JP2018109036A - 改善されたがん治療のための局所および全身性免疫修飾療法の組み合わせ - Google Patents
改善されたがん治療のための局所および全身性免疫修飾療法の組み合わせ Download PDFInfo
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Abstract
【解決手段】病巣内ケモアブレーション用医薬組成物としてはローズベンガルなど、全身性免疫修飾抗がん剤としては、抗CTLA−4抗体、抗PD−L1抗体又は抗PD−1抗体など。
【選択図】なし
Description
本発明は、特定の局所治療モダリティ、具体的には、例えばPV−10またはその他のハロゲン化キサンテン薬剤を用いるILケモアブレーションなどの局所免疫修飾療法を、特定の全身治療モダリティと組み合わせることによる、予期せぬ相乗効果の結果としての側面を有する。この組み合わせは、両方の治療モダリティの治療活性を高めることができ、またそれぞれの療法を別々に用いた場合に通常生じる副作用(morbidity)を大幅に増大させる恐れがなく、むしろこれを全体的に低減する可能性がある。
局所免疫修飾療法と、イピリムマブおよびトレメリムマブを非限定的に含む抗CTLA−4抗体などの、1つ以上の免疫系下方制御に対する全身性阻害剤との組み合わせ;
局所免疫修飾療法は、好ましい実施形態として、ローズベンガルまたはその他のハロゲン化キサンテンを使用する病巣内ケモアブレーションを含む。好ましい分子形態であるローズベンガル二ナトリウムは、以下の化学式で表される:
より侵襲性の低い局部的な療法には、鼠径部で経皮的ルートを介して血管にアクセスする四肢分離注入(ILI)がある。
ILブレオマイシン単剤を用いた電気化学療法治療についても実質的な有効性が報告されている。しかし、シスプラチンの場合と同様、大きな腫瘍では総じて反応が低減する。
Claims (25)
- ヒトの悪性黒色腫、あるいは原発性または転移性肝がんの治療のために、(1)少なくとも一つの悪性黒色腫、あるいは原発性または転移性肝がん性の腫瘍のアブレーションを誘起する治療有効量の病巣内(IL)ケモアブレーション用医薬組成物と、(2)抗CTLA−4抗体、抗PD−L1抗体又は抗PD−1抗体を含む、治療有効量の全身性免疫修飾抗がん剤と、を別々に投与することを含む方法であって、
前記病巣内(IL)ケモアブレーション用医薬組成物は、ローズベンガルを0.1%(w/v)以上の濃度で含有する水溶液、またはローズベンガルの生理的に許容可能な塩を含む、適切な医薬組成物中にローズベンガル(4,5,6,7−テトラクロロ−2’,4’,5’,7’−テトラヨードフルオレセイン)を含有する病巣内(IL)ケモアブレーション用薬剤、を含み、前記病巣内(IL)ケモアブレーション用医薬組成物は、少なくとも一つの前記悪性黒色腫、あるいは原発性または転移性肝がん性の腫瘍の病巣内へ0.1mL/cc病変体積から2mL/cc病変体積投与されることを特徴とする方法。 - 請求項1に記載の方法であって、免疫系下方制御に対する全身性阻害剤である前記全身性免疫修飾抗がん剤は、抗CTLA−4抗体を含む、ことを特徴とする方法。
- 請求項1に記載の方法であって、前記ローズベンガルはローズベンガル二ナトリウムである、ことを特徴とする方法。
- 請求項1に記載の方法であって、前記ローズベンガルは、0.1%(w/v)〜20%(w/v)の濃度で存在し、前記医薬組成物は、ナトリウム、カリウム、カルシウム、およびマグネシウムからなる群より選択される少なくとも1つのカチオンと、塩化物、リン酸塩、および硝酸塩からなる群より選択される少なくとも1つのアニオンとを含む電解質を含み、前記電解質の濃度は0.1%(w/v)〜2%(w/v)である、ことを特徴とする方法。
- 請求項4に記載の方法であって、前記病巣内(IL)ケモアブレーション用医薬組成物中の前記電解質の濃度は0.5%(w/v)〜1.5%(w/v)である、ことを特徴とする方法。
