Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

Du, Hongwei; Hirabayashi, Koichi; Ahn, Sarah; Kren, Nancy P.; Montgomery, Stephanie A.; Wang, Xinhui; Tiruthani, Karthik; Mirlekar, Bhalchandra; Michaud, Daniel; Greene, Kevin; Herrera, Silvia G.; Xu, Yingxin; Sun, Chuang; Chen, Yuhui; Ma, Xingcong; Ferrone, Cristina R.; Pylayeva-Gupta, Yuliya; Yeh, Jen Jen; Liu, Rihe; Savoldo, Barbara; Dotti, Gianpietro

doi:10.1016/j.ccell.2019.01.002

Cited by 323 publications

(353 citation statements)

References 57 publications

(85 reference statements)

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“…Meanwhile, we showed overexpression of membranous B7-H3 in a variety of human malignancies, but minimal staining of B7-H3 protein in the cytoplasm of normal tissues that were largely limited in focal liver cells and a few luminal epithelial cells of the stomach and colon, which is consistent with previous reports. 12 Therefore, B7-H3 specific CAR-T cells are expected to have minimal toxicity in normal tissues. Nevertheless, potential toxicities upon recognition of the antigen expressed in normal tissues require further investigation.…”

Section: Discussionmentioning

confidence: 99%

“…11 While it appears that B7-H3 mRNA is ubiquitously expressed in various mouse and human tissues under normal conditions, immunohistochemical (IHC) analysis demonstrates that the expression of its protein is limited to a select subset of tissues. 12,13 Interestingly, B7-H3 protein is frequently upregulated in the majority of solid human tumors such as prostate cancer, non-small-cell lung cancer, pancreatic cancer, breast cancer, ovarian cancer and colorectal cancer [14][15][16][17][18][19][20][21][22][23][24] and within the tumor vasculature as well. 25 Several studies have also shown that B7-H3 overexpression is associated with tumor progression, metastatic potential and a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

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B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models

et al. 2019

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The application of chimeric antigen receptor (CAR)-T cell therapy in patients with advanced solid tumors remains a significant challenge. Simultaneously targeting antigen and the solid tumor microenvironment are two major factors that greatly impact CART cell therapy outcomes. In this study, we engineered CART cells to specifically target B7-H3, a protein commonly found in solid human tumors, using a single-chain variable fragment (scFv) derived from an anti-B7-H3 monoclonal antibody. We tested the antitumor activity of B7-H3 CART cells in mouse models with solid human tumors and determined that B7-H3 CART cells exhibited potent antitumor activity against B7-H3 + tumor cells in vitro and in vivo. In addition, PD-1 decoy receptors were engineered to include extracellular PD-1 fused to the intracellular stimulatory domain of either CD28 or IL-7 receptor, respectively, which were then introduced into B7-H3 CART cells. As a result, these newly modified, superior CART cells exhibited more persistent antitumor activity in B7-H3 + /B7-H1 + tumors in vivo. Our findings indicate that B7-H3 specific CART cells have the potential to treat multiple types of advanced solid tumors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models

et al. 2019

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“…Recently, CAR-T cells that were genetically engineered to graft specific recognition ability for T cells were generated with B7-H3 as the target [56]. In this research, they explored the treatment efficacy of CAR-T cells targeting B7-H3 on pancreatic ductal adenocarcinoma, ovarian cancer, and neuroblastoma, both in vitro and in orthotopic and metastatic xenograft mouse models including patient-derived xenograft.…”

Section: Targeting B7-h3 Therapymentioning

confidence: 99%

B7-H3, a checkpoint molecule, as a target for cancer immunotherapy

2020

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B7-H3 (also known as CD276) is a newly found molecule of B7 family, which may be a promising target for cancer treatment. B7-H3 protein was demonstrated to be expressed in several kinds of tumor tissues including non-small-cell lung cancer (NSCLC) and prostate cancer. Its expression is highly associated with undesirable treatment outcomes and survival time, due to function of the immune checkpoint molecule. It was classified as either a co-stimulatory molecule for T cell activation or the nonimmunological role of regulating signaling pathways. Although there is still no agreed conclusion on the function of B7-H3, it may be a valuable target for cancer therapy. This review aims to provide a comprehensive, up-to-date summary of the advances in B7-H3 targeting approaches in cancer therapy. Although several challenges remain, B7-H3 offers a new therapeutic target with increased efficacy and less toxicity in future cancer treatment.

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“…While the mentioned results are reassuring regarding saftey of CAR T cell therapy, different strategies are currently under investigation to further improve the safety profile of CAR T cells. These strategies include: (I) modification of the chimeric antigen receptor cell itself [85,86]; (II) identification of predictive biomarkers for CAR T cell toxicity [84]; (III) "safety switches" such as inducible suicide genes [87]; and (IV) novel drugs to mitigate CRS and NE [88].…”

Section: Chimeric Antigen Receptor T Cellsmentioning

confidence: 99%

Advances in cancer immunotherapy 2019 – latest trends

Krüger

Ilmer

Kobold

et al. 2019

J Exp Clin Cancer Res

462

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Immunotherapy has become an established pillar of cancer treatment improving the prognosis of many patients with a broad variety of hematological and solid malignancies. The two main drivers behind this success are checkpoint inhibitors (CPIs) and chimeric antigen receptor (CAR) T cells. This review summarizes seminal findings from clinical and translational studies recently presented or published at important meetings or in top-tier journals, respectively. For checkpoint blockade, current studies focus on combinational approaches, perioperative use, new tumor entities, response prediction, toxicity management and use in special patient populations. Regarding cellular immunotherapy, recent studies confirmed safety and efficacy of CAR T cells in larger cohorts of patients with acute lymphoblastic leukemia or diffuse large B cell lymphoma. Different strategies to translate the striking success of CAR T cells in B cell malignancies to other hematological and solid cancer types are currently under clinical investigation. Regarding the regional distribution of registered clinical immunotherapy trials a shift from PD-1 / PD-L1 trials (mainly performed in the US and Europe) to CAR T cell trials (majority of trials performed in the US and China) can be noted.

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Antitumor Responses in the Absence of Toxicity in Solid Tumors by Targeting B7-H3 via Chimeric Antigen Receptor T Cells

Cited by 323 publications

References 57 publications

B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models

B7-H3 specific T cells with chimeric antigen receptor and decoy PD-1 receptors eradicate established solid human tumors in mouse models

B7-H3, a checkpoint molecule, as a target for cancer immunotherapy

Advances in cancer immunotherapy 2019 – latest trends

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