JP7393384B2 - がん治療で使用するためのチェックポイント阻害剤及び全細胞マイコバクテリウム - Google Patents
がん治療で使用するためのチェックポイント阻害剤及び全細胞マイコバクテリウム Download PDFInfo
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Classifications
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Description
成体C57BL/6マウスの側腹部に、KPCマウス(Hingorani et al. Cancer Cell, 2005, 7:469-48)から得た膵臓癌細胞系由来の105個の細胞を皮下注射した。これらのマウス膵臓癌細胞はKras、p53、及びPdx-Creに変異を有する(Hingorani et al. Cancer Cell, 2005, 7:469-48)。
(1)0.1mgのM.obuense NTCT13365/マウス。実験期間にわたり、5日間1日交代で首筋及び尾底部へ交互の皮下注射を行い、2日間休止;
(2)10mg/kgの抗PDL-1 mAb又は10mg/kgの抗PD-1 mAb、腹腔内、週1回;
(3)抗PDL-1又は抗PD-1とM.obuense NTCT13365との組合せを、単独で用いた上記2つの化合物について上述した用量及びスケジュールで行った。
皮下B16-F10腫瘍を担持するC57BL/6マウスにおいて、IMM-101及びチェックポイント阻害剤を用いた併用療法の効果を調べた。マウスには0日目に移植を行った。マウスは、1日目に無作為化され、1日目、3日目、5日目、7日目、9日目、11日目、13日目及び15日目(生存マウスの半数)若しくは16日目(生存マウスの半数)(隔日(Q2D)×8回)における、0.1mg/マウスのIMM-101の合計8回皮下注射、又は、10mg/kgの抗PD1若しくは抗CTLA4の合計4回の腹腔内注射(週2回を連続で2週間、1日目、5日目、8日目及び12日目:週2回(TW)×2回)を、単独又は併用で施された。15日目及び16日目、最後の処置の後に、全生存マウスの半数を屠殺した。腫瘍中の免疫浸潤細胞及び脾臓中の免疫細胞(CD3+CD8+細胞及びFoxP3制御性T細胞の比率)の特徴付けを、FACS解析を用いた定量化により行った(図3)。
(付記)
本開示は以下の態様を含む。
<1> 非病原性加熱殺菌全細胞マイコバクテリウムを含み、チェックポイント阻害処置が計画される患者におけるがんを治療、減少、阻害、又は制御するのに使用するための免疫調節薬であって、
前記チェックポイント阻害処置は、CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、B7-H3、B7-H4、B7-H6、A2AR、又はIDOに対する、細胞、タンパク質、ペプチド、抗体、又は抗体の抗原結合性断片、及びそれらの組合せから選択される遮断薬を投与することを含み、
前記チェックポイント阻害処置は治療量より少ない量及び/又は期間で前記遮断薬を投与することを含むか又は含まず、
前記免疫調節薬はチェックポイント阻害処置における投薬と同時、別個、又は逐次に投与される、
前記免疫調節薬。
<2> 前記遮断薬が、CTLA-4、PD-1、又はPD-L1に対する、細胞、タンパク質、ペプチド、抗体、又は抗体の抗原結合性断片、及びそれらの組合せから選択される遮断薬の投与を含む、<1>に記載の免疫調節薬。
<3> 前記遮断薬は、イピリムマブ、ニボルマブ、ペンブロリズマブ、アテゾリズマブ(azetolizumab)、トレメリムマブ、及びそれらの組合せからなる群より選択される抗体である、<1>又は<2>に記載の免疫調節薬。
<4> 前記遮断薬はペンブロリズマブであり、
前記患者は、前記がんと関連するミスマッチ修復欠損腫瘍を有する、且つ/又は、SP142免疫組織化学抗体アッセイを用いて測定された場合に腫瘍細胞の少なくとも10%、又は少なくとも20%、又は少なくとも30%、又は少なくとも40%、又は少なくとも50%若しくはそれ以上においてPD-L1発現を示す、<3>に記載の免疫調節薬。<5> 前記遮断薬はイピリムマブであり、3週間毎に2mg/mg以下の用量で、所望により最大4回の点滴において、静脈内投与される、<3>に記載の免疫調節薬。
<6> 前記遮断薬はニボルマブであり、少なくとも3mg/mg、又は少なくとも5mg/mg、又は少なくとも10mg/mg若しくはそれ以上の用量で、4週間毎に静脈内投与され、
