GD2 targeting by dinutuximab beta is a promising immunotherapeutic approach against malignant glioma

Marx, Sascha; Wilken, Fabian; Wagner, Isabel; Marx, Marlies; Troschke-Meurer, Sascha; Zumpe, Maxi; Bien-Moeller, Sandra; Weidemeier, Martin; Baldauf, Jörg; Fleck, Steffen; Rauch, Bernhard; Schroeder, Henry W. S.; Lode, Holger N.; Siebert, Nikolai

doi:10.1007/s11060-020-03470-3

Cited by 21 publications

(17 citation statements)

References 25 publications

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“…Attention to GD2 is especially increasing, i.e., as cancer-associated glycolipids in various cancers, and a marker to indicate higher malignant properties of cancers [ 22 ], and/or cancer stem cells [ 17 ] and triple-negative breast cancers [ 18 ]. GD2 has been used as a target of antibody therapy [ 31 , 32 ] towards neuroblastomas [ 33 ], gliomas [ 34 ], and breast cancers [ 26 ], and also of CAR-T therapy of various cancers [ 19 , 20 ]. Furthermore, the biological function of GD2 has been reported, i.e., in EMT [ 35 , 36 ], tumor invasion [ 37 ], and cancer metastasis [ 38 ], though it had been expected based on the clinical samples with different disease stages [ 16 ].…”

Section: Discussionmentioning

confidence: 99%

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

Yesmin

Bhuiyan

Ohmi

et al. 2021

IJMS

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Gangliosides have been considered to modulate cell signals in the microdomain of the cell membrane, lipid/rafts, or glycolipid-enriched microdomain/rafts (GEM/rafts). In particular, cancer-associated gangliosides were reported to enhance the malignant properties of cancer cells. In fact, GD2-positive (GD2+) cells showed increased proliferation, invasion, and adhesion, compared with GD2-negative (GD2−) cells. However, the precise mechanisms by which gangliosides regulate cell signaling in GEM/rafts are not well understood. In order to analyze the roles of ganglioside GD2 in the malignant properties of melanoma cells, we searched for GD2-associating molecules on the cell membrane using the enzyme-mediated activation of radical sources combined with mass spectrometry, and integrin β1 was identified as a representative GD2-associating molecule. Then, we showed the physical association of GD2 and integrin β1 by immunoprecipitation/immunoblotting. Close localization was also shown by immuno-cytostaining and the proximity ligation assay. During cell adhesion, GD2+ cells showed multiple phospho-tyrosine bands, i.e., the epithelial growth factor receptor and focal adhesion kinase. The knockdown of integrin β1 revealed that the increased malignant phenotypes in GD2+ cells were clearly cancelled. Furthermore, the phosphor-tyrosine bands detected during the adhesion of GD2+ cells almost completely disappeared after the knockdown of integrin β1. Finally, immunoblotting to examine the intracellular distribution of integrins during cell adhesion revealed that large amounts of integrin β1 were localized in GEM/raft fractions in GD2+ cells before and just after cell adhesion, with the majority being localized in the non-raft fractions in GD2− cells. All these results suggest that GD2 and integrin β1 cooperate in GEM/rafts, leading to enhanced malignant phenotypes of melanomas.

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Section: Discussionmentioning

confidence: 99%

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

Yesmin

Bhuiyan

Ohmi

et al. 2021

IJMS

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“…22 Dinutuximab also induces stronger ADCC than other anti-GD2 antibodies in GD2 + neuroblastoma cells. 45 Recently, Marx et al 46 reported that incubation of glioblastoma multiforme cells with effector cells and dinutuximab induced a robust ADCC against the majority of the cell lines analyzed, clearly indicating the antitumor efficacy of GD2-directed treatment against glioblastoma. Our studies in TNBC cells demonstrated that treatment with dinutuximab substantially reduced in vivo TNBC tumor growth, which parallels the activity of dinutuximab in GD2 + melanoma cells in vivo.…”

Section: Open Accessmentioning

confidence: 96%

Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2⁺ breast cancer stem-like cells

