Overcoming Resistance of Human Non-Hodgkin's Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors.
Overcoming Resistance of Human Non-Hodgkin's Lymphoma to CD19-CAR CTL Therapy by Celecoxib and Histone Deacetylase Inhibitors.
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DOI：
10.3390/cancers10060200
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发表时间：
2018-06-14
期刊：
影响因子：
5.2
通讯作者：
Jazirehi AR
中科院分区：
文献类型：
--
作者：
Torres-Collado AX;Jazirehi AR
B细胞非霍奇金淋巴瘤（B-NHL）患者对一线治疗方案无反应或产生耐药性，预后不良。这意味着需要开发替代治疗策略。CD 19-嵌合抗原受体（CAR）T细胞重定向免疫治疗是一种有吸引力的新选择，在复发/难治性NHL的I期临床试验中显示出令人鼓舞的结果。然而，NHL中获得性抗CD 19 CAR CD 8 + T细胞（CTL）抗性的潜在机制和克服方法仍然难以捉摸。CD 19 CAR转导的原代人CTL以CD 19和半胱天冬酶依赖性方式杀死CD 19+人NHL，主要通过肿瘤坏死因子相关凋亡诱导配体（TRAIL）凋亡途径。为了了解耐药性发展的动力学，我们分析了几种抗CD 19 CAR CTL耐药NHL亚系（R-NHL），这些亚系是通过将敏感亲本系连续暴露于过量的抗CD 19 CAR CTL，然后进行有限稀释分析而获得的。R-NHL保留表面CD 19表达，并被CD 19 CAR CTL有效识别。然而，R-NHL对CD 19 CAR转导的人原代CTL和Jurkat人T细胞系、活化的Jurkat和淋巴因子活化的杀伤（LAK）细胞产生交叉抗性，表明抗性的获得与CD 19损失无关，并且可能是由于异常的凋亡机制。我们假设，R-NHL对CD 19 CAR CTL杀伤的不应性可以通过具有抗肿瘤基因调节作用的小分子敏化剂部分挽救。染色质修饰剂和塞来昔布部分逆转了R-NHL细胞对抗CD 19 CAR CTL和rhTRAIL的细胞毒性作用的抗性。这些体外结果，虽然他们需要进一步的检查，可能会提供一个合理的生物学基础的联合治疗的CD 19 CAR CTL为基础的治疗NHL的管理。
Patients with B-cell non-Hodgkin’s lymphoma (B-NHL) who fail to respond to first-line treatment regimens or develop resistance, exhibit poor prognosis. This signifies the need to develop alternative treatment strategies. CD19-chimeric antigen receptor (CAR) T cell-redirected immunotherapy is an attractive and novel option, which has shown encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. However, the underlying mechanisms of, and approaches to overcome, acquired anti-CD19CAR CD8+ T cells (CTL)-resistance in NHL remain elusive. CD19CAR transduced primary human CTLs kill CD19+ human NHLs in a CD19- and caspase-dependent manner, mainly via the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) apoptotic pathway. To understand the dynamics of the development of resistance, we analyzed several anti-CD19CAR CTL-resistant NHL sublines (R-NHL) derived by serial exposure of sensitive parental lines to excessive numbers of anti-CD19CAR CTLs followed by a limiting dilution analysis. The R-NHLs retained surface CD19 expression and were efficiently recognized by CD19CAR CTLs. However, R-NHLs developed cross-resistance to CD19CAR transduced human primary CTLs and the Jurkat human T cell line, activated Jurkat, and lymphokine activated killer (LAK) cells, suggesting the acquisition of resistance is independent of CD19-loss and might be due to aberrant apoptotic machinery. We hypothesize that the R-NHL refractoriness to CD19CAR CTL killing could be partially rescued by small molecule sensitizers with apoptotic-gene regulatory effects. Chromatin modifiers and Celecoxib partially reversed the resistance of R-NHL cells to the cytotoxic effects of anti-CD19CAR CTLs and rhTRAIL. These in vitro results, though they require further examination, may provide a rational biological basis for combination treatment in the management of CD19CAR CTL-based therapy of NHL.
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DOI：
10.1111/j.1749-6632.2009.04905.x
发表时间：
2009-01-01
期刊：
NATURAL COMPOUNDS AND THEIR ROLE IN APOPTOTIC CELL SIGNALING PATHWAYS
影响因子：
--
作者：
Corazza, Nadia;Kassahn, Daniela;Brunner, Thomas
通讯作者：
Brunner, Thomas
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
带有嵌合抗原受体的T细胞具有有效的抗肿瘤作用，可以在晚期白血病患者中建立记忆。
影响因子：
17.1
作者：
Kalos M;Levine BL;Porter DL;Katz S;Grupp SA;Bagg A;June CH
通讯作者：
June CH
影响因子：
--
作者：
Chiappetta G;Valentino T;Vitiello M;Pasquinelli R;Monaco M;Palma G;Sepe R;Luciano A;Pallante P;Palmieri D;Aiello C;Rea D;Losito SN;Arra C;Fusco A;Fedele M
通讯作者：
Fedele M