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 | |
dc.contributor.author | Parker, Scott | |
dc.contributor.author | McDowall, Charlotte | |
dc.contributor.author | Yu, Yen-Rei | |
dc.contributor.author | Healy, Patrick | |
dc.contributor.author | Desjardins, Annick | |
dc.contributor.author | Gunn, Michael D | |
dc.contributor.author | Gromeier, Matthias | |
dc.contributor.author | Nair, Smita K | |
dc.contributor.author | Pastan, Ira H | |
dc.contributor.author | 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 | BackgroundD2C7-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.MethodsTo 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.ResultsD2C7-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.ConclusionsThese 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 | ||
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 | |
dc.subject | Animals | |
dc.subject | Mice, Inbred C57BL | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Brain Neoplasms | |
dc.subject | Disease Models, Animal | |
dc.subject | Immunotoxins | |
dc.subject | 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 | |
pubs.organisational-group | School of Medicine | |
pubs.organisational-group | Basic Science Departments | |
pubs.organisational-group | Clinical Science Departments | |
pubs.organisational-group | Institutes and Centers | |
pubs.organisational-group | Immunology | |
pubs.organisational-group | Molecular Genetics and Microbiology | |
pubs.organisational-group | Medicine | |
pubs.organisational-group | Pathology | |
pubs.organisational-group | Surgery | |
pubs.organisational-group | Medicine, Cardiology | |
pubs.organisational-group | Medicine, Infectious Diseases | |
pubs.organisational-group | Medicine, Pulmonary, Allergy, and Critical Care Medicine | |
pubs.organisational-group | Surgery, Surgical Sciences | |
pubs.organisational-group | Duke Cancer Institute | |
pubs.organisational-group | Neurology | |
pubs.organisational-group | Neurology, General & Community Neurology | |
pubs.organisational-group | Neurosurgery | |
pubs.organisational-group | Neurosurgery, Neuro-Oncology | |
pubs.publication-status | Published | |
pubs.volume | 7 |
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