Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.

dc.contributor.author

Chandramohan, Vidyalakshmi

dc.contributor.author

Bao, Xuhui

dc.contributor.author

Yu, Xin

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Parker, Scott

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McDowall, Charlotte

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Yu, Yen-Rei

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Healy, Patrick

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Desjardins, Annick

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Gunn, Michael D

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Gromeier, Matthias

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Nair, Smita K

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Pastan, Ira H

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Bigner, Darell D

dc.date.accessioned

2022-09-01T13:31:44Z

dc.date.available

2022-09-01T13:31:44Z

dc.date.issued

2019-05-29

dc.date.updated

2022-09-01T13:31:42Z

dc.description.abstract

Background

D2C7-IT is a novel immunotoxin (IT) targeting wild-type epidermal growth factor receptor (EGFRwt) and mutant EGFR variant III (EGFRvIII) proteins in glioblastoma. In addition to inherent tumoricidal activity, immunotoxins induce secondary immune responses through the activation of T cells. However, glioblastoma-induced immune suppression is a major obstacle to an effective and durable immunotoxin-mediated antitumor response. We hypothesized that D2C7-IT-induced immune response could be effectively augmented in combination with αCTLA-4/αPD-1/αPD-L1 therapies in murine models of glioma.

Methods

To study this, we overexpressed the D2C7-IT antigen, murine EGFRvIII (dmEGFRvIII), in established glioma lines, CT-2A and SMA560. The reactivity and therapeutic efficacy of D2C7-IT against CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII cells was determined by flow cytometry and in vitro cytotoxicity assays, respectively. Antitumor efficacy of D2C7-IT was examined in immunocompetent, intracranial murine glioma models and the role of T cells was assessed by CD4+ and CD8+ T cell depletion. In vivo efficacy of D2C7-IT/αCTLA-4/αPD-1 monotherapy or D2C7-IT+αCTLA-4/αPD-1 combination therapy was evaluated in subcutaneous unilateral and bilateral CT-2A-dmEGFRvIII glioma-bearing immunocompetent mice. Further, antitumor efficacy of D2C7-IT+αCTLA-4/αPD-1/αPD-L1/αTim-3/αLag-3/αCD73 combination therapy was evaluated in intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII glioma-bearing mice. Pairwise differences in survival curves were assessed using the generalized Wilcoxon test.

Results

D2C7-IT effectively killed CT-2A-dmEGFRvIII (IC50 = 0.47 ng/mL) and SMA560-dmEGFRvIII (IC50 = 1.05 ng/mL) cells in vitro. Treatment of intracranial CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII tumors with D2C7-IT prolonged survival (P = 0.0188 and P = 0.0057, respectively), which was significantly reduced by the depletion of CD4+ and CD8+ T cells. To augment antitumor immune responses, we combined D2C7-IT with αCTLA-4/αPD-1 in an in vivo subcutaneous CT-2A-dmEGFRvIII model. Tumor-bearing mice exhibited complete tumor regressions (4/10 in D2C7-IT+αCTLA-4 and 5/10 in D2C7-IT+αPD-1 treatment groups), and combination therapy-induced systemic antitumor response was effective against both dmEGFRvIII-positive and dmEGFRvIII-negative CT-2A tumors. In a subcutaneous bilateral CT-2A-dmEGFRvIII model, D2C7-IT+αCTLA-4/αPD-1 combination therapies showed dramatic regression of the treated tumors and measurable regression of untreated tumors. Notably, in CT-2A-dmEGFRvIII and SMA560-dmEGFRvIII intracranial glioma models, D2C7-IT+αPD-1/αPD-L1 combinations improved survival, and in selected cases generated cures and protection against tumor re-challenge.

Conclusions

These data support the development of D2C7-IT and immune checkpoint blockade combinations for patients with malignant glioma.
dc.identifier

10.1186/s40425-019-0614-0

dc.identifier.issn

2051-1426

dc.identifier.issn

2051-1426

dc.identifier.uri

https://hdl.handle.net/10161/25628

dc.language

eng

dc.publisher

BMJ

dc.relation.ispartof

Journal for immunotherapy of cancer

dc.relation.isversionof

10.1186/s40425-019-0614-0

dc.subject

Cell Line, Tumor

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Animals

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Mice, Inbred C57BL

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Humans

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Mice

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Brain Neoplasms

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Disease Models, Animal

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Immunotoxins

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Female

dc.subject

ErbB Receptors

dc.title

Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.

dc.type

Journal article

duke.contributor.orcid

Chandramohan, Vidyalakshmi|0000-0002-0653-3014

duke.contributor.orcid

Bao, Xuhui|0000-0003-4653-0288

duke.contributor.orcid

Gunn, Michael D|0000-0003-4602-0667

duke.contributor.orcid

Nair, Smita K|0000-0001-7019-1912

duke.contributor.orcid

Bigner, Darell D|0000-0001-5548-4899

pubs.begin-page

142

pubs.issue

1

pubs.organisational-group

Duke

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School of Medicine

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Basic Science Departments

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Clinical Science Departments

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Institutes and Centers

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Immunology

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Molecular Genetics and Microbiology

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Medicine

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Pathology

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Surgery

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Medicine, Cardiology

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Medicine, Infectious Diseases

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Medicine, Pulmonary, Allergy, and Critical Care Medicine

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Surgery, Surgical Sciences

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Duke Cancer Institute

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Neurology

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Neurology, General & Community Neurology

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Neurosurgery

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Neurosurgery, Neuro-Oncology

pubs.publication-status

Published

pubs.volume

7

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