期刊
JOURNAL OF HEMATOLOGY & ONCOLOGY
卷 14, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13045-021-01128-9
关键词
CAR-T cell; IL-7; CCL19; Glypican-3; Mesothelin; Pancreatic carcinoma; Hepatocellular carcinoma; Complete response
资金
- National Natural Science Foundation of China [81672276, 81961128003, 81972672, 81872613, 81573142, 81872069]
- Guangzhou Science and Technology program [201803010038]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDB19030205, XDA12050305]
- National Major Scientific and Technological Special Project for Significant New Drugs Development [2018ZX090201002-005]
- Guangdong provincial Significant New Drugs Development [2019B020202003]
- Guangdong Special Support Program [2017TX04R102]
- Guangzhou Science and Technology Plan Project [201907010042, 2020B1212060052]
- Frontier Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory [2018GZR110105003]
- Science and Technology Planning Project of Guangdong province, China [2017B030314056]
- University Grants Committee/Research Grants Council of the Hong Kong Special Administrative Region, China [AoE/M-401/20]
The study found that engineering human CAR-T cells to secrete human IL-7 and CCL19 (7x19) enhanced expansion and migration capabilities in vitro, and showed superior tumor suppression ability in experimental models compared to conventional CAR-T cells. In clinical trials, the incorporation of 7x19 into CAR-T cells led to significant tumor disappearance in patients with advanced HCC and PC, demonstrating the enhanced antitumor activity against human solid tumors.
Although chimeric antigen receptor (CAR)-engineered T cells have shown great success in the treatment of B cell malignancies, this strategy has limited efficacy in patients with solid tumors. In mouse CAR-T cells, IL-7 and CCL19 expression have been demonstrated to improve T cell infiltration and CAR-T cell survival in mouse tumors. Therefore, in the current study, we engineered human CAR-T cells to secrete human IL-7 and CCL19 (7x19) and found that these 7x19 CAR-T cells showed enhanced capacities of expansion and migration in vitro. Furthermore, 7x19 CAR-T cells showed superior tumor suppression ability compared to conventional CAR-T cells in xenografts of hepatocellular carcinoma (HCC) cell lines, primary HCC tissue samples and pancreatic carcinoma (PC) cell lines. We then initiated a phase 1 clinical trial in advanced HCC/PC/ovarian carcinoma (OC) patients with glypican-3 (GPC3) or mesothelin (MSLN) expression. In a patient with advanced HCC, anti-GPC3-7x19 CAR-T treatment resulted in complete tumor disappearance 30 days post intratumor injection. In a patient with advanced PC, anti-MSLN-7x19 CAR-T treatment resulted in almost complete tumor disappearance 240 days post-intravenous infusion. Our results demonstrated that the incorporation of 7x19 into CAR-T cells significantly enhanced the antitumor activity against human solid tumor.
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