Cancer Center, the First Hospital of Jilin University, Changchun, China.
Innovative Cellular Therapeutics Co, Ltd, Shanghai, China.
JAMA Oncol. 2024 Nov 1;10(11):1532-1536. doi: 10.1001/jamaoncol.2024.3891.
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).
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.
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.
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 × 106 cells/kg or 2 × 106 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).
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.
Chinese Clinical Trial Registry: ChiCTR2000040645.
嵌合抗原受体 (CAR) T 细胞疗法 (CART) 改变了血液系统癌症的治疗格局，但对成人实体瘤几乎没有影响。在这项试验中，一种自体 CAR T 细胞产品在转移性结直肠癌 (mCRC) 患者中显示出抗肿瘤活性。
评估鸟苷酸环化酶-C (GCC) 19 自体 CAR T 细胞（GCC19CART）在转移性结直肠癌（mCRC）患者中的安全性和疗效。
设计、地点和参与者：这是一项单臂、非随机、1 期临床试验，于 2020 年 12 月 3 日至 2022 年 4 月 13 日在吉林大学第一医院进行。数据分析于 2022 年 5 月至 2024 年 4 月进行。患有复发和难治性 mCRC 且表达 GCC 的成年人接受了 GCC19CART 治疗，这是一种由慢病毒载体转导的自体 CAR T 细胞混合物，表达编码 CD-19 CAR 或 GCC CAR 的基因。
在没有治疗选择的情况下，针对 mCRC 患者的靶向 GCC 的 CAR T 细胞疗法具有合理的临床获益可能性，其安全性和耐受性可被评估。其他结果包括客观缓解率、无进展生存期、总生存期和免疫激活。
在 15 名患者中，有 9 名（60%）为女性，中位（范围）年龄为 44（33-61）岁。大多数患者在接受 GCC19CART 治疗后会出现细胞因子释放综合征和腹泻，所有这些反应都是自限性的，易于管理。客观缓解率为 40%，8 名患者中有 2 名和 7 名患者中有 4 名分别接受了 1×106 个细胞/kg 或 2×106 个细胞/kg 的治疗，达到了部分缓解。数据截止时，中位总生存期为 22.8 个月（95%CI，13.4-26.1）；高剂量组的中位无进展生存期为 6.0 个月（95%CI，3.0 至不可用）。
这项非随机临床试验的结果表明，在接受过多线治疗的 mCRC 患者中，GCC19CART 是安全且耐受良好的，并且是已知可在难治性癌症中产生客观临床活性的第一种 CAR T 细胞疗法。鉴于最近几十年为结直肠癌开发的有效疗法很少，观察到 CD-19 CART 靶点结合能够强烈诱导 GCC19CART 靶点结合，从而产生客观活性，这可能为 mCRC 和其他实体瘤的有效细胞疗法的开发奠定基础。
中国临床试验注册中心：ChiCTR2000040645。
