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      Targeting CD276 by CAR-T cells induces regression of esophagus squamous cell carcinoma in xenograft mouse models

      research-article
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      Translational Oncology
      Neoplasia Press
      Esophageal cancer, CD276, CAR-T cell, Co-stimulation, Patient-derived xenograft, BLI, bioluminescence imaging, CAR, chimeric antigen receptor, CSC, cancer stem cell, CRISPR, clustered regularly interspaced short palindromic repeats, EAC, esophageal adenocarcinoma, ELISA, enzyme-linked immunosorbent assay, ESCC, esophagus squamous cell carcinoma, FFluc, firefly luciferase, IFN-γ, interferon-γ, IHC, immunohistochemistry, IL-2, interleukin-2, PDX, patient-derived xenograft

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          Highlights

          • CD276 is homogeneously overexpressed in ESCC and EAC.

          • CD276-directed CAR-T cells demonstrate remarkable anti-tumor effects in ESCC PDX model.

          • CD276-targeting CAR-T cells are successfully generated with patients T cells and show potent cytotoxicity against autologous tumor cells.

          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.

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          Most cited references42

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          Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries

          This article provides a status report on the global burden of cancer worldwide using the GLOBOCAN 2018 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer, with a focus on geographic variability across 20 world regions. There will be an estimated 18.1 million new cancer cases (17.0 million excluding nonmelanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) in 2018. In both sexes combined, lung cancer is the most commonly diagnosed cancer (11.6% of the total cases) and the leading cause of cancer death (18.4% of the total cancer deaths), closely followed by female breast cancer (11.6%), prostate cancer (7.1%), and colorectal cancer (6.1%) for incidence and colorectal cancer (9.2%), stomach cancer (8.2%), and liver cancer (8.2%) for mortality. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality). Among females, breast cancer is the most commonly diagnosed cancer and the leading cause of cancer death, followed by colorectal and lung cancer (for incidence), and vice versa (for mortality); cervical cancer ranks fourth for both incidence and mortality. The most frequently diagnosed cancer and the leading cause of cancer death, however, substantially vary across countries and within each country depending on the degree of economic development and associated social and life style factors. It is noteworthy that high-quality cancer registry data, the basis for planning and implementing evidence-based cancer control programs, are not available in most low- and middle-income countries. The Global Initiative for Cancer Registry Development is an international partnership that supports better estimation, as well as the collection and use of local data, to prioritize and evaluate national cancer control efforts. CA: A Cancer Journal for Clinicians 2018;0:1-31. © 2018 American Cancer Society.
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            Cancer statistics, 2019

            Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2015, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2016, were collected by the National Center for Health Statistics. In 2019, 1,762,450 new cancer cases and 606,880 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2006-2015) was stable in women and declined by approximately 2% per year in men, whereas the cancer death rate (2007-2016) declined annually by 1.4% and 1.8%, respectively. The overall cancer death rate dropped continuously from 1991 to 2016 by a total of 27%, translating into approximately 2,629,200 fewer cancer deaths than would have been expected if death rates had remained at their peak. Although the racial gap in cancer mortality is slowly narrowing, socioeconomic inequalities are widening, with the most notable gaps for the most preventable cancers. For example, compared with the most affluent counties, mortality rates in the poorest counties were 2-fold higher for cervical cancer and 40% higher for male lung and liver cancers during 2012-2016. Some states are home to both the wealthiest and the poorest counties, suggesting the opportunity for more equitable dissemination of effective cancer prevention, early detection, and treatment strategies. A broader application of existing cancer control knowledge with an emphasis on disadvantaged groups would undoubtedly accelerate progress against cancer.
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              Genome engineering using the CRISPR-Cas9 system.

              Targeted nucleases are powerful tools for mediating genome alteration with high precision. The RNA-guided Cas9 nuclease from the microbial clustered regularly interspaced short palindromic repeats (CRISPR) adaptive immune system can be used to facilitate efficient genome engineering in eukaryotic cells by simply specifying a 20-nt targeting sequence within its guide RNA. Here we describe a set of tools for Cas9-mediated genome editing via nonhomologous end joining (NHEJ) or homology-directed repair (HDR) in mammalian cells, as well as generation of modified cell lines for downstream functional studies. To minimize off-target cleavage, we further describe a double-nicking strategy using the Cas9 nickase mutant with paired guide RNAs. This protocol provides experimentally derived guidelines for the selection of target sites, evaluation of cleavage efficiency and analysis of off-target activity. Beginning with target design, gene modifications can be achieved within as little as 1-2 weeks, and modified clonal cell lines can be derived within 2-3 weeks.
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                Author and article information

                Contributors
                Journal
                Transl Oncol
                Transl Oncol
                Translational Oncology
                Neoplasia Press
                1936-5233
                27 May 2021
                August 2021
                27 May 2021
                : 14
                : 8
                : 101138
                Affiliations
                [a ]Biotherapy Center, Cancer Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
                [b ]Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China
                [c ]School of Life Sciences, Zhengzhou University, Zhengzhou, Henan, China
                [d ]Medical Research Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
                [e ]Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
                [f ]State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, Henan, China
                [g ]China-US Hormel (Henan) Cancer Institute, Zhengzhou, Henan, China
                Author notes
                [* ]Corresponding authors at: Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou, Henan 450052, China. yizhang@ 123456zzu.edu.cn lifeng01@ 123456msn.com
                [** ]Corresponding author at: Department of Pathophysiology, School of Basic Medical Sciences, Zhengzhou University, 100 Science Avenue, Zhengzhou, Henan 450052, China. kdliu@ 123456zzu.edu.cn
                [1]

                These authors contributed equally.

                Article
                S1936-5233(21)00130-3 101138
                10.1016/j.tranon.2021.101138
                8176370
                34052626
                39ff63e5-313f-4078-ac19-9f5305477ed7
                © 2021 The Authors. Published by Elsevier Inc.

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 20 May 2021
                : 20 May 2021
                Categories
                Original Research

                esophageal cancer,cd276,car-t cell,co-stimulation,patient-derived xenograft,bli, bioluminescence imaging,car, chimeric antigen receptor,csc, cancer stem cell,crispr, clustered regularly interspaced short palindromic repeats,eac, esophageal adenocarcinoma,elisa, enzyme-linked immunosorbent assay,escc, esophagus squamous cell carcinoma,ffluc, firefly luciferase,ifn-γ, interferon-γ,ihc, immunohistochemistry,il-2, interleukin-2,pdx, patient-derived xenograft

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