Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer

医学 嵌合抗原受体 结直肠癌 耐受性 肿瘤科 内科学 临床试验 癌症 细胞因子释放综合征 免疫疗法 不利影响
作者
Naifei Chen,Chengfei Pu,Lingling Zhao,Wei Li,Li Wang,Ruihong Zhu,Tingting Liang,Chao Niu,Xi Huang,Haiyang Tang,Li Wang,Jing Wang,Beibei Jia,Xianyang Jiang,Guiting Han,Li Wang,Dongqi Chen,Yiming Wang,Eric K. Rowinsky,Eugene P. Kennedy,Victor X. Lu,Guozhen Cui,Zhao Wu,Lei Xiao,Jiuwei Cui
出处
期刊:JAMA Oncology [American Medical Association]
标识
DOI:10.1001/jamaoncol.2024.3891
摘要

Importance Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC). Objective To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC). Design, Setting, and Participants This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR. Main Outcomes and Measures Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation. Results Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 10 6 cells/kg or 2 × 10 6 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available). Conclusions and Relevance The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers. Trial Registration Chinese Clinical Trial Registry: ChiCTR2000040645
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