Title:
骨髄由来抑制細胞の抑制及び免疫チェックポイント阻害の方法
Document Type and Number:
Japanese Patent JP6626085
Kind Code:
B2
Abstract:
Impressive responses have been observed in patients treated with checkpoint inhibitory anti-PD-1 or anti-CTLA-4 antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Treatment with both anti-PD-1 and anti-CTLA-4 antibodies were unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. However, co-treatment with epigenetic modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of them. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K-inhibitor that reduced circulating MDSCs also cured 80% of mice with metastatic 4T1 tumors when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.
Inventors:
Butterfly civin
Vogelstein Bart
Kinsler Kenneth W.
Kim Kibem
Vogelstein Bart
Kinsler Kenneth W.
Kim Kibem
Application Number:
JP2017502263A
Publication Date:
December 25, 2019
Filing Date:
July 13, 2015
Export Citation:
Assignee:
The Johns Hopkins University
International Classes:
A61K31/4406; A61K31/706; A61K35/742; A61K39/395; A61K45/00; A61P35/00; A61P43/00
Other References:
Journal of Leukocyte Biology,2012年 5月,91,p.701-709
View of NCT01928576 on 2013_08_23,ClinicalTrials.gov archive,2013年 8月23日,URL,https://clinicaltrials.gov/archive/NCT01928576/2013_08_23
Wolchok,J.D. et al.,Nivolumab plus ipilimumab in advanced melanoma.,N. Engl. J. Med.,2013年 7月11日,Vol.369, No.2,p.122-33
Schmidt-Kitller,O. et al.,PI3Kα inhibitors that inhibit metastasis.,Oncotarget,2010年 9月,Vol.1, No.5,p.339-48
Dang,L.H. et al.,Combination bacteriolytic therapy fot the treatment of experimental tumors.,Proc. Natl. Acad. Sci. USA,2001年12月18日,Vol.98, No.26,p.15155-60
Mikyskova,R. et al.,DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment.,J Leukoc. Biol.,2014年 5月,Vol.94, No.5,p.743-53
View of NCT01928576 on 2013_08_23,ClinicalTrials.gov archive,2013年 8月23日,URL,https://clinicaltrials.gov/archive/NCT01928576/2013_08_23
Wolchok,J.D. et al.,Nivolumab plus ipilimumab in advanced melanoma.,N. Engl. J. Med.,2013年 7月11日,Vol.369, No.2,p.122-33
Schmidt-Kitller,O. et al.,PI3Kα inhibitors that inhibit metastasis.,Oncotarget,2010年 9月,Vol.1, No.5,p.339-48
Dang,L.H. et al.,Combination bacteriolytic therapy fot the treatment of experimental tumors.,Proc. Natl. Acad. Sci. USA,2001年12月18日,Vol.98, No.26,p.15155-60
Mikyskova,R. et al.,DNA demethylating agent 5-azacytidine inhibits myeloid-derived suppressor cells induced by tumor growth and cyclophosphamide treatment.,J Leukoc. Biol.,2014年 5月,Vol.94, No.5,p.743-53
Attorney, Agent or Firm:
Hatsushi Shimizu
Masao Haruna
Hirotaka Yamaguchi
Toshi Gobe
Ryuichi Inoue
Toshimitsu Sato
Koichi Niimi
Tomohiko Kobayashi
Hideki Kodera
Masato Ozeki
Yoshihiro Igarashi
Kazuya Kawamoto
Masao Haruna
Hirotaka Yamaguchi
Toshi Gobe
Ryuichi Inoue
Toshimitsu Sato
Koichi Niimi
Tomohiko Kobayashi
Hideki Kodera
Masato Ozeki
Yoshihiro Igarashi
Kazuya Kawamoto