open‐label, single‐arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho‐depleting non‐myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low‐dose IL‐2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL‐ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL‐ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short‐term partial response, one relatively long‐stable disease, and one experienced disease progression. Whole‐exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL‐ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell‐recruiting chemokines, as well as various immunosuppressive factors including TGF‐β, VEGF, Wnt/β‐catenin, and MAPK signaling and epithelial‐to‐mesenchymal transition, which might influence the efficacy of TIL‐ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL‐ACT. Further studies of immune‐resistant mechanisms of TIL‐ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431). Various factors involved in the balance of immunostimulation and immunosuppression are important in the TIL‐ACT response for melanoma patients.
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影响因子：
6.2
作者：
Shoushtari, Alexander N.;Munhoz, Rodrigo R.;Kuk, Deborah;Ott, Patrick A.;Johnson, Douglas B.;Tsai, Katy K.;Rapisuwon, Suthee;Eroglu, Zeynep;Sullivan, Ryan J.;Luke, Jason J.;Gangadhar, Tara C.;Salama, April K. S.;Clark, Varina;Burias, Clare;Puzanov, Igor;Atkins, Michael B.;Algazi, Alain P.;Ribas, Antoni;Wolchok, Jedd D.;Postow, Michael A.
通讯作者：
Postow, Michael A.
DOI：
10.1056/nejmoa1709684
发表时间：
2017-10-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Wolchok JD;Chiarion-Sileni V;Gonzalez R;Rutkowski P;Grob JJ;Cowey CL;Lao CD;Wagstaff J;Schadendorf D;Ferrucci PF;Smylie M;Dummer R;Hill A;Hogg D;Haanen J;Carlino MS;Bechter O;Maio M;Marquez-Rodas I;Guidoboni M;McArthur G;Lebbé C;Ascierto PA;Long GV;Cebon J;Sosman J;Postow MA;Callahan MK;Walker D;Rollin L;Bhore R;Hodi FS;Larkin J
通讯作者：
Larkin J
DOI：
10.5402/2012/381428
发表时间：
2012
期刊：
ISRN molecular biology
影响因子：
--
作者：
Lebrun JJ
通讯作者：
Lebrun JJ
影响因子：
5.8
作者：
Kim, Hong Kwan;Joung, Je-Gun;Kim, Jhingook
通讯作者：
Kim, Jhingook
DOI：
10.1158/1078-0432.ccr-12-1177
发表时间：
2012-12-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Radvanyi LG;Bernatchez C;Zhang M;Fox PS;Miller P;Chacon J;Wu R;Lizee G;Mahoney S;Alvarado G;Glass M;Johnson VE;McMannis JD;Shpall E;Prieto V;Papadopoulos N;Kim K;Homsi J;Bedikian A;Hwu WJ;Patel S;Ross MI;Lee JE;Gershenwald JE;Lucci A;Royal R;Cormier JN;Davies MA;Mansaray R;Fulbright OJ;Toth C;Ramachandran R;Wardell S;Gonzalez A;Hwu P
通讯作者：
Hwu P