Phase I Escalating-Dose Trial of CAR-T Therapy Targeting CEA+ Metastatic Colorectal Cancers

• Published in: Molecular therapy 2017-05, Vol.25 (5), p.1248-1258
• Main Authors: Zhang, Chengcheng, Wang, Zhe, Yang, Zhi, Wang, Meiling, Li, Shiqi, Li, Yunyan, Zhang, Rui, Xiong, Zhouxing, Wei, Zhihao, Shen, Junjie, Luo, Yongli, Zhang, Qianzhen, Liu, Limei, Qin, Hong, Liu, Wei, Wu, Feng, Chen, Wei, Pan, Feng, Zhang, Xianquan, Bie, Ping, Liang, Houjie, Pecher, Gabriele, Qian, Cheng
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - diagnostic imaging; Adenocarcinoma - immunology; Adenocarcinoma - secondary; Adenocarcinoma - therapy; Aged; Antigens; CAR-T; Carcinoembryonic antigen; Carcinoembryonic Antigen - genetics; Carcinoembryonic Antigen - immunology; CEA; Cell proliferation; Chimeric antigen receptors; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - diagnostic imaging; Colorectal Neoplasms - immunology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - therapy; Computed tomography; Cytotoxicity, Immunologic; dose escalating; Dose-Response Relationship, Immunologic; Embryos; Female; Fever; Gene Expression; Humans; Immunotherapy, Adoptive; Inflammatory bowel disease; Liver; Liver Neoplasms - diagnostic imaging; Liver Neoplasms - immunology; Liver Neoplasms - secondary; Liver Neoplasms - therapy; Lymphocyte Activation; Lymphocyte Depletion; Lymphocytes; Lymphocytes T; Magnetic Resonance Imaging; Male; Metastases; Metastasis; Middle Aged; Mutant Chimeric Proteins - genetics; Mutant Chimeric Proteins - immunology; Neoplasm Recurrence, Local - diagnostic imaging; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - therapy; Nonsteroidal anti-inflammatory drugs; Original; Patients; Peripheral blood; phase I; Positron emission tomography; Protein Engineering; R&D; Radiation therapy; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - immunology; Research & development; safety and efficacy; Solid tumors; T-Lymphocytes - cytology; T-Lymphocytes - immunology; T-Lymphocytes - transplantation; Tumors
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2017.03.010

Chimeric antigen receptor T (CAR-T) cells have shown promising efficacy in treatment of hematological malignancies, but its applications in solid tumors need further exploration. In this study, we investigated CAR-T therapy targeting carcino-embryonic antigen (CEA)-positive colorectal cancer (CRC) patients with metastases to evaluate its safety and efficacy. Five escalating dose levels (DLs) (1 × 105 to 1 × 108/CAR+/kg cells) of CAR-T were applied in 10 CRC patients. Our data showed that severe adverse events related to CAR-T therapy were not observed. Of the 10 patients, 7 patients who experienced progressive disease (PD) in previous treatments had stable disease after CAR-T therapy. Two patients remained with stable disease for more than 30 weeks, and two patients showed tumor shrinkage by positron emission tomography (PET)/computed tomography (CT) and MRI analysis, respectively. Decline of serum CEA level was apparent in most patients even in long-term observation. Furthermore, we observed persistence of CAR-T cells in peripheral blood of patients receiving high doses of CAR-T therapy. Importantly, we observed CAR-T cell proliferation especially in patients after a second CAR-T therapy. Taken together, we demonstrated that CEA CAR-T cell therapy was well tolerated in CEA+ CRC patients even in high doses, and some efficacy was observed in most of the treated patients. CAR-T therapy for solid tumors remains challenging. This paper by Dr. Zhang describes a clinical trial of CAR-T therapy targeting CEA in relapsed and refractory colorectal cancer. The authors find that CEA CAR-T therapy was well tolerated, and some evidence of efficacy was observed in most treated patients.