- 請求項1に記載の方法であって、前記病巣内(IL)ケモアブレーション用医薬組成物の浸透圧は、100mOsm/kgより大きい、ことを特徴とする方法。
- 請求項4に記載の方法であって、前記電解質は塩化ナトリウムである、ことを特徴とする方法。
- 請求項1に記載の方法であって、前記医薬組成物は親水性賦形剤を含む、ことを特徴とする方法。
- 請求項1に記載の方法であって、前記医薬組成物のpHは、4〜10である、ことを特徴とする方法。
- 請求項9に記載の方法であって、前記医薬組成物のpHは、5〜7である、ことを特徴とする方法。
- ヒトの悪性黒色腫、あるいは原発性または転移性肝がんの治療のために、併用治療レジメンにおいて、(1)少なくとも一つの悪性黒色腫、あるいは原発性または転移性肝がん性の腫瘍のアブレーションを誘起する治療有効量の病巣内(IL)ケモアブレーション用医薬組成物と、(2)免疫系下方制御に対する全身性阻害剤または免疫系上方制御に対する全身性促進剤である、治療有効量の全身性免疫修飾抗がん剤と、を別々に投与することを含む方法であって、
前記病巣内(IL)ケモアブレーション用医薬組成物は、ローズベンガルを0.1%(w/v)以上の濃度で含有する水溶液、またはローズベンガルの生理的に許容可能な塩を含む、適切な医薬組成物中にローズベンガル(4,5,6,7−テトラクロロ−2’,4’,5’,7’−テトラヨードフルオレセイン)を含有する病巣内(IL)ケモアブレーション用薬剤、を含み、前記病巣内(IL)ケモアブレーション用医薬組成物は、少なくとも一つの前記悪性黒色腫、あるいは原発性または転移性肝がん性の腫瘍の病巣内へ0.1mL/cc病変体積から2mL/cc病変体積投与され、
免疫系下方制御に対する全身性阻害剤である前記全身性免疫修飾抗がん剤は、抗CTLA−4抗体、抗PD−L1抗体又は抗PD−1抗体を含むことを特徴とする方法。 - ヒトの悪性黒色腫、あるいは原発性または転移性肝がんの治療のために、(1)少なくとも一つの悪性黒色腫、あるいは原発性または転移性肝がん性の腫瘍のアブレーションを誘起する治療有効量の病巣内(IL)ケモアブレーション用医薬組成物と、(2)抗CTLA−4抗体、抗PD−L1抗体又は抗PD−1抗体を含む、治療有効量の全身性免疫修飾抗がん剤と、を別々に投与することを含む方法であって、前記病巣内(IL)ケモアブレーション用医薬組成物は、ハロゲン化キサンテンまたはその混合物を0.1%(w/v)以上の濃度で含有する水溶液、またはハロゲン化キサンテンの生理的に許容可能な塩を含む、適切な医薬組成物中にハロゲン化キサンテンを含有する病巣内(IL)ケモアブレーション用薬剤、を含むことを特徴とする方法。
- 請求項12に記載の方法であって、前記ハロゲン化キサンテンは、エリスロシンB、フロキシンB、4,5,6,7−テトラブロモ−2’,4’,5’,7’−テトラヨードフルオレセイン、2’,4,5,6,7−ペンタクロロ−4’,5’,7’−トリヨードフルオレセイン、4,4’,5,6,7−ペンタクロロ−2’,5’,7’−トリヨードフルオレセイン、2’,4,5,6,7,7’−ヘキサクロロ−4’,5’−ジヨードフルオレセイン、4,4’,5,5’,6,7−ヘキサクロロ−2’,7’−ジヨードフルオレセイン、2’,4,5,5’,6,7−ヘキサクロロ−4’,7’−ジヨードフルオレセイン、4,5,6,7−テトラクロロ−2’,4’,5’−トリヨードフルオレセイン、4,5,6,7−テトラクロロ−2’,4’,7’−トリヨードフルオレセイン、4,5,6,7−テトラブロモ−2’,4’,5’−トリヨードフルオレセイン、および4,5,6,7−テトラブロモ−2’,4’,7’−トリヨードフルオレセイン、からなる群より選択される、ことを特徴とする方法。
- 請求項12に記載の方法であって、前記ハロゲン化キサンテンは、ローズベンガル(4,5,6,7−テトラクロロ−2’,4’,5’,7’−テトラヨードフルオレセイン)またはローズベンガルの生理的に許容可能な塩である、ことを特徴とする方法。
- 請求項14に記載の方法であって、前記ハロゲン化キサンテンはローズベンガル二ナトリウムである、ことを特徴とする方法。
