Chimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer.
Chimeric Antigen Receptor T Cell Therapy Targeting ICAM-1 in Gastric Cancer.
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DOI：
10.1016/j.omto.2020.08.009
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发表时间：
2020-09-25
期刊：
影响因子：
--
通讯作者：
Jin MM
中科院分区：
文献类型：
--
作者：
Jung M;Yang Y;McCloskey JE;Zaman M;Vedvyas Y;Zhang X;Stefanova D;Gray KD;Min IM;Zarnegar R;Choi YY;Cheong JH;Noh SH;Rha SY;Chung HC;Jin MM
利用嵌合抗原受体（CAR）T细胞的过继转移的癌症疗法已经在血液恶性肿瘤中显示出显著的临床结果。然而，CAR T细胞应用于实体瘤的成功有限，部分原因是缺乏肿瘤特异性抗原和免疫抑制性肿瘤微环境。从胃癌患者的肿瘤组织中，我们发现细胞间粘附分子1（ICAM-1）的表达与晚期和较短的生存期显著相关。在这项研究中，我们报告了一项使用ICAM-1靶向CAR T细胞对抗胃癌的概念验证研究。ICAM-1 CAR T细胞的功效与体外靶细胞中ICAM-1的表达水平显着相关。在人类胃癌的动物模型中，靶向ICAM-1的CAR T细胞有效地消除了在肺中发展的肿瘤，而它们对腹膜中的肿瘤的疗效更有限。为了增强CAR T细胞对腹膜内肿瘤的活性，探索了与紫杉醇或CAR活化依赖性白细胞介素（IL）-12释放的组合，并发现其显著增加抗肿瘤活性和存活益处。总的来说，ICAM-1靶向CAR T细胞单独或与化疗联合代表了治疗ICAM-1+晚期胃癌患者的有希望的策略。在这项研究中，我们证明了靶向ICAM-1的CAR T细胞在胃癌全身和腹膜内转移的临床前模型中的治疗潜力。发现与紫杉醇或具有诱导型IL-12的装甲CAR T细胞的组合显著增强CAR T细胞的治疗效果。
Cancer therapy utilizing adoptive transfer of chimeric antigen receptor (CAR) T cells has demonstrated remarkable clinical outcomes in hematologic malignancies. However, CAR T cell application to solid tumors has had limited success, partly due to the lack of tumor-specific antigens and an immune-suppressive tumor microenvironment. From the tumor tissues of gastric cancer patients, we found that intercellular adhesion molecule 1 (ICAM-1) expression is significantly associated with advanced stage and shorter survival. In this study, we report a proof-of-concept study using ICAM-1-targeting CAR T cells against gastric cancer. The efficacy of ICAM-1 CAR T cells showed a significant correlation with the level of ICAM-1 expression in target cells in vitro. In animal models of human gastric cancer, ICAM-1-targeting CAR T cells potently eliminated tumors that developed in the lungs, while their efficacy was more limited against the tumors in the peritoneum. To augment CAR T cell activity against intraperitoneal tumors, combinations with paclitaxel or CAR activation-dependent interleukin (IL)-12 release were explored and found to significantly increase anti-tumor activity and survival benefit. Collectively, ICAM-1-targeting CAR T cells alone or in combination with chemotherapy represent a promising strategy to treat patients with ICAM-1+ advanced gastric cancer. In this study, we demonstrated the therapeutic potential of CAR T cells targeting ICAM-1 in preclinical models of systemic and intraperitoneal metastases of gastric cancer. A combination with paclitaxel or armoring CAR T cells with inducible IL-12 was found to significantly enhance the treatment effect of CAR T cells.
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影响因子：
45.3
作者：
Ahmed, Nabil;Brawley, Vita S.;Gottschalk, Stephen
通讯作者：
Gottschalk, Stephen
DOI：
10.1073/pnas.1610544113
发表时间：
2016-11-29
影响因子：
11.1
作者：
Hurton, Lenka V.;Singh, Harjeet;Cooper, Laurence J. N.
通讯作者：
Cooper, Laurence J. N.
影响因子：
4.6
作者：
Figenschau SL;Knutsen E;Urbarova I;Fenton C;Elston B;Perander M;Mortensen ES;Fenton KA
通讯作者：
Fenton KA
影响因子：
4.8
作者：
Brehm, Michael A.;Kenney, Laurie L.;Shultz, Leonard D.
通讯作者：
Shultz, Leonard D.
影响因子：
28.4
作者：
Ahmed N;Brawley V;Hegde M;Bielamowicz K;Kalra M;Landi D;Robertson C;Gray TL;Diouf O;Wakefield A;Ghazi A;Gerken C;Yi Z;Ashoori A;Wu MF;Liu H;Rooney C;Dotti G;Gee A;Su J;Kew Y;Baskin D;Zhang YJ;New P;Grilley B;Stojakovic M;Hicks J;Powell SZ;Brenner MK;Heslop HE;Grossman R;Wels WS;Gottschalk S
通讯作者：
Gottschalk S