Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice

Li, Dan; Li, Nan; Zhang, Yifan; Fu, Haiying; Feng, Mingqian; Schneider, Dina; Su, Ling; Wu, Xiaolin; Zhou, Jing; Mackay, Sean; Kramer, Josh; Duan, Zhijian; Yang, Hyun-Jin; Kolluri, Aarti; Hummer, Alissa; Torres, Madeline B.; Zhu, Hongguang; Hall, Matthew D.; Luo, Xi; Chen, Jinqiu; Wang, Qun; Abate-Daga, Daniel; Dropulić, Boro; Hewitt, Stephen M.; Orentas, Rimas J.; Greten, Tim F.; Ho, Mitchell

doi:10.1053/j.gastro.2020.02.011

Cited by 108 publications

(103 citation statements)

References 42 publications

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“…In the present study, we were interested in developing a novel anti-GPC3 monoclonal antibody that would recognize an epitope outside of the Wnt-binding motif or known epitope of other GPC3 antibodies and would be used to construct more effective antibody-based immunotherapies, such as immunotoxins [24,25] and CAR-T cells [26,27]. We obtained a human monoclonal antibody (32A9) against GPC3 by phage display technology.…”

mentioning

confidence: 99%

32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma

Liu¹,

Gao²,

Jiang³

et al. 2020

J Transl Med

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Background: Treatment of hepatocellular carcinoma (HCC) using antibody-based targeted therapies, such as antibody conjugates and chimeric antigen receptor T (CAR-T) cell therapy, shows potent antitumor efficacy. Glypican-3 (GPC3) is an emerging HCC therapeutic target; therefore, antibodies against GPC3 would be useful tools for developing immunotherapies for HCC. Methods: We isolated a novel human monoclonal antibody, 32A9, by phage display technology. We determined specificity, affinity, epitope and anti-tumor activity of 32A9, and developed 32A9-based immunotherapy technologies for evaluating the potency of HCC treatment in vitro or in vivo. Results: 32A9 recognized human GPC3 with potent affinity and specificity. The epitope of 32A9 was located in the region of the GPC3 protein core close to the modification sites of the HS chain and outside of the Wnt-binding site of GPC3. The 32A9 antibody significantly inhibited HCC xenograft tumor growth in vivo. We then pursued two 32A9-based immunotherapeutic strategies by constructing an immunotoxin and CART cells. The 32A9 immunotoxin exhibited specific cytotoxicity to GPC3-positive cancer cells, while 32A9 CART cells efficiently eliminated GPC3-positive HCC cells in vitro and caused HCC xenograft tumor regressions in vivo. Conclusions: Our study provides a rationale for 32A9 as a promising GPC3-specific antibody candidate for HCC immunotherapy.

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confidence: 99%

32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma

Liu¹,

Gao²,

Jiang³

et al. 2020

J Transl Med

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“…For enhancement immunotherapy, cytokines (IL-2, IFNs), cancer vaccines and cell therapy (CAR-T) have been approved by the FDA. Although some of the above methods have achieved a certain effect in liver cancer therapy, 192 highfrequency negative trials with high toxicity pushed scientists to find other ways. 193 Immune checkpoints inhibitors targeting the TME but with lower toxicity have begun to emerge.…”

Section: Treatments For the Immune Microenvironmentmentioning

confidence: 99%

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Tian

Zhu

et al. 2020

CMAR

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Hepatocellular carcinoma (HCC) is a tumor that exhibits glucometabolic reprogramming, with a high incidence and poor prognosis. Usually, HCC is not discovered until an advanced stage. Sorafenib is almost the only drug that is effective at treating advanced HCC, and promising metabolism-related therapeutic targets of HCC are urgently needed. The "Warburg effect" illustrates that tumor cells tend to choose aerobic glycolysis over oxidative phosphorylation (OXPHOS), which is closely related to the features of the tumor microenvironment (TME). The HCC microenvironment consists of hypoxia, acidosis and immune suppression, and contributes to tumor glycolysis. In turn, the glycolysis of the tumor aggravates hypoxia, acidosis and immune suppression, and leads to tumor proliferation, angiogenesis, epithelial-mesenchymal transition (EMT), invasion and metastasis. In 2017, a mechanism underlying the effects of gluconeogenesis on inhibiting glycolysis and blockading HCC progression was proposed. Treating HCC by increasing gluconeogenesis has attracted increasing attention from scientists, but few articles have summarized it. In this review, we discuss the mechanisms associated with the TME, glycolysis and gluconeogenesis and the current treatments for HCC. We believe that a treatment combination of sorafenib with TME improvement and/or anti-Warburg therapies will set the trend of advanced HCC therapy in the future.

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“…A 50 amino acid fragment from the C-terminus (residues 511-560) was used to immunize BALB/c mice [24]. We now know the actual epitope for YP7 to be located between residues 521-530 [28]. This antibody was found to have an affinity of 0.3 nM on cells overexpressing GPC3 [24].…”

Section: Optimizing Antibody Targeting Of Gpc3mentioning

confidence: 99%

“…We and others have demonstrated that GPC3 is a suitable target for antibody-based therapeutics for several reasons [18]. First, as an oncofetal proteoglycan, GPC3 is primarily expressed in embryonic tissues and has virtually no expression in healthy human tissues [15][16][17][22][23][24][25][26][27][28]. Consequently, GPC3 has a high tumor specificity due to its upregulation in hepatocellular carcinoma and lack of expression in healthy human tissues.…”

Section: Introductionmentioning

confidence: 99%

Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update

Fleming

2020

Biomolecules

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Hepatocellular carcinoma (HCC) accounts for most liver cancers and represents one of the deadliest cancers in the world. Despite the global demand for liver cancer treatments, there remain few options available. The U.S. Food and Drug Administration (FDA) recently approved Lumoxiti, a CD22-targeting immunotoxin, as a treatment for patients with hairy cell leukemia. This approval helps to demonstrate the potential role that immunotoxins can play in the cancer therapeutics pipeline. However, concerns have been raised about the use of immunotoxins, including their high immunogenicity and short half-life, in particular for treating solid tumors such as liver cancer. This review provides an overview of recent efforts to develop a glypican-3 (GPC3) targeting immunotoxin for treating HCC, including strategies to deimmunize immunotoxins by removing B- or T-cell epitopes on the bacterial toxin and to improve the serum half-life of immunotoxins by incorporating an albumin binding domain.

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Persistent Polyfunctional Chimeric Antigen Receptor T Cells That Target Glypican 3 Eliminate Orthotopic Hepatocellular Carcinomas in Mice

Cited by 108 publications

References 42 publications

32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma

32A9, a novel human antibody for designing an immunotoxin and CAR-T cells against glypican-3 in hepatocellular carcinoma

<p>Glucometabolic Reprogramming in the Hepatocellular Carcinoma Microenvironment: Cause and Effect</p>

Development of Glypican-3 Targeting Immunotoxins for the Treatment of Liver Cancer: An Update

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