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25.04.2019 | Laboratory Investigation

Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment

verfasst von: Adela Wu, Russell Maxwell, Yuanxuan Xia, Pina Cardarelli, Miho Oyasu, Zineb Belcaid, Eileen Kim, Alice Hung, Andrew S. Luksik, Tomas Garzon-Muvdi, Christopher M. Jackson, Dimitrios Mathios, Debebe Theodros, John Cogswell, Henry Brem, Drew M. Pardoll, Michael Lim

Erschienen in: Journal of Neuro-Oncology | Ausgabe 2/2019

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Abstract

Background

Emerging evidence suggests that myeloid cells play a critical role in glioblastoma (GBM) immunosuppression. Disappointing results of recent checkpoint inhibitor trials suggest that combination immunotherapy with alternative agents could be fruitful in overcoming immunosuppression. Overexpression of chemokine receptor CXCR4 is associated with poor prognosis in GBM. We investigate the treatment effects of combination immunotherapy with anti-PD-1 and anti-CXCR4 in a murine glioma model.

Methods

C57BL/6 mice were implanted with GL261-Luc+ glioma cells and randomized into 4 arms: (1) control (2) anti-PD-1 (3) anti-CXCR4, and (4) anti-PD-1 and anti-CXCR4 therapy. Overall survival and median survival were assessed. Cell populations were assessed by flow cytometry.

Results

Combination therapy conferred a significant survival benefit compared to control and monotherapy arms. Mice that received combination therapy demonstrated immune memory and decreased populations of immunosuppressive tumor-infiltrating leukocytes, such as monocytic myeloid-derived suppressor cells and microglia within the brain. Furthermore, combination therapy improved CD4+/CD8+ ratios in the brain as well as contributed to increased levels of pro-inflammatory cytokines.

Conclusions

Anti-CXCR4 and anti-PD-1 combination immunotherapy modulates tumor-infiltrating populations of the glioma microenvironment. Targeting myeloid cells with anti-CXCR4 facilitates anti-PD-1 to promote an antitumor immune response and improved survival rates.

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Titel: Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment
verfasst von: Adela Wu
Russell Maxwell
Yuanxuan Xia
Pina Cardarelli
Miho Oyasu
Zineb Belcaid
Eileen Kim
Alice Hung
Andrew S. Luksik
Tomas Garzon-Muvdi
Christopher M. Jackson
Dimitrios Mathios
Debebe Theodros
John Cogswell
Henry Brem
Drew M. Pardoll
Michael Lim
Publikationsdatum: 25.04.2019
Verlag: Springer US
Erschienen in: Journal of Neuro-Oncology / Ausgabe 2/2019
Print ISSN: 0167-594X
Elektronische ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-019-03172-5

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Combination anti-CXCR4 and anti-PD-1 immunotherapy provides survival benefit in glioblastoma through immune cell modulation of tumor microenvironment

Abstract

Background

Methods

Results

Conclusions

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Abstract

Background

Methods

Results

Conclusions

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