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Published on: November 12, 2019
Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models
Yujing Xuan1, Yuqiao Sheng2, Daiqun Zhang1
1Biotherapy Center, Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China; State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China.
Abstract:
Esophageal cancer, including esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC), has a poor prognosis and limited therapeutic options. Chimeric antigen receptor (CAR)-T cells represent a potential ESCC treatment. In this study, we examined CD276 expression in healthy and esophageal tumor tissues and explored the tumoricidal potential of CD276-targeting CAR-T cells in ESCC. CD276 was strongly and homogenously expressed in ESCC and EAC tumor lesions but mildly in healthy tissues, representing a good target for CAR-T cell therapy. We generated CD276-directed CAR-T cells with a humanized antigen-recognizing domain and CD28 or 4-1BB co-stimulation. CD276-specific CAR-T cells efficiently killed ESCC tumor cells in an antigen-dependent manner both in vitro and in vivo. In patient-derived xenograft models, CAR-T cells induced tumor regression and extended mouse survival. In addition, CAR-T cells generated from patient T cells demonstrated potent cytotoxicity against autologous tumor cells. Our study indicates that CD276 is an attractive target for ESCC therapy, and CD276-targeting CAR-T cells are worth testing in ESCC clinical trials.
Insights
Chimeric antigen receptor (CAR)-T cell therapy targeting CD276 shows promise for esophageal cancer. This approach effectively eliminated esophageal squamous cell carcinoma (ESCC) cells in preclinical models, suggesting potential for clinical trials.
Area of Science:
- Oncology
- Immunotherapy
- Cell Therapy
Background:
- Esophageal cancer, including ESCC and EAC, has a poor prognosis and limited treatment options.
- Chimeric antigen receptor (CAR)-T cell therapy is an emerging treatment modality for various cancers.
Purpose of the Study:
- To evaluate CD276 as a therapeutic target for esophageal cancer.
- To assess the efficacy of CD276-targeting CAR-T cells against ESCC in vitro and in vivo.
Main Methods:
- CD276 expression analysis in healthy and tumor esophageal tissues.
- Generation of CD276-directed CAR-T cells with CD28 or 4-1BB co-stimulation.
- In vitro and in vivo efficacy studies using ESCC cell lines and patient-derived xenograft models.
Main Results:
- CD276 is highly expressed on ESCC and EAC tumor cells but minimally on healthy tissues.
- CD276-specific CAR-T cells demonstrated potent, antigen-dependent killing of ESCC cells.
- CAR-T cell therapy led to tumor regression and improved survival in preclinical models.
- Autologous CAR-T cells showed cytotoxicity against patient-derived ESCC cells.
Conclusions:
- CD276 is a viable and attractive target for esophageal cancer immunotherapy.
- CD276-targeting CAR-T cells exhibit significant preclinical anti-tumor activity against ESCC.
- Further clinical investigation of CD276-CAR-T cells for ESCC treatment is warranted.