前記患者は、SP142免疫組織化学抗体アッセイを用いて測定された場合に腫瘍細胞の少なくとも1%、少なくとも5%、又は少なくとも10%若しくはそれ以上においてPD-L1発現を示すか又は示さない、<3>に記載の免疫調節薬。
<7> 前記遮断薬はアテゾリズマブ(azetolizumab)であり、少なくとも10mg/kg又は少なくとも15mg/kg若しくはそれ以上の用量で三週間毎に静脈内投与され、
前記患者はSP142免疫組織化学抗体アッセイを用いて測定された場合に腫瘍細胞並びに/又はB細胞及びNK細胞から選択される腫瘍浸潤免疫細胞の少なくとも1%、少なくとも5%、又は少なくとも10%若しくはそれ以上においてPD-L1発現を示すか又は示さない、<3>に記載の免疫調節薬。
<8> 前記遮断薬は、AMP-224、BMS-986016、MGA-271、及びその組合せから選択される抗体である、<1>に記載の免疫調節薬。
<9> 前記遮断薬は、約20mg~約8000mgの用量で2週間毎に、所望により最大48回の点滴において、静脈内投与される、BMS-986016である、<8>に記載の免疫調節薬。
<10> 前記がんが、前立腺癌、肝臓癌、腎癌、肺癌、乳癌、結腸直腸癌、乳癌、膵臓癌、脳癌、肝細胞癌、リンパ腫、白血病、胃癌、子宮頸癌、卵巣癌、甲状腺癌、黒色腫、癌腫、頭頸部癌、皮膚癌、及び軟組織肉腫から選択される、<1>~<9>のいずれか一項に記載の免疫調節薬。
<11> 前記がんが、膵臓癌、結腸直腸癌、前立腺癌、及び卵巣癌から選択される、<1>~<10>のいずれか一項に記載の免疫調節薬。
<12> 前記がんが転移性である、<1>~<11>のいずれか一項に記載の免疫調節薬。
<13> 前記非病原性加熱殺菌全細胞マイコバクテリウムが、M.vaccae、M.obuense、M.parafortuitum、M.aurum、M.indicus pranii、M. phlei、及びそれらの組合せから選択される、<1>~<12>のいずれか一項に記載の免疫調節薬。
<14> 前記非病原性加熱殺菌マイコバクテリウムが、好ましくはR型である、<1>~<13>のいずれか一項に記載の免疫調節薬。
<15> 前記非病原性加熱殺菌マイコバクテリウム及び/又は前記遮断薬が、非経口経路、経口経路、舌下経路、経鼻経路、又は肺経路を介して投与される、<1>~<14>のいずれか一項に記載の免疫調節薬。
<16> 前記非経口経路が、皮下(subcutaneous)、皮内、皮下(subdermal)、腹腔内、又は静脈内から選択される、<15>に記載の免疫調節薬。
<17> 前記非経口経路が腫瘍内注射を含む、<15>又は<16>に記載の免疫調節薬。
<18> 前記免疫調節薬の投与が、前記チェックポイント阻害処置の前及び/又は後である、<1>~<17>のいずれか一項に記載の免疫調節薬。
<19> 対象における新生物、腫瘍、又はがんを治療する、減少させる、阻害する、又は制御する方法であって、
(i)CTLA-4、PD-1、PD-L1、PD-L2、LAG-3、B7-H3、B7-H4、B7-H6、A2AR、又はIDOに対する、細胞、タンパク質、ペプチド、抗体、又は抗体の抗原結合性断片、及びそれらの組合せから選択されるチェックポイント阻害剤及び(ii)免疫調節薬を同時、別個、又は逐次に前記対象に投与することを含み、
前記方法により、前記チェックポイント阻害剤又は前記免疫調節薬の単独投与と比べて治療有効性が増大し、
前記免疫調節薬は非病原性加熱殺菌全細胞マイコバクテリウムを含み、
治療量より少ない量の前記チェックポイント阻害剤を投与することを含むか又は含まない、方法。
<20> 前記チェックポイント阻害剤が、CTLA-4、PD-1、又はPD-L1に対する、細胞、タンパク質、ペプチド、抗体、抗体の断片、及びそれらの組合せから選択される、<19>に記載の方法。
<21> 前記チェックポイント阻害剤は、イピリムマブ、ニボルマブ、ペンブロリズマブ、アテゾリズマブ(azetolizumab)、トレメリムマブ、及びそれらの組合せからなる群より選択される抗体である、<19>又は<20>に記載の方法。
<22> 前記チェックポイント阻害剤はペンブロリズマブであり、
前記患者は、ミスマッチ修復欠損腫瘍を有する、且つ/又は、SP142免疫組織化学抗体アッセイを用いて測定された場合に腫瘍細胞の少なくとも10%、又は少なくとも20%、又は少なくとも30%、又は少なくとも40%、又は少なくとも50%若しくはそれ以上においてPD-L1発現を示す、<21>に記載の方法。
