Skip to main content
Journal cover image

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

Publication ,  Journal Article
Chandramohan, V; Bao, X; Yu, X; Parker, S; McDowall, C; Yu, Y-R; Healy, P; Desjardins, A; Gunn, MD; Gromeier, M; Nair, SK; Pastan, IH; Bigner, DD
Published in: J Immunother Cancer
May 29, 2019

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

J Immunother Cancer

DOI

EISSN

2051-1426

Publication Date

May 29, 2019

Volume

7

Issue

1

Start / End Page

142

Location

England

Related Subject Headings

  • Mice, Inbred C57BL
  • Mice
  • Immunotoxins
  • Humans
  • Female
  • ErbB Receptors
  • Disease Models, Animal
  • Cell Line, Tumor
  • Brain Neoplasms
  • Animals
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Chandramohan, V., Bao, X., Yu, X., Parker, S., McDowall, C., Yu, Y.-R., … Bigner, D. D. (2019). Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. J Immunother Cancer, 7(1), 142. https://doi.org/10.1186/s40425-019-0614-0
Chandramohan, Vidyalakshmi, Xuhui Bao, Xin Yu, Scott Parker, Charlotte McDowall, Yen-Rei Yu, Patrick Healy, et al. “Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.J Immunother Cancer 7, no. 1 (May 29, 2019): 142. https://doi.org/10.1186/s40425-019-0614-0.
Chandramohan V, Bao X, Yu X, Parker S, McDowall C, Yu Y-R, et al. Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. J Immunother Cancer. 2019 May 29;7(1):142.
Chandramohan, Vidyalakshmi, et al. “Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations.J Immunother Cancer, vol. 7, no. 1, May 2019, p. 142. Pubmed, doi:10.1186/s40425-019-0614-0.
Chandramohan V, Bao X, Yu X, Parker S, McDowall C, Yu Y-R, Healy P, Desjardins A, Gunn MD, Gromeier M, Nair SK, Pastan IH, Bigner DD. Improved efficacy against malignant brain tumors with EGFRwt/EGFRvIII targeting immunotoxin and checkpoint inhibitor combinations. J Immunother Cancer. 2019 May 29;7(1):142.
Journal cover image

Published In

J Immunother Cancer

DOI

EISSN

2051-1426

Publication Date

May 29, 2019

Volume

7

Issue

1

Start / End Page

142

Location

England

Related Subject Headings

  • Mice, Inbred C57BL
  • Mice
  • Immunotoxins
  • Humans
  • Female
  • ErbB Receptors
  • Disease Models, Animal
  • Cell Line, Tumor
  • Brain Neoplasms
  • Animals