JPWO2018037595A1 - 微小血管血流低減剤およびその利用 - Google Patents
微小血管血流低減剤およびその利用 Download PDFInfo
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Abstract
Description
しかし、腫瘍血管は前述のとおり、細かな血管網を形成しているため、腫瘍血管のみを選択的に塞栓することは困難であり、多くの場合腫瘍血管が分岐している元の血管を塞栓することで栄養の伝達を阻止する方法が採られる。しかしこの方法は正常な血管を塞栓させる必要があるため、正常組織への影響が懸念される。
(1)免疫チェックポイント阻害剤を含む、微小血管血流低減剤 。
(2)微小血管が、腫瘍血管および炎症血管である、(1)の微小血管血流低減剤。
(3)免疫チェックポイント阻害剤が、抗CTLA−4抗体、抗PD−1抗体および抗PDL−1抗体からなる群から選択される阻害剤である、(1)または(2)の微小血管血流低減剤。
(4)マイクロカテーテルにより目標血管に投与される、(1)〜(3)に記載の微小血管血流低減剤。
(5)免疫チェックポイント阻害剤の投与量が、1回あたり1〜50mgとなる用量で投与される、(1)〜(4)に記載の微小血管血流低減剤。
(6)さらにナノ化抗がん剤および/または抗炎症剤と組み合わせて用いられる、(1)〜(5)に記載の微小血管血流低減剤。
<1>本発明の微小血管血流低減剤
本発明において、「微小血管」とは、特定の疾患部位において新生される微小血管網を構成する血管を意味する。微小血管の特徴として、通常の血管と比較して無秩序、過密であり、動静脈の短絡を多く持ち、血管壁の浸透性が高いことが挙げられる。微小血管の例としては、これに限定するものではないが、例えば腫瘍血管、炎症血管、虚血の周りの血管、長く続く痛みの部位の血管などが挙げられる。本発明の一態様において、微小血管は、好ましくは腫瘍血管および炎症血管であり、より好ましくは腫瘍血管である。
本発明において「炎症血管」とは、炎症部位で産生される炎症性サイトカインにより誘導された新生血管を意味し、典型的には、例えばリウマチにおいて滑膜で新生した血管網を構成する血管などが挙げられる。
本発明において、「腫瘍(tumor)」は、良性腫瘍および悪性腫瘍(がん、悪性新生物)を含む。がん(cancer)は、造血器の腫瘍、上皮性の悪性腫瘍(癌、carcinoma)と非上皮性の悪性腫瘍(肉腫、sarcoma)とを含む。本発明の剤が特に治療効果を発揮するのは、腫瘍血管を有するがん、典型的には固形がんである。
小さな粒度分布を達成する方法としては、例えば振とう、希釈、撹拌など、当該技術分野において通常用いられる方法を用いることができる。
本発明は上述のとおり、免疫チェックポイント阻害剤を微小血管に導入すると、血流を低減させる効果を発揮することを新たに見出したことに端を発するものである。したがって本発明は一側面において、免疫チェックポイント阻害剤または免疫チェックポイント阻害剤を含む微小血管血流低減剤を用いて微小血管の血流を低減する方法に関する。
本発明の好ましい一態様において、免疫チェックポイント阻害剤は、対象の微小血管に局所投与される。局所投与の方法としては、典型的には動注法が挙げられ、中でもカテーテルを目的血管の近傍まで導入し、直接薬剤を投与する方法が好ましい。本発明の方法においては、目的血管が微小血管であるため、目的血管のより近傍までカテーテルを導入するために、カテーテルはマイクロカテーテルを用いるのが好ましい。マイクロカテーテルを用いた微小血管への局所投与方法は当該技術分野において公知であり、これに限定するものではないが、例えば超選択的動注法などが挙げられる。
本発明の微小血管血流低減剤は、特に腫瘍血管に投与した場合、当該腫瘍血管の血流を低減させ、それにより低酸素状態を改善し、腫瘍血管密度を低下させることができることが本発明者により見出された。したがって本発明の微小血管血流低減剤は、固形腫瘍周辺の微小環境(ニッチ)を改善することにより、固形腫瘍を処置する方法に用いることができる。すなわち本発明は、一側面において、腫瘍血管の血流を低減させることによる固形腫瘍の処置方法に関する。
