The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity.
The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity.
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DOI：
10.1007/s00262-017-2034-7
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发表时间：
2017-11
期刊：
影响因子：
--
通讯作者：
Hawkins RE
中科院分区：
文献类型：
--
作者：
Thistlethwaite FC;Gilham DE;Guest RD;Rothwell DG;Pillai M;Burt DJ;Byatte AJ;Kirillova N;Valle JW;Sharma SK;Chester KA;Westwood NB;Halford SER;Nabarro S;Wan S;Austin E;Hawkins RE
这项临床试验的主要目的是确定向晚期CEACAM 5+恶性肿瘤患者提供第一代CAR T细胞疗法的可行性。次要目的是评估临床疗效、免疫效应子功能和CAR T细胞的最佳剂量。三组患者在氟达拉滨预处理后接受增加剂量的CEACAM 5+特异性CAR T细胞加上T细胞输注后的全身性IL 2支持。队列4中的患者接受增加强度的预处理（环磷酰胺和氟达拉滨）、全身性IL 2支持和CAR T细胞。未观察到客观临床缓解。队列4内患者的CAR T细胞植入显著更高。然而，植入是短暂的，系统性CAR T细胞在14天内迅速下降。队列4中的患者具有短暂的急性呼吸道毒性，再加上缺乏长期的CAR T细胞持久性，导致试验提前结束。系统性IFNγ和IL-6水平的升高意味着CEACAM 5特异性T细胞在体内经历了免疫激活，但仅在接受高强度预处理的患者中。CEACAM 5在肺上皮上的表达可能导致这种短暂毒性。在这些患者中，血清细胞因子（包括IL-6）水平升高，表明细胞因子释放是加剧所观察到的呼吸道毒性的几个潜在因素之一。虽然改进的CAR设计和T细胞产生方法可以改善全身持久性和活性，但需要控制CAR T“靶向、组织外”毒性的方法来实现该方法在实体恶性肿瘤中的临床影响。本文的在线版本（doi：10.1007/s 00262 -017-2034-7）包含补充材料，可供授权用户使用。
The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5+ malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5+-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T ‘on-target, off-tissue’ toxicity are required to enable a clinical impact of this approach in solid malignancies. The online version of this article (doi:10.1007/s00262-017-2034-7) contains supplementary material, which is available to authorized users.
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影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
第一阶段的肝免疫疗法用于转移研究的动脉内嵌合抗原受体修饰的T细胞疗法用于CEA+肝转移。
DOI：
10.1158/1078-0432.ccr-14-1421
发表时间：
2015-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Katz SC;Burga RA;McCormack E;Wang LJ;Mooring W;Point GR;Khare PD;Thorn M;Ma Q;Stainken BF;Assanah EO;Davies R;Espat NJ;Junghans RP
通讯作者：
Junghans RP
影响因子：
82.9
作者：
Klebanoff CA;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
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
影响因子：
--
作者：
Chester, KA;Bhatia, J;Begent, RHJ
通讯作者：
Begent, RHJ