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

Liu, Xiaoyu; Gao, Fang; Jiang, Lijia; Meng, Jiao; Ao, Lei; Lü, Ming; Gou, Liming; Ho, Mitchell; Jia, Shaochang; Chen, Fei

doi:10.1186/s12967-020-02462-1

Cited by 40 publications

(29 citation statements)

References 45 publications

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“…The use of Glypican-3 (GPC3) antibody in combination with CAR T therapy can be a useful method in the treatment of liver malignancies. Liu and coworkers showed that the use of 32A9 monoclonal antibody /CAR T cells kill (GPC3 + ) HCC cells in vitro and regresses liver xenograft tumor in vivo [100]. Another study illustrated that GPC3/CAR T cells expressing IL15/21 promoted the antitumor responses of T cells against HCC [101].…”

Section: Liver Cancermentioning

confidence: 99%

CAR T cells in solid tumors: challenges and opportunities

et al. 2021

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Background CARs are simulated receptors containing an extracellular single-chain variable fragment (scFv), a transmembrane domain, as well as an intracellular region of immunoreceptor tyrosine-based activation motifs (ITAMs) in association with a co-stimulatory signal. Main body Chimeric antigen receptor (CAR) T cells are genetically engineered T cells to express a receptor for the recognition of the particular surface marker that has given rise to advances in the treatment of blood disorders. The CAR T cells obtain supra-physiological properties and conduct as “living drugs” presenting both immediate and steady effects after expression in T cells surface. But, their efficacy in solid tumor treatment has not yet been supported. The pivotal challenges in the field of solid tumor CAR T cell therapy can be summarized in three major parts: recognition, trafficking, and surviving in the tumor. On the other hand, the immunosuppressive tumor microenvironment (TME) interferes with T cell activity in terms of differentiation and exhaustion, and as a result of the combined use of CARs and checkpoint blockade, as well as the suppression of other inhibitor factors in the microenvironment, very promising results were obtained from the reduction of T cell exhaustion. Conclusion Nowadays, identifying and defeating the mechanisms associated with CAR T cell dysfunction is crucial to establish CAR T cells that can proliferate and lyse tumor cells severely. In this review, we discuss the CAR signaling and efficacy T in solid tumors and evaluate the most significant barriers in this process and describe the most novel therapeutic methods aiming to the acquirement of the promising therapeutic outcome in non-hematologic malignancies.

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Section: Liver Cancermentioning

confidence: 99%

CAR T cells in solid tumors: challenges and opportunities

et al. 2021

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“…Antibodies and recombinant proteins YP7 and 32A9 are GPC3-specific monoclonal antibodies generated in our previous studies. [30][31][32] YP7 is a mouse antibody and was humanized (named hYP7) for the generation of CAR-T cells. The recombinant sGPC3 (Q25-S550) protein with a hexa-histidine tag at the C-terminal end, or with a wild-type human Fc (hFc) tag or mutant hFc tag containing three mutations (N297A/ L234A/L235A) reported to abolish unexpected binding to the Fcγ receptor 33 34 were cloned into the pFUSE vector (InvivoGen, San Diego, California, USA).…”

Section: Clinical Samples and Cellsmentioning

confidence: 99%

Shed antigen-induced blocking effect on CAR-T cells targeting Glypican-3 in Hepatocellular Carcinoma

Sun

Gao

et al. 2021

J Immunother Cancer

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BackgroundGlypican-3 (GPC3), a cell surface glycoprotein that is pathologically highly expressed in hepatocellular carcinoma (HCC), is an attractive target for immunotherapies, including chimeric antigen receptor (CAR) T cells. The serum GPC3 is frequently elevated in HCC patients due to the shedding effect of cell surface GPC3. The shed GPC3 (sGPC3) is reported to block the function of cell-surface GPC3 as a negative regulator. Therefore, it would be worth investigating the potential influence of antigen shedding in anti-GPC3 CAR-T therapy for HCC.MethodsIn this study, we constructed two types of CAR-T cells targeting distinct epitopes of GPC3 to examine how sGPC3 influences the activation and cytotoxicity of CAR-T cells in vitro and in vivo by introducing sGPC3 positive patient serum or recombinant sGPC3 proteins into HCC cells or by using sGPC3-overexpressing HCC cell lines.ResultsBoth humanized YP7 CAR-T cells and 32A9 CAR-T cells showed GPC3-specific antitumor functions in vitro and in vivo. The existence of sGPC3 significantly inhibited the release of cytokines and the cytotoxicity of anti-GPC3 CAR-T cells in vitro. In animal models, mice carrying Hep3B xenograft tumors expressing sGPC3 exhibited a worse response to the treatment with CAR-T cells under both a low and high tumor burden. sGPC3 bound to CAR-T cells but failed to induce the effective activation of CAR-T cells. Therefore, sGPC3 acted as dominant negative regulators when competed with cell surface GPC3 to bind anti-GPC3 CAR-T cells, leading to an inhibitory effect on CAR-T cells in HCC.ConclusionsWe provide a proof-of-concept study demonstrating that GPC3 shedding might cause worse response to CAR-T cell treatment by competing with cell surface GPC3 for CAR-T cell binding, which revealed a new mechanism of tumor immune escape in HCC, providing a novel biomarker for patient enrolment in future clinical trials and/or treatments with GPC3-targeted CAR-T cells.

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“…Antibody-targeting of SDC1 has been used alone or combined with chemotherapy to treat multiple myeloma [231], and a clinical trial using CAR-T cells recognising SDC1 suggests that the treatment is safe, well-tolerable and has potential antitumour activity [232]. In the same line, in hepatocellular carcinoma, the strategies of immunotoxin and CAR-T cells against GPC3 are showing promising results and are under clinical trials [233][234][235].…”

Section: Heparan Sulfate-based Therapeutic Opportunitiesmentioning

confidence: 99%

Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management

et al. 2021

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In an era when cancer glycobiology research is exponentially growing, we are witnessing a progressive translation of the major scientific findings to the clinical practice with the overarching aim of improving cancer patients’ management. Many mechanistic cell biology studies have demonstrated that heparan sulfate (HS) glycosaminoglycans are key molecules responsible for several molecular and biochemical processes, impacting extracellular matrix properties and cellular functions. HS can interact with a myriad of different ligands, and therefore, hold a pleiotropic role in regulating the activity of important cellular receptors and downstream signalling pathways. The aberrant expression of HS glycan chains in tumours determines main malignant features, such as cancer cell proliferation, angiogenesis, invasion and metastasis. In this review, we devote particular attention to HS biological activities, its expression profile and modulation in cancer. Moreover, we highlight HS clinical potential to improve both diagnosis and prognosis of cancer, either as HS-based biomarkers or as therapeutic targets.

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

Cited by 40 publications

References 45 publications

CAR T cells in solid tumors: challenges and opportunities

CAR T cells in solid tumors: challenges and opportunities

Shed antigen-induced blocking effect on CAR-T cells targeting Glypican-3 in Hepatocellular Carcinoma

Heparan Sulfate Glycosaminoglycans: (Un)Expected Allies in Cancer Clinical Management

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