免疫チェックポイント阻害剤の局所投与による連続的な処置を、94例(男性48例、女性46例、平均年齢62.1歳)に対して行い、初回の治療の病期別短期(1か月)縮小効果を調査した。さらに初回治療4か月後の画像評価が可能な35例について、病期別長期(4か月)縮小効果についても解析した。
免疫チェックポイント阻害剤(CTL4抗体イピリムマブ(エルボイ、Bristol-Myers-Squibb)2〜4mg/body(平均2.2mg/body)、PD1抗体ニボルマブ(オプジーボ,Bristol-Myers-Squibb)4〜45mg/body(平均15.6mg/body)、PD1抗体ペンブロリズマブ(キートルーダ、Merck Sharp & Dohme Limited)2〜20mg/body(平均9.23mg/body)、PDL−1抗体アテゾリズマブ(テーセントリック、Roche)30〜90mg/body(平均60mg/body)のいずれかと、抗炎症剤(マキサカルシトール10〜20μg/bodyおよび/またはボルテゾミブ0.35〜0.7mg/bodyおよび/またはエタネルセプト25mg/bodyおよび/またはトロンボモデュリン3200〜6400U/body)とを生理食塩水100〜150mlに溶解しスターラーを用いて攪拌し、責任血管に導入した。
投与後1か月における短期の腫瘍縮小効果について、MRIまたはCT画像により評価した。結果を下表に示す。表中、CRは画像上消失、PRは腫瘍径縮小>50%、MRは腫瘍径縮小>30%、NCは腫瘍径縮小<30%、PDは腫瘍径が増大したものを示す。
CRを4点、PRを3点、MRを2点、NCを1点、PDを0点として、各疾患群で平均点数を求め、腫瘍縮小効果を評価した。結果を下表に示す。
(1)処置対象群
同じ症例に施行した2回のがんの血管内治療の治療間隔日数を、2462例の対象に対して比較した。主にナノ化した抗がん剤と抗炎症剤をもちいたA群2137例と、CTL4抗体、PD1抗体またはPDL1抗体いずれかと抗炎症剤を用いたB群325例を比較した。A、B2群の、年齢、性別、治療時の病期(ステージ0〜IV)、治療対象とした原疾患のICD分類について、下表に記す。
治療前に病変部位をMRIまたはCTで撮像し、その画像から目標血管を検討し、できる限り全ての病変を対象として腫瘍血管を同定した後、血管内治療を行った。
A群では主にナノ化した抗がん剤(ゲムシタビン200mg/body、グリシルリチン酸80mg/body、オキサリプラチン50mg/body、マイトマイシン4mg/body、アブラキサン25mg/body)を混和し60〜120nm径の粒度分布としたものと、抗炎症剤(マキサカルシトール10〜20μg/body、ボルテゾミブ0.35〜0.7mg/body、エタネルセプト25mg/body、トロンボモデュリン3200〜6400U/body)とを責任血管に注入し、腫瘍血管密度の低下を目標に治療した。より凝集の少ないナノ化薬剤を作成する目的で、任意に閃ウラン鉱石をもちいて150μSv/hの放射線を30分間薬剤に照射し、粒度分布を3〜5nm径まで低下させた後、注入直前までスターラーをもちい攪拌して投与した。
結果を下表に示す。下表からわかるとおり、B群において、A群と比較して明らかに治療間隔が延長されていた。このことは、免疫チェックポイント阻害剤が血管内治療用の血流低減剤として効果を奏すること、および血管内治療において、従来用いられていた血流低減剤よりも効果の持続が長いことを意味している。
(1)乳癌患者A
乳癌に罹患した患者Aに対し、ニボルマブ10mg、ペルツズマブ60mg、ボルテゾミブ0.7mg、トロンボモデュリン3200Uおよびマキサカルシトール10μgを用いた血管内治療を行った。この患者はかかる処置によりCRとなった。病変部における腫瘍血管の様子を図1に示す。
右大腿部に悪性線維性組織球腫を罹患した患者Bに対し、ニボルマブ20mgを用いた血管内治療を行った。この患者は、ニボルマブ20mgの各回投与により、3回の処置でCRとなった。病変部における腫瘍血管の様子を図2に示す。
