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Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma

Authors
 Junseong Park  ;  Chang Gon Kim  ;  Jin-Kyoung Shim  ;  Jong Hoon Kim  ;  Hoyoung Lee  ;  Jae Eun Lee  ;  Min Hwan Kim  ;  Keeok Haam  ;  Inkyung Jung  ;  Su-Hyung Park  ;  Jong Hee Chang  ;  Eui-Cheol Shin  ;  Seok-Gu Kang 
Citation
 Oncoimmunology, Vol.8(1) : e1525243, 2018 
Journal Title
 Oncoimmunology 
ISSN
 2162-4011 
Issue Date
2018
Keywords
PD-1 ; checkpoint inhibitor ; combination therapy ; glioblastoma ; temozolomide
Abstract
Background: Although programmed death-1 (PD-1) blockade is effective in treating several types of cancer, the efficacy of this agent in glioblastoma (GBM) is largely unknown. Methods: We evaluated therapeutic effects of anti-PD-1, temozolomide (TMZ), and their combination in an orthotopic murine GBM model. The phenotype, number, and composition of lymphocytes were evaluated using flow cytometry. Transcriptional profiles of tumor tissues were analyzed using microarrays. Generation of antitumor immunological memory was investigated upon rechallenge. Results: Combined treatment with anti-PD-1 and TMZ yielded synergistic antitumor efficacy in the presence of donor-originated PD-1+CD8+ T cells in vitro, necessitating in vivo validation. Whereas TMZ did not rescue GBM-implanted mice, anti-PD-1 completely eradicated GBM in 44.4% of mice, and combination of anti-PD-1 and TMZ in all mice. Anti-PD-1 significantly increased the number of tumor-infiltrating lymhpocytes (TILs), and reduced frequencies of exhausted T cells and regulatory T cells. However, combining TMZ with anti-PD-1 significantly decreased the number of TILs, which was also observed with TMZ treatment alone. A transcriptome analysis of tumor tissues revealed that anti-PD-1 monotherapy perturbed immune-related genes, distinctly with combined therapy. Upon rechallenge, tumor growth was not observed in mice cured by anti-PD-1 monotherapy, whereas tumors regrew in the combination group. Furthermore, an analysis of peripheral blood revealed that antitumor memory T cells were generated in mice cured by anti-PD-1 monotherapy, not in the combination group. Conclusion: PD-1 blockade induces long-term therapeutic response, and combination with TMZ further enhances antitumor efficacy. However, immunological memory is provoked by anti-PD-1 monotherapy, not by combined therapy.
Full Text
https://www.tandfonline.com/doi/full/10.1080/2162402X.2018.1525243
DOI
10.1080/2162402X.2018.1525243
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
강석구(Kang, Seok Gu) ORCID logo https://orcid.org/0000-0001-5676-2037
장종희(Chang, Jong Hee)
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URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/166851
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