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

 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 
 ONCOIMMUNOLOGY, Vol.8(1) : e1525243, 2019-01 
Journal Title
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PD-1 ; checkpoint inhibitor ; combination therapy ; glioblastoma ; temozolomide
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.
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1. College of Medicine (의과대학) > Dept. of Dermatology (피부과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurosurgery (신경외과학교실) > 1. Journal Papers
Yonsei Authors
Kang, Seok Gu(강석구) ORCID logo https://orcid.org/0000-0001-5676-2037
Kim, Jong Hoon(김종훈) ORCID logo https://orcid.org/0000-0002-3385-8180
Park, Junseong(박준성)
Chang, Jong Hee(장종희) ORCID logo https://orcid.org/0000-0003-1509-9800
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