Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma.
Ibrutinib improves the efficacy of anti-CD19-CAR T-cell therapy in patients with refractory non-Hodgkin lymphoma.
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DOI：
10.1111/cas.14915
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发表时间：
2021-07
期刊：
影响因子：
5.7
通讯作者：
Qian Z
中科院分区：
文献类型：
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作者：
Liu M;Deng H;Mu J;Li Q;Pu Y;Jiang Y;Deng Q;Qian Z
在难治性B细胞淋巴瘤患者中，观察了首次抗CD 19-CAR T细胞治疗失败后，第二次人源化CD 19嵌合抗原受体（CD 19-CAR）T细胞治疗和后续伊曲替尼挽救治疗的疗效和副作用。在我们的研究中，3例难治性套细胞淋巴瘤（MCL）患者和4例难治性滤泡性淋巴瘤（FL）患者在首次人源化抗CD 19-CAR T细胞治疗后达到疾病稳定（SD）、部分缓解（PR）或疾病进展（PD）。他们接受了伊布替尼作为挽救治疗，并在随后的7 - 16个月内保持SD，但在伊布替尼挽救治疗期间，他们的疾病再次进展。所有7例患者均接受了第二次人源化抗CD 19-CAR T细胞治疗，与首次抗CD 19-CAR T细胞治疗相同。总体而言，3名MCL患者和3名FL患者在第二次抗CD 19-CAR T细胞治疗联合伊曲替尼后达到完全缓解（CR），而1名FL患者达到PR。2例抗CD 19-CAR T细胞治疗之间的转导效率和增殖无差异。然而，第二次抗CD 19-CAR T细胞治疗导致抗CD 19-CAR T细胞和抗CD 19-CAR基因拷贝的峰值更高，但细胞因子释放综合征（CRS）级别也更高，血液学毒性更严重。第二次抗CD 19-CAR T细胞治疗的成功结果可能表明，先前的伊鲁替尼治疗改善了抗CD 19-CAR T细胞的活性。抗CD 19-CAR T细胞治疗失败的7例患者中有6例在第二次抗CD 19-CAR T细胞治疗联合伊曲替尼治疗中获得CR。我们的研究结果直接显示了与伊鲁替尼联合治疗对抗CD 19 CAR T细胞治疗的益处，这与我们之前的研究结果一致。伊布替尼可能通过改善肿瘤微环境与抗CD 19-CAR T-细胞产生协同效应，这些机制需要进一步研究来阐明。
The efficacy and side effects of the second‐time humanized CD19 chimeric antigen receptor (CD19‐CAR) T‐cell therapy after unsuccessful first‐time anti‐CD19‐CAR T‐cell therapy and subsequent ibrutinib salvage treatment were observed in patients with refractory B‐cell lymphoma. In our study, 3 patients with refractory mantle cell lymphoma (MCL) and 4 patients with refractory follicular lymphoma (FL) reached stable disease (SD), partial remission (PR), or progression of disease (PD) after first‐time humanized anti‐CD19‐CAR T‐cell therapy. They received ibrutinib as a salvage treatment and kept an SD in the following 7‐16 mo, but their disease progressed again during ibrutinib salvage treatment. All 7 patients received a second‐time humanized anti‐CD19‐CAR T‐cell therapy, which was the same as their first‐time anti‐CD19‐CAR T‐cell therapy. In total, 3 MCL patients and 3 FL patients reached complete response (CR) with the second‐time anti‐CD19‐CAR T‐cell therapy combined with ibrutinib, whereas 1 FL patient reached PR. There were no differences in the transduction efficiency and proliferation between the 2 instances of anti‐CD19‐CAR T‐cell therapy. However, the second‐time anti‐CD19‐CAR T‐cell therapy led to higher peaks of anti‐CD19‐CAR T cells and anti‐CD19‐CAR gene copies, but also to higher grades of cytokine release syndrome (CRS) and more serious hematological toxicity. The successful outcome of the second‐time anti‐CD19‐CAR T‐cell therapy might suggest that the previous ibrutinib treatment improved the activities of anti‐CD19‐CAR T cells. Six of the 7 patients who suffered failure anti‐CD19‐CAR T‐cell therapy had CR in their second‐time anti‐CD19‐CAR T‐cell therapy combined with ibrutinib treatment. Our results directly showed the benefits of combined therapy with ibrutinib to anti‐CD19 CAR T‐cell therapy that was consistent with our previous research results. Ibrutinib might have a synergistic effect with anti‐CD19‐CAR T‐cells by improving the tumor microenvironment, and these mechanisms need further studies to elucidate.
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DOI：
10.1056/nejmoa1707447
发表时间：
2017-12-28
期刊：
The New England journal of medicine
影响因子：
--
作者：
Neelapu SS;Locke FL;Bartlett NL;Lekakis LJ;Miklos DB;Jacobson CA;Braunschweig I;Oluwole OO;Siddiqi T;Lin Y;Timmerman JM;Stiff PJ;Friedberg JW;Flinn IW;Goy A;Hill BT;Smith MR;Deol A;Farooq U;McSweeney P;Munoz J;Avivi I;Castro JE;Westin JR;Chavez JC;Ghobadi A;Komanduri KV;Levy R;Jacobsen ED;Witzig TE;Reagan P;Bot A;Rossi J;Navale L;Jiang Y;Aycock J;Elias M;Chang D;Wiezorek J;Go WY
通讯作者：
Go WY
影响因子：
45.3
作者：
Gopal, Ajay K.;Schuster, Stephen J.;Salles, Gilles
通讯作者：
Salles, Gilles
影响因子：
20.3
作者：
Flinn, Ian W.;van der Jagt, Richard;Burke, John M.
通讯作者：
Burke, John M.
影响因子：
20.3
作者：
Fraietta, Joseph A.;Beckwith, Kyle A.;Maus, Marcela V.
通讯作者：
Maus, Marcela V.
影响因子：
50.5
作者：
Cheah, C. Y.;Chihara, D.;Wang, M. L.
通讯作者：
Wang, M. L.