CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.
CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience.
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DOI：
10.1136/jitc-2021-004128
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Smith EL
中科院分区：
文献类型：
--
作者：
Palomba ML;Qualls D;Monette S;Sethi S;Dogan A;Roshal M;Senechal B;Wang X;Rivière I;Sadelain M;Brentjens RJ;Park JH;Smith EL
瓦尔登斯特伦巨球蛋白血症（WM）是一种不治之症，虽然可以治疗，但可能对现有疗法产生耐药性，并致命。针对CD 19抗原的嵌合抗原受体（CAR）T细胞疗法已在复发性或难治性B淋巴恶性肿瘤中显示出疗效，并且现在被批准用于B细胞急性淋巴母细胞白血病和某些B细胞淋巴瘤。然而，CAR T疗法尚未被评估用于WM。我们进行了临床前研究，证明了CAR T细胞在体外对WM细胞的活性，并开发了一种WM的体内鼠模型，该模型证明了使用CAR T疗法延长的存活期。然后，我们报告了在临床试验中用CD19导向的CAR T细胞治疗其疾病的前三名多重复发和难治性WM患者。治疗耐受性良好，观察到的毒性与CAR T治疗其他疾病中观察到的毒性一致，没有发生3级或更高级别的细胞因子释放综合征或神经毒性事件。所有三名患者都至少对治疗有临床反应，包括一个最小的残留疾病阴性完全反应，尽管所有三名患者最终在初始治疗后3至26个月内复发。本报告总结了CD19导向的CAR T疗法在WM中的临床前和临床活性，证明了WM患者的早期耐受性和疗效，并代表了重度预治疗和复发或难治性WM患者的可能治疗选择。沿着对CAR T治疗耐药机制的进一步评估，有必要进行更大规模的研究来评估WM中的CAR T治疗。
Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM. We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment. This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.
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DOI：
10.3816/clm.2005.n.007
发表时间：
2005-03-01
期刊：
CLINICAL LYMPHOMA
影响因子：
--
作者：
Ocio, EM;Hernández, JM;San Miguel, JF
通讯作者：
San Miguel, JF
影响因子：
168.9
作者：
Abramson, Jeremy S.;Palomba, M. Lia;Siddiqi, Tanya
通讯作者：
Siddiqi, Tanya
影响因子：
8
作者：
Geyer, Mark B.;Riviere, Isabelle;Brentjens, Renier J.
通讯作者：
Brentjens, Renier J.
影响因子：
82.9
作者：
Shah, Nirav N.;Johnson, Bryon D.;Hari, Parameswaran
通讯作者：
Hari, Parameswaran
DOI：
10.1056/nejmoa1709919
发表时间：
2018-02-01
期刊：
The New England journal of medicine
影响因子：
--
作者：
Park JH;Rivière I;Gonen M;Wang X;Sénéchal B;Curran KJ;Sauter C;Wang Y;Santomasso B;Mead E;Roshal M;Maslak P;Davila M;Brentjens RJ;Sadelain M
通讯作者：
Sadelain M