C型肝炎を罹患した患者Cにおいて生じた肝臓癌に対し、ニボルマブ10mg、ボルテゾミブ0.7mg、エタネルセプト25mg、マキサカルシトール10μg、イミペネム/シラスタチンナトリウム500mg/bodyの各回投与による血管内治療を行った。この患者は、2回の処置でCRとなった。病変部における腫瘍血管の様子を図3に示す。
慢性骨髄性白血病を罹患していた患者Dにおいて、筋層浸潤を伴う膀胱癌が見出され、転移癌と考えられた。この患者には、ニボルマブ10mg、ボルテゾミブ0.7mg、エタネルセプト25mg、マキサカルシトール10μg、トロンボモデュリン3200Uを用いた血管内治療を行い、かかる処置によりCRとなった。また、血管内治療後、慢性骨髄性白血病のマーカーであるBCR−ABL mRNAのIS%も低下し、慢性骨髄性白血病も寛解と判断された。図4は、同患者における膀胱がんの血管内治療前後のBCR−ABL mRNAのIS%の推移を表すグラフである。
免疫チェックポイント阻害剤は、いずれも単剤投与により、腫瘍血管からの注入後2〜3分後には明らかな腫瘍血行動態の変化を生じることがわかった。また、投与により即時的にがん性疼痛の軽減も確認される。これにさらに本来の効果である免疫チェックポイント阻害による効果も期待できるため、単剤の投与により比較的長く奏功することが期待される。その結果、示されたような治療間隔の延長効果が発揮されたものと考えられる。
長く続く痛みの部位の血管を有する対象として、下表に示す14例の対象に対し、ペンブロリズマブを用いた血管内治療を以下のとおり施した。
全例において処置前に脂肪抑制T2強調MRI画像を撮像し、対象血管を選定した。セルジンガー法にて大腿動脈から3Fr動脈留置シース(メディキット社製)を挿入し、同じくメディキット社製3Fr血管造影カテーテル、テルモ社製ラジフォーカス0.032”外径ガイドワイヤー、朝日インテック社製マイクロカテーテルASAHI Tellus C3、ASAHI Meister0.016”マイクロガイドワイヤーを適宜もちいて目標血管に到達し、造影にて異常血管網を同定した。
その後、表に示すごとくペンブロリズマブ1〜4mg/body(平均1.86mg/body、中央値2mg/body)を生理食塩水100mlに併用薬剤と混和し、スターラーにて攪拌しつつ、該当血管へ注入、十分な異常血管密度の低下が確認される量を注入した。
1〜2mg/bodyという極少量の免疫チェックポイント阻害剤(ペンブロリズマブ)の生理食塩水希釈1〜2%溶液による痛みの部位への選択的動注により、慢性の痛みの解除が可能であり、かかる処置は、副作用なく安全にかつ経済的な治療となることが示された。
長引く痛みの部位における血管新生の継続が、免疫チェックポイント阻害剤治療により明らかに改善されることから、長引く痛みにともなう血管新生状態そのものも、免疫寛容となって難治となった状況であることが示唆され、局所でのCD8+Tリンパ球の関与が示唆される。痛みの根本的治療としての局所免疫チェックポイント阻害治療(RCBT)が期待される。
Claims (6)
- 免疫チェックポイント阻害剤を含む、微小血管血流低減剤。
- 微小血管が、腫瘍血管および炎症血管である、請求項1に記載の微小血管血流低減剤。
- 免疫チェックポイント阻害剤が、抗CTLA−4抗体、抗PD−1抗体および抗PDL−1抗体からなる群から選択される阻害剤である、請求項1または2に記載の微小血管血流低減剤。
- マイクロカテーテルにより目標血管に投与される、請求項1〜3のいずれか一項に記載の微小血管血流低減剤。
- 免疫チェックポイント阻害剤の投与量が、1回あたり1〜50mgとなる用量で投与される、請求項1〜4のいずれか一項に記載の微小血管血流低減剤。
- さらにナノ化抗がん剤および/または抗炎症剤と組み合わせて用いられる、請求項1〜5のいずれか一項に記載の微小血管血流低減剤。
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