A phase I dose escalation and cohort expansion study of T-cell redirecting bispecific antibody against Glypican 3 in patients with advanced solid tumors.

Hashimoto, Kenji; Perera, A. G. U.; Ogita, Yoshitaka; Nakamura, Mikiko; Ishiguro, Takahiro; Sano, Yuji; Kinoshita, Yasuko; Sakurai, Mika Kamata; Frings, Werner; Komatsu, Shunichiro; Kaneko, Akihisa; Ueda, Masamichi; Kishishita, Shohei; Gianella‐Borradori, Athos

doi:10.1200/jco.2016.34.15_suppl.tps2592

Cited by 4 publications

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“…A humanized antibody targeting this TAA, PRL3-zumab, was shown to enhance the intra-tumoral recruitment of B cells, NK cells and macrophages, suggesting that this antibody might promote tumor killing by ADCC ( 120 ). Similarly, the elevated expression of GPC3 in >70% of HCC, and its association with poor prognosis ( 121 ), has led to the development of several immunotherapeutic strategies, including the humanized monoclonal antibody codrituzumab ( 122 ), bi-specific antibodies ( 123 ), CAR-T cells ( 124 ), antibody-drug conjugates ( 125 ), and vaccines ( 126 ). GPC3-CAR-T cells have been shown to be polyfunctional and capable of eliminating HCC in a transplantable orthotopic mouse model ( 127 ), and there are currently at least 5 phase I clinical trials recruiting patients with HCC to test GPC3-CAR-T cells ( Table 1 ; ClinicalTrials.gov , December 2020).…”

Section: The Future Of Immunotherapies In Hcc Beyond Icimentioning

confidence: 99%

Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies

et al. 2021

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Hepatocellular carcinoma (HCC) is the most common liver tumor and among the deadliest cancers worldwide. Advanced HCC overall survival is meager and has not improved over the last decade despite approval of several tyrosine kinase inhibitors (TKi) for first and second-line treatments. The recent approval of immune checkpoint inhibitors (ICI) has revolutionized HCC palliative care. Unfortunately, the majority of HCC patients fail to respond to these therapies. Here, we elaborate on the immune landscapes of the normal and cirrhotic livers and of the unique HCC tumor microenvironment. We describe the molecular and immunological classifications of HCC, discuss the role of specific immune cell subsets in this cancer, with a focus on myeloid cells and pathways in anti-tumor immunity, tumor promotion and immune evasion. We also describe the challenges and opportunities of immunotherapies in HCC and discuss new avenues based on harnessing the anti-tumor activity of myeloid, NK and γδ T cells, vaccines, chimeric antigen receptors (CAR)-T or -NK cells, oncolytic viruses, and combination therapies.

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Section: The Future Of Immunotherapies In Hcc Beyond Icimentioning

confidence: 99%

Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies

et al. 2021

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“…To reduce the chance of cytokine release, corticosteroids were tested without compromising the anti-tumor effect [47]. A phase I clinical trial to assess the safety and efficacy of the antibody is in progress (NCT02748837).…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies

Hoseini

Cheung

2017

Cancer Letters

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide with an overall survival rate of less than 15% in developed countries. Despite attempts at new therapeutic strategies, the majority of patients succumb to this cancer. Buttressed by the highly successful clinical impact in melanoma, immunotherapy is gaining momentum as the next treatment modality for many human cancers. Chimeric antigen receptors (CAR) contain the antigen binding moieties of a monoclonal antibody and the co-stimulatory and signaling domains associated with effector receptor signaling. Bispecific antibodies (BsAb) combine the binding specificities of two different monoclonal antibodies, one activating a receptor on a killer effector cell, while the other engaging a tumor-associated antigen to initiate tumor cytotoxicity. In this review, we survey the HCC targets for which CARs and bispecific antibodies have been generated. The pros and cons of these targets for T-cell and Natural Killer cell based immunotherapy will be discussed.

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“…(11) Emerging anti-GPC3 chimeric antigen receptor (CAR) T-cell immunotherapy, bispecific mAb, and immunotoxin showed high potency in vivo. (12)(13)(14) Our previous work showed that immunotoxins consisting of antibody variable domains (HN3 and YP7) fused to Pseudomonas exotoxin had potent anticancer activity in vitro and in vivo. (10) However, a major drawback for immunotoxin therapy is the severe immunogenicity of the Pseudomonas exotoxin.…”

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confidence: 99%

Glypican‐3‐Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma

Urban

Nani

et al. 2019

Hepatology

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Hepatocellular carcinoma (HCC) is the second most common cause of cancer‐related death in the world. Therapeutic outcomes of HCC remain unsatisfactory, and novel treatments are urgently needed. GPC3 (glypican‐3) is an emerging target for HCC, given the findings that 1) GPC3 is highly expressed in more than 70% of HCC; (2) elevated GPC3 expression is linked with poor HCC prognosis; and (3) GPC3‐specific therapeutics, including immunotoxin, bispecific antibody and chimeric antigen receptor T cells. have shown promising results. Here, we postulate that GPC3 is a potential target of antibody‐drug conjugates (ADCs) for treating liver cancer. To determine the payload for ADCs against liver cancer, we screened three large drug libraries (> 9,000 compounds) against HCC cell lines and found that the most potent drugs are DNA‐damaging agents. Duocarmycin SA and pyrrolobenzodiazepine dimer were chosen as the payloads to construct two GPC3‐specific ADCs: hYP7‐DC and hYP7‐PC. Both ADCs showed potency at picomolar concentrations against a panel of GPC3‐positive cancer cell lines, but not GPC3 negative cell lines. To improve potency, we investigated the synergetic effect of hYP7‐DC with approved drugs. Gemcitabine showed a synergetic effect with hYP7‐DC in vitro and in vivo. Furthermore, single treatment of hYP7‐PC induced tumor regression in multiple mouse models. Conclusion: We provide an example of an ADC targeting GPC3, suggesting a strategy for liver cancer therapy.

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A phase I dose escalation and cohort expansion study of T-cell redirecting bispecific antibody against Glypican 3 in patients with advanced solid tumors.

Cited by 4 publications

References 0 publications

Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies

Hepatocellular Carcinoma Immune Landscape and the Potential of Immunotherapies

Immunotherapy of hepatocellular carcinoma using chimeric antigen receptors and bispecific antibodies

Glypican‐3‐Specific Antibody Drug Conjugates Targeting Hepatocellular Carcinoma

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