- 請求項12に記載の方法であって、前記ローズベンガルは、0.1%(w/v)〜20%(w/v)の濃度で存在し、前記医薬組成物は、ナトリウム、カリウム、カルシウム、およびマグネシウムからなる群より選択される少なくとも1つのカチオンと、塩化物、リン酸塩、および硝酸塩からなる群より選択される少なくとも1つのアニオンとを含む電解質を含み、前記電解質の濃度は0.1%(w/v)〜2%(w/v)である、ことを特徴とする方法。
- 請求項16に記載の方法であって、前記病巣内(IL)ケモアブレーション用医薬組成物中の前記電解質の濃度は0.5%(w/v)〜1.5%(w/v)である、ことを特徴とする方法。
- 請求項17に記載の方法であって、前記病巣内(IL)ケモアブレーション用医薬組成物の浸透圧は、100mOsm/kgより大きい、ことを特徴とする方法。
- 請求項16に記載の方法であって、前記電解質は塩化ナトリウムである、ことを特徴とする方法。
- 請求項12に記載の方法であって、前記医薬組成物は親水性賦形剤を含む、ことを特徴とする方法。
- 請求項12に記載の方法であって、前記医薬組成物のpHは、4〜10である、ことを特徴とする方法。
- 請求項21に記載の方法であって、前記医薬組成物のpHは、5〜7である、ことを特徴とする方法。
- 請求項12に記載の方法であって、前記全身性免疫修飾抗がん剤は、抗CTLA−4抗体、抗PD−L1抗体又は抗PD−1抗体を1つ以上含む、ことを特徴とする方法。
- 請求項23に記載の方法であって、前記全身性免疫修飾抗がん剤の投与は、前記病巣内(IL)ケモアブレーション用医薬組成物の投与の前に開始される、ことを特徴とする方法。
- 請求項24に記載の方法であって、前記ローズベンガルはローズベンガル二ナトリウムである、ことを特徴とする方法。
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MX2013010340A (es) | 2013-11-01 |
EP2710137B1 (en) | 2018-09-19 |
US9107887B2 (en) | 2015-08-18 |
US20150290165A1 (en) | 2015-10-15 |
WO2012122444A1 (en) | 2012-09-13 |
EP2710137A4 (en) | 2014-12-31 |
MX360254B (es) | 2018-10-26 |
CA2828940C (en) | 2024-04-16 |
JP6322413B2 (ja) | 2018-05-09 |
JP2014510728A (ja) | 2014-05-01 |
US20200138942A1 (en) | 2020-05-07 |
US9808524B2 (en) | 2017-11-07 |
US9839688B2 (en) | 2017-12-12 |
US20180055926A1 (en) | 2018-03-01 |
US20150290309A1 (en) | 2015-10-15 |
ES2699965T3 (es) | 2019-02-13 |
US10471144B2 (en) | 2019-11-12 |
US20220008534A1 (en) | 2022-01-13 |
KR20140038382A (ko) | 2014-03-28 |
US11071781B2 (en) | 2021-07-27 |
US20120263677A1 (en) | 2012-10-18 |
CN103476943A (zh) | 2013-12-25 |
CA2828940A1 (en) | 2012-09-13 |
US20150290318A1 (en) | 2015-10-15 |
EP2710137A1 (en) | 2014-03-26 |
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