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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere1525243
JournalOncoImmunology
Volume8
Issue number1
DOIs
Publication statusPublished - 2019 Jan 2

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temozolomide
Glioblastoma
Therapeutics
Neoplasms
Immunologic Memory
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Oncology

Cite this

Park, J., Kim, C. G., Shim, J. K., Kim, J. H., Lee, H., Lee, J. E., ... Kang, S-G. (2019). Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma. OncoImmunology, 8(1), [e1525243]. https://doi.org/10.1080/2162402X.2018.1525243
Park, Junseong ; Kim, Chang Gon ; Shim, Jin Kyoung ; Kim, Jong Hoon ; Lee, Hoyoung ; Lee, Jae Eun ; Kim, Min Hwan ; Haam, Keeok ; Jung, Inkyung ; Park, Su Hyung ; Chang, Jong Hee ; Shin, Eui Cheol ; Kang, Seok-Gu. / Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma. In: OncoImmunology. 2019 ; Vol. 8, No. 1.
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title = "Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma",
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.",
author = "Junseong Park and Kim, {Chang Gon} and Shim, {Jin Kyoung} and Kim, {Jong Hoon} and Hoyoung Lee and Lee, {Jae Eun} and Kim, {Min Hwan} and Keeok Haam and Inkyung Jung and Park, {Su Hyung} and Chang, {Jong Hee} and Shin, {Eui Cheol} and Seok-Gu Kang",
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Park, J, Kim, CG, Shim, JK, Kim, JH, Lee, H, Lee, JE, Kim, MH, Haam, K, Jung, I, Park, SH, Chang, JH, Shin, EC & Kang, S-G 2019, 'Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma', OncoImmunology, vol. 8, no. 1, e1525243. https://doi.org/10.1080/2162402X.2018.1525243

Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma. / Park, Junseong; Kim, Chang Gon; Shim, Jin Kyoung; Kim, Jong Hoon; Lee, Hoyoung; Lee, Jae Eun; Kim, Min Hwan; Haam, Keeok; Jung, Inkyung; Park, Su Hyung; Chang, Jong Hee; Shin, Eui Cheol; Kang, Seok-Gu.

In: OncoImmunology, Vol. 8, No. 1, e1525243, 02.01.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Effect of combined anti-PD-1 and temozolomide therapy in glioblastoma

AU - Park, Junseong

AU - Kim, Chang Gon

AU - Shim, Jin Kyoung

AU - Kim, Jong Hoon

AU - Lee, Hoyoung

AU - Lee, Jae Eun

AU - Kim, Min Hwan

AU - Haam, Keeok

AU - Jung, Inkyung

AU - Park, Su Hyung

AU - Chang, Jong Hee

AU - Shin, Eui Cheol

AU - Kang, Seok-Gu

PY - 2019/1/2

Y1 - 2019/1/2

N2 - 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.

AB - 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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