Anand

El-Dana

et al. 2021

J Immunother Cancer

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BackgroundTriple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with no effective standard therapy. Breast cancer stem-like cells (BCSCs) in primary TNBCs are reported to be responsible for metastatic spread of the disease and resistance to chemotherapy, but no available therapeutic tools target BCSCs. We previously reported that the ganglioside GD2 is highly expressed on BCSCs and that inhibition of its expression hampers TNBC growth. We therefore hypothesized that the anti-GD2 antibody dinutuximab (ch14.18) targets GD2+ BCSCs and inhibits TNBC growth.MethodTo test our hypothesis, we first determined GD2 expression via immunohistochemistry in frozen primary tumor samples from patients with TNBC (n=89). Then, we examined the effects of dinutuximab on TNBC cell adhesion, migration, and mammosphere formation in vitro and on tumor growth in vivo using TNBC cell-line and patient-derived xenograft (PDX) models.ResultsWe found that GD2 was expressed in around 60% of primary TNBC tumors at variable levels and was associated with worse overall survival of patients with TNBC (p=0.002). GD2 was found to be expressed in tumors and stroma, but normal ducts and lobules in adjacent tissues have shown low or no GD2 staining, indicating that GD2 is potentially a novel biomarker for tumor and its microenvironment. Treatment with dinutuximab significantly decreased adhesion and migration of MDA-MB-231 and SUM159 TNBC cells. Moreover, dinutuximab treatment inhibited mTOR signaling, which has been shown to be regulated by GD2 in BCSCs. Dinutuximab also reduced tumor growth in nude mice bearing TNBC cell-line xenografts. Finally, dinutuximab in combination with activated natural killer cells inhibited tumor growth in a TNBC PDX model and improved overall survival of tumor-bearing mice.ConclusionsDinutuximab successfully eliminated GD2+ cells and reduced tumor growth in both in vivo models. Our data provide proof-of-concept for the criticality of GD2 in BCSCs and demonstrate the potential of dinutuximab as a novel therapeutic approach for TNBC.

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“…We first sought to comprehensively profile GD2 expression in GBM, as published reports of expression levels are limited 19,24,25 , using the same 14g2a antibody clone from which our CAR is derived. To this end, we used an extensive collection of human tumor tissues obtained from the SA Neurological Tumor Bank (a summary of patient material used in this study can be found in Supplementary Table 1 ).…”

Section: Resultsmentioning

confidence: 99%

GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma

Gargett

Ebert

Truong

et al. 2022

Preprint

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Background: Aggressive primary brain tumors such as glioblastoma are uniquely challenging to treat. The intracranial location poses barriers to therapy, and the potential for severe toxicity. Effective treatments for primary brain tumors are limited, and 5-year survival rates remain poor. Immune checkpoint inhibitor therapy has transformed treatment of some other cancers but has yet to significantly benefit patients with glioblastoma. Early phase trials of CAR-T cell therapy have demonstrated that this approach is safe and feasible, but with limited evidence of its effectiveness. The choices of appropriate target antigens for CAR-T cell therapy also remain limited. Methods: We profiled an extensive biobank of patients' biopsy tissues and patient-derived early passage glioma neural stem cell lines for GD2 expression using immunomicroscopy and flow cytometry. We then employed an approved clinical manufacturing process to make CAR-T cells from peripheral blood of glioblastoma and diffuse midline glioma patients and characterized their phenotype and function in vitro. Finally, we tested intravenously administered CAR-T cells in an aggressive intracranial xenograft model of glioblastoma and used multicolor flow cytometry, multicolor whole-tissue immunofluorescence and next-generation RNA sequencing to uncover markers associated with effective tumor control. Results: Here we show that the tumor-associated antigen GD2 is highly and consistently expressed in primary glioblastoma tissue removed at surgery. Moreover, despite glioblastoma patients having perturbations in their immune system, highly functional GD2-specific CAR-T cells can be produced from their peripheral T cells using an approved clinical manufacturing process. Finally, after intravenous administration, GD2-CAR-T cells effectively infiltrated the brain and controlled tumor growth in an aggressive orthotopic xenograft model of glioblastoma. Tumor control was further improved using CAR-T cells manufactured with a clinical retroviral vector encoding an IL-15 transgene alongside the GD2-specific CAR. These CAR-T cells achieved a striking 50% complete response rate by bioluminescence imaging in established intracranial tumors. Markers associated with tumor control included those related to T-cell homing, infiltration, and cytotoxicity. Conclusions: Targeting GD2 using a clinically deployed CAR-T therapy has a sound scientific and clinical rationale as a treatment for glioblastoma and other aggressive primary brain tumors.

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GD2 targeting by dinutuximab beta is a promising immunotherapeutic approach against malignant glioma

Cited by 21 publications

References 25 publications

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2⁺ breast cancer stem-like cells

GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma

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GD2 targeting by dinutuximab beta is a promising immunotherapeutic approach against malignant glioma

Cited by 21 publications

References 25 publications

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins

Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2+ breast cancer stem-like cells

GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma

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Anti-GD2 antibody dinutuximab inhibits triple-negative breast tumor growth by targeting GD2⁺ breast cancer stem-like cells