Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models.

Abstract

Background

Sym004 is a mixture of two monoclonal antibodies (mAbs), futuximab and modotuximab, targeting non-overlapping epitopes on the epidermal growth factor receptor (EGFR). Previous studies have shown that Sym004 is more efficient at inducing internalization and degradation of EGFR than individual components, which translates into superior cancer cell inhibition. We investigated whether Sym004 induces removal of EGFRvIII and if this removal translates into tumor growth inhibition in hard-to-treat glioblastomas (GBMs) harboring the mutated, constitutively active EGFR variant III (EGFRvIII).

Methods

To address this question, we tested the effect of Sym004 versus cetuximab in eight patient-derived GBM xenograft models expressing either wild-type EGFR (EGFRwt) and/or mutant EGFRvIII. All models were tested as both subcutaneous and orthotopic intracranial xenograft models.

Results

In vitro studies demonstrated that Sym004 internalized and removed EGFRvIII more efficiently than mAbs, futuximab, modotuximab, and cetuximab. Removal of EGFRvIII by Sym004 translated into significant in vivo anti-tumor activity in all six EGFRvIII xenograft models. Furthermore, the anti-tumor activity of Sym004 in vivo was superior to that of its individual components, futuximab and modotuximab, suggesting a clear synergistic effect of the mAbs in the mixture.

Conclusion

These results demonstrate the broad activity of Sym004 in patient-derived EGFRvIII-expressing GBM xenograft models and provide a clear rationale for clinical evaluation of Sym004 in EGFRvIII-positive adult GBM patients.

Department

Description

Provenance

Subjects

Subcutaneous Tissue, Animals, Mice, Inbred BALB C, Humans, Mice, Nude, Glioblastoma, Brain Neoplasms, Antineoplastic Agents, Antibodies, Monoclonal, Xenograft Model Antitumor Assays, Female, Male, ErbB Receptors

Citation

Published Version (Please cite this version)

10.1007/s11060-018-2832-6

Publication Info

Keir, Stephen T, Vidyalakshmi Chandramohan, Carlee D Hemphill, Michael M Grandal, Maria Carlsen Melander, Mikkel W Pedersen, Ivan D Horak, Michael Kragh, et al. (2018). Sym004-induced EGFR elimination is associated with profound anti-tumor activity in EGFRvIII patient-derived glioblastoma models. Journal of neuro-oncology, 138(3). pp. 489–498. 10.1007/s11060-018-2832-6 Retrieved from https://hdl.handle.net/10161/25630.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Keir

Stephen Thomas Keir

Professor in Neurosurgery

Brain Tumors, Preclinical Testing, Translational Research

Chandramohan

Vidyalakshmi Chandramohan

Associate Professor in Neurosurgery

The research work in my laboratory focuses on identifying novel immunotherapeutic targets for the treatment of brain tumors, specifically glioblastoma (GBM). My previous work includes the development of the dual-specific immunotoxin (IT) D2C7-IT, which is currently in Phase I clinical trials in recurrent GBM (rGBM) patients. My current research seeks to identify novel strategies to enhance the efficacy of D2C7-IT and other GBM-targeted cytotoxic therapies. In conjunction with this, my research includes the investigation of immune-related biomarkers to predict the clinical outcome of D2C7-IT therapy in patients with GBM.

Desjardins

Annick Desjardins

Professor of Neurosurgery
Friedman

Henry Seth Friedman

James B. Powell, Jr. Distinguished Professor of Pediatric Oncology, in the School of Medicine

Overview: Our laboratory is pursuing a comprehensive analysis of the biology and therapy of adult and childhood central nervous system malignancies, particularly high-grade medulloblastoma, glioma, and ependymoma.

Laboratory Studies: Active programs, using human adult and pediatric CNS tumor continuous cell lines, transplantable xenografts growing subcutaneously and intracranially in athymic nude mice and rats, and as well as in the subarachnoid space of the athymic nude rats, and patients tumor specimens, are defining:

1) the chemotherapeutic profile of medulloblastoma, adult and childhood glioma and ependymoma
2) mechanisms of resistance to classical bifunctional alkylators, nitrosoureas and methylators operational in malignant glioma and medulloblastoma, particularly DNA adduct and crosslink repair, O6-alkylguanine-DNA alkyltransferase elevation and DNA mismatch repair deficiency.
3) modulations designed to over come or circumvent specific mechanisms of resistance
4) the activity of signal pathway inhibitors of EGFR, m-tor and other targets
5) the therapeutic advantages of intrathecal and intratumoral drug delivery in the treatment of neoplastic meningitis and intracranial malignancies, respectively.

The results of the therapeutic studies to date have demonstrated the marked activity of alkylating agents, particularly melphalan and cyclophosphamide and the role of glutathione, AGT glutathione-S-transferase, abnormal drug transport and alterations in formation and repair of DNA-DNA crosslinks in modulating cytotoxicity of these agents. Modulations shown to be effective in enhancing alkylator activity/reversing alkylator resistance include BSO-mediated glutathione depletion, inhibition of DNA-DNA crosslink repair and inhibition of 06-alkylguanine-DNA alkyltransferase by 06-benzylguanine. Recent studies have demonstrated profound activity of temozolomide, CPT-11 topotecan, irofulven, and karenitecin as well as the combination of CPT-11 or topotecan plus BCNU or temozolomide. Successful treatment of neoplastic meningitis in nude rats with intrathecal 4-hydroperoxycyclophosphamide, melphalan, temozolomide and busulfan, and intracranial glioma in nude rats with intratumoral temozolomide has also been demonstrated. More recent studies have revealed cyclophosphamide resistance secondary to DNA interstrand crosslink repair. Additional studies have shown that cyclophosphamide crosslinks are formed at the 1,3 N7 position, serving as the basis for construction of a defined crosslink in a plasmid vector to assay for crosslink repair and allowing demonstration of the lack of a role of nucleotide excision repair. Mismatch repair deficiency has been shown as a mechanism mediating acquired methylator (procarbazine and temozolomide) resistance in an adult glioblastoma xenograft.

Clinical Studies: Clinical investigations are designed to translate laboratory programs into successful treatment for adults and children with malignant brain tumors, particularly medulloblastoma. Clinical trials for adults include phase II trials of temozolomide, ZD1839 (Iressa), karenitecin, and temozolomide plus O6-BG as well as phase I trials of topotecan plus BCNU, CPT-11 plus temozolomide, and PTK787 ± temozolomide or CCNU. Studies are in progress in children evaluating the activity CPT-11 plus temozolomide, intrathecal busulfan and cyclophosphamide/melphalan or cyclophosphamide/busulfan plus autologous bone marrow support . Extension of these studies to a larger cohort of patients is being performed nationally under the auspices of the Pediatric Brain Tumor Consortium (Henry S. Friedman -- Head of New Agents Committee).

Future studies will address the role of agents designed to decrease repair of interstrand crosslinks when given in combination with alkylating agents, as well as newer signal pathway inhibitors such as RAD001, PKI166, and DB-67.


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