Skip to main content

A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors.

Publication ,  Conference
Bao, X; Keir, ST; Nair, SK; Pastan, I; Bigner, DD; Chandramohan, V
Published in: Journal of Clinical Oncology
March 1, 2017

102 Background: Immunotoxins can induce direct and rapid cytotoxicity by targeting specific tumor antigens. D2C7 is a unique recombinant immunotoxin targeting EGFRwt/EGFRvIII, two frequently overexpressed proteins on gliomas, and is currently being tested in a phase I/II clinical trial (NCT02303678) for recurrent malignant gliomas. Immunotoxins have also been shown to induce a secondary antitumor immune response via stimulation of cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors, which have successfully treated several advanced tumors by promoting the antitumor function of CTLs, may further enhance this immunotoxin-induced antitumor response. Thus, we hypothesize that combining D2C7 with immune checkpoint inhibitors will promote long-term tumor regression due to primary cytotoxicity and enhanced anti-tumor immunity. Methods: We developed a CT2A-mD2C7 mouse glioma cell line with robust in vitro cytotoxicity of D2C7 (IC= 0.47 ng/mL). In vivo anti-tumor efficacy was evaluated by intratumoral injection of D2C7 combined with intraperitoneal injection of anti-CTLA4 or anti-PD1 antibodies in single-side and bilateral subcutaneous (SC) CT2A-mD2C7 glioma models in C57BL/6 immunocompetent mice. Results: In the single-side model, D2C7 monotherapy and combinatorial therapy showed a significant tumor growth delay (P < 0.01). Complete regression ( ≥ 40%) was only observed in combinatorial therapy groups. All cured mice rejected the rechallenging of CT2A parental cells in the contralateral flank and the subsequent rechallenging of CT2A-mD2C7 cells in the brain. In the bilateral model, the larger right tumors were treated with D2C7/anti-CTLA4/anti-PD1 monotherapy or D2C7+anti-CTLA4/PD1 combinatorial therapy, while the left tumors were untreated by D2C7. In the groups where the right tumors were treated with monotherapy or combinatorial therapy, the left untreated tumors also grew much slower. Furthermore, the combinatorial therapy led to the most significantly delayed growth of the left untreated tumors (P < 0.05). Conclusions: Immune checkpoint inhibitors can enhance D2C7-induced anti-tumor immunity to achieve a synergistic long-term tumor regression.

Duke Scholars

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

March 1, 2017

Volume

35

Issue

7_suppl

Start / End Page

102 / 102

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Bao, X., Keir, S. T., Nair, S. K., Pastan, I., Bigner, D. D., & Chandramohan, V. (2017). A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors. In Journal of Clinical Oncology (Vol. 35, pp. 102–102). American Society of Clinical Oncology (ASCO). https://doi.org/10.1200/jco.2017.35.7_suppl.102
Bao, Xuhui, Stephen T. Keir, Smita K. Nair, Ira Pastan, Darell D. Bigner, and Vidyalakshmi Chandramohan. “A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors.” In Journal of Clinical Oncology, 35:102–102. American Society of Clinical Oncology (ASCO), 2017. https://doi.org/10.1200/jco.2017.35.7_suppl.102.
Bao X, Keir ST, Nair SK, Pastan I, Bigner DD, Chandramohan V. A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors. In: Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2017. p. 102–102.
Bao, Xuhui, et al. “A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors.Journal of Clinical Oncology, vol. 35, no. 7_suppl, American Society of Clinical Oncology (ASCO), 2017, pp. 102–102. Crossref, doi:10.1200/jco.2017.35.7_suppl.102.
Bao X, Keir ST, Nair SK, Pastan I, Bigner DD, Chandramohan V. A combinatorial immunotherapy for malignant brain tumors: D2C7 immunotoxin and immune checkpoint inhibitors. Journal of Clinical Oncology. American Society of Clinical Oncology (ASCO); 2017. p. 102–102.

Published In

Journal of Clinical Oncology

DOI

EISSN

1527-7755

ISSN

0732-183X

Publication Date

March 1, 2017

Volume

35

Issue

7_suppl

Start / End Page

102 / 102

Publisher

American Society of Clinical Oncology (ASCO)

Related Subject Headings

  • Oncology & Carcinogenesis
  • 1112 Oncology and Carcinogenesis
  • 1103 Clinical Sciences