Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results.
Mesothelin-targeting T cell receptor fusion construct cell therapy in refractory solid tumors: phase 1/2 trial interim results.
复制标题
DOI：
10.1038/s41591-023-02452-y
复制
发表时间：
2023-08
期刊：
影响因子：
82.9
通讯作者：
Hong, David
中科院分区：
文献类型：
--
作者：
Hassan, Raffit;Butler, Marcus;O'Cearbhaill, Roisin E. E.;Oh, David Y. Y.;Johnson, Melissa;Zikaras, Kevin;Smalley, Munisha;Ross, Michael;Tanyi, Janos L. L.;Ghafoor, Azam;Shah, Nirali N. N.;Saboury, Babak;Cao, Liang;Quintas-Cardama, Alfonso;Hong, David
T 细胞受体融合构建体 (TRuC) gavocabtagene autoleucel (gavo-cel) 由单域抗间皮素抗体组成，该抗体整合到内源性 T 细胞受体 (TCR) 中，并在间皮素结合时发挥整个 TCR 的信号传导能力。在这里，我们描述了正在进行的 gavo-cel 1/2 期试验的 1 期结果，该试验针对难治性表达间皮素的实体瘤患者。主要目标是评估安全性并确定推荐的 2 期剂量 (RP2D)。次要目标包括功效。 32 名患者接受了逐渐增加剂量的 gavo-cel 治疗，无论是作为单一药物（n = 3）还是在淋巴细胞清除后（LD，n = 29）。注意到 3 级肺炎和 5 级细支气管肺泡出血的剂量限制毒性。 LD后RP2D确定为每平方米1 × 108个细胞。 16% 的患者出现 3 级或以上肺炎，而在 RP2D 时没有出现这种情况； 25% 的患者发生 3 级或更高级别的细胞因子释放综合征，RP2D 时发生率为 15%。在 30 名可评估患者中，总体缓解率和疾病控制率分别为 20%（13% 确诊）和 77%，6 个月总体生存率为 70%。鉴于 Gavo-cel 具有令人鼓舞的抗肿瘤活性，值得在表达间皮素的癌症患者中进行进一步研究，但它的治疗窗可能很窄。 ClinicalTrials.gov 标识符：NCT03907852。含有与内源性 T 细胞受体信号复合物成分融合的抗间皮素单域抗体的 T 细胞表现出显着的毒性，但在治疗难治性间皮瘤和卵巢癌患者中却有令人鼓舞的临床反应。
The T cell receptor fusion construct (TRuC) gavocabtagene autoleucel (gavo-cel) consists of single-domain anti-mesothelin antibody that integrates into the endogenous T cell receptor (TCR) and engages the signaling capacity of the entire TCR upon mesothelin binding. Here we describe phase 1 results from an ongoing phase1/2 trial of gavo-cel in patients with treatment-refractory mesothelin-expressing solid tumors. The primary objectives were to evaluate safety and determine the recommended phase 2 dose (RP2D). Secondary objectives included efficacy. Thirty-two patients received gavo-cel at increasing doses either as a single agent (n = 3) or after lymphodepletion (LD, n = 29). Dose-limiting toxicities of grade 3 pneumonitis and grade 5 bronchioalveolar hemorrhage were noted. The RP2D was determined as 1 × 108 cells per m2 after LD. Grade 3 or higher pneumonitis was seen in 16% of all patients and in none at the RP2D; grade 3 or higher cytokine release syndrome occurred in 25% of all patients and in 15% at the RP2D. In 30 evaluable patients, the overall response rate and disease control rate were 20% (13% confirmed) and 77%, respectively, and the 6-month overall survival rate was 70%. Gavo-cel warrants further study in patients with mesothelin-expressing cancers given its encouraging anti-tumor activity, but it may have a narrow therapeutic window. ClinicalTrials.gov identifier: NCT03907852. T cells containing an anti-mesothelin single-domain antibody fused to a component of the endogenous T cell receptor signaling complex exhibit notable toxicities but encouraging clinical responses in patients with treatment-refractory mesothelioma and ovarian cancer.
登录
查看更多内容
影响因子：
12.4
作者：
Haas, Andrew R.;Tanyi, Janos L.;Beatty, Gregory L.
通讯作者：
Beatty, Gregory L.
影响因子：
8.4
作者：
Eisenhauer, E. A.;Therasse, P.;Verweij, J.
通讯作者：
Verweij, J.
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：
158.5
作者：
Del Bufalo, Francesca;De Angelis, Biagio;Locatelli, Franco
通讯作者：
Locatelli, Franco
影响因子：
45.3
作者：
Hassan, Raffit;Thomas, Anish;Pastan, Ira
通讯作者：
Pastan, Ira