Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells

Alexei F Kirkin; Karine N Dzhandzhugazyan; Per Guldberg; Johnny Jon Fang; Rikke S Andersen; Christina Dahl; Jann Mortensen; Tim Lundby; Aase Wagner; Ian Law; Helle Broholm; Line Madsen; Christer Lundell-Ek; Morten F Gjerstorff; Henrik J Ditzel; Martin R Jensen; Walter Fischer

doi:10.1038/s41467-018-03217-9

Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells

Alexei F Kirkin, Karine N Dzhandzhugazyan, Per Guldberg, Johnny Jon Fang, Rikke S Andersen, Christina Dahl, Jann Mortensen, Tim Lundby, Aase Wagner, Ian Law, Helle Broholm, Line Madsen, Christer Lundell-Ek, Morten F Gjerstorff, Henrik J Ditzel, Martin R Jensen, Walter Fischer

Institut for Klinisk Medicin

10 Citationer (Scopus)

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Abstract

In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

Originalsprog	Engelsk
Artikelnummer	785
Tidsskrift	Nature Communications
Vol/bind	9
Antal sider	12
ISSN	2041-1723
DOI	https://doi.org/10.1038/s41467-018-03217-9
Status	Udgivet - 1 dec. 2018

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10.1038/s41467-018-03217-9Licens: CC BY

s41467-018-03217-9Forlagets udgivne version, 2,7 MBLicens: CC BY

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Kirkin, A. F., Dzhandzhugazyan, K. N., Guldberg, P., Fang, J. J., Andersen, R. S., Dahl, C., Mortensen, J., Lundby, T., Wagner, A., Law, I., Broholm, H., Madsen, L., Lundell-Ek, C., Gjerstorff, M. F., Ditzel, H. J., Jensen, M. R., & Fischer, W. (2018). Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells. Nature Communications, 9, Artikel 785. https://doi.org/10.1038/s41467-018-03217-9

Kirkin, AF, Dzhandzhugazyan, KN, Guldberg, P, Fang, JJ, Andersen, RS, Dahl, C, Mortensen, J, Lundby, T, Wagner, A, Law, I, Broholm, H, Madsen, L, Lundell-Ek, C, Gjerstorff, MF, Ditzel, HJ, Jensen, MR & Fischer, W 2018, 'Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells', Nature Communications, bind 9, 785. https://doi.org/10.1038/s41467-018-03217-9

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abstract = "In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.",

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AU - Kirkin, Alexei F

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AU - Andersen, Rikke S

AU - Dahl, Christina

AU - Mortensen, Jann

AU - Lundby, Tim

AU - Wagner, Aase

AU - Law, Ian

AU - Broholm, Helle

AU - Madsen, Line

AU - Lundell-Ek, Christer

AU - Gjerstorff, Morten F

AU - Ditzel, Henrik J

AU - Jensen, Martin R

AU - Fischer, Walter

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N2 - In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

AB - In cancer cells, cancer/testis (CT) antigens become epigenetically derepressed through DNA demethylation and constitute attractive targets for cancer immunotherapy. Here we report that activated CD4+ T helper cells treated with a DNA-demethylating agent express a broad repertoire of endogenous CT antigens and can be used as antigen-presenting cells to generate autologous cytotoxic T lymphocytes (CTLs) and natural killer cells. In vitro, activated CTLs induce HLA-restricted lysis of tumor cells of different histological types, as well as cells expressing single CT antigens. In a phase 1 trial of 25 patients with recurrent glioblastoma multiforme, cytotoxic lymphocytes homed to the tumor, with tumor regression ongoing in three patients for 14, 22, and 27 months, respectively. No treatment-related adverse effects were observed. This proof-of-principle study shows that tumor-reactive effector cells can be generated ex vivo by exposure to antigens induced by DNA demethylation, providing a novel, minimally invasive therapeutic strategy for treating cancer.

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KW - Brain Neoplasms/genetics

KW - DNA/genetics

KW - DNA Methylation

KW - Female

KW - Glioblastoma/genetics

KW - Humans

KW - Immunotherapy, Adoptive

KW - Male

KW - Prospective Studies

KW - T-Lymphocytes, Cytotoxic/immunology

KW - T-Lymphocytes, Helper-Inducer/immunology

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Adoptive cancer immunotherapy using DNA-demethylated T helper cells as antigen-presenting cells

Abstract

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