<23> 前記チェックポイント阻害剤はイピリムマブであり、3週間毎に2mg/mg以下の用量で、所望により最大4回の点滴において、静脈内投与される、<21>に記載の方法。
<24> 前記チェックポイント阻害剤はニボルマブであり、少なくとも3mg/mg、又は少なくとも5mg/mg、又は少なくとも10mg/mg若しくはそれ以上の用量で、4週間毎に静脈内投与され、
前記患者は、SP142免疫組織化学抗体アッセイを用いて測定された場合に腫瘍細胞の少なくとも1%、少なくとも5%、又は少なくとも10%若しくはそれ以上においてPD-L1発現を示すか又は示さない、<21>に記載の方法。
<25> 前記チェックポイント阻害剤はアテゾリズマブ(azetolizumab)であり、少なくとも10mg/kg又は少なくとも15mg/kg若しくはそれ以上の用量で三週間毎に静脈内投与され、
前記患者はSP142免疫組織化学抗体アッセイを用いて測定された場合に腫瘍細胞並びに/又はB細胞及びNK細胞から選択される腫瘍浸潤免疫細胞の少なくとも1%、少なくとも5%、又は少なくとも10%若しくはそれ以上においてPD-L1発現を示すか又は示さない、<21>に記載の方法。
<26> 前記チェックポイント阻害剤は、AMP-224、BMS-986016、MGA-271、及びその組合せから選択される抗体である、<19>に記載の方法。
<27> 前記チェックポイント阻害剤は、約20mg~約8000mgの用量で2週間毎に、所望により最大48回の点滴において、静脈内投与される、BMS-986016である、<26>に記載の方法。
<28> 前記新生物、前記腫瘍、又は前記がんが、前立腺癌、肝臓癌、腎癌、肺癌、乳癌、結腸直腸癌、乳癌、膵臓癌、脳癌、肝細胞癌、リンパ腫、白血病、胃癌、子宮頸癌、卵巣癌、甲状腺癌、黒色腫、癌腫、頭頸部癌、皮膚癌、及び軟組織肉腫から選択されるがんに関連する、<19>に記載の方法。
<29> 前記新生物、前記腫瘍、又は前記がんが、膵臓癌、結腸直腸癌、前立腺癌、及び卵巣癌から選択されるがんに関連する、<28>に記載の方法。
<30> 前記新生物、前記腫瘍、又は前記がんが転移性である、<19>、<28>、又は<29>に記載の方法。
<31> 前記非病原性加熱殺菌全細胞マイコバクテリウムが、M.vaccae、M.obuense、M.parafortuitum、M.aurum、M.indicus pranii、M. phlei、及びそれらの組合せから選択される、<19>又は及び<28>~<30>のいずれか一項に記載の方法。
<32> 前記非病原性加熱殺菌マイコバクテリウムが、R型である、<19>又は<28>~<31>のいずれか一項に記載の方法。
<33> 前記非病原性加熱殺菌全細胞マイコバクテリウム及び/又は前記チェックポイント阻害剤が、非経口経路、経口経路、舌下経路、経鼻経路、又は肺経路を介して投与される、<32>に記載の方法。
<34> 前記非経口経路が、皮下(subcutaneous)、皮内、皮下(subdermal)、腹腔内、又は静脈内から選択される、<33>に記載の方法。
<35> 前記非経口経路が腫瘍内注射を含む、<33>又は<34>に記載の方法。
<36> 投与される前記非病原性加熱殺菌マイコバクテリウムの量が107細胞~109細胞である、<19>又は<28>~<35>のいずれか一項に記載の方法。
<37> 治療有効性の増大が、全生存期間の延長により測定される、<19>に記載の方法。
<38> 治療有効性の増大が、無増悪生存期間の延長により測定される、<19>に記載の方法。
<39> 治療有効性の増大が、腫瘍サイズの減少又は安定化により測定される、<19>に記載の方法。
<40> 治療有効性の増大が、全奏効率の改善又は生活の質の向上により測定される、<19>に記載の方法。
Claims (13)
- チェックポイント阻害処置と組み合わせてがんを治療、減少、阻害、又は制御するのに使用するための免疫調節薬であって、
前記チェックポイント阻害処置は、MEDI-4736、MSB001078C、MEDI-0680、及びそれらの組合せから選択される遮断薬を投与することを含み、
前記免疫調節薬は、非病原性加熱殺菌全細胞Mycobacterium obuenseを含み、
前記免疫調節薬はチェックポイント阻害処置における投薬と同時、別個、又は逐次に投与される、
前記免疫調節薬。 - 前記がんが、前立腺癌、肝臓癌、腎癌、肺癌、乳癌、結腸直腸癌、膵臓癌、脳癌、肝細胞癌、リンパ腫、白血病、胃癌、子宮頸癌、卵巣癌、甲状腺癌、黒色腫、頭頸部癌、皮膚癌、及び軟組織肉腫から選択される、請求項1に記載の免疫調節薬。
- 前記がんが、黒色腫、膵臓癌、結腸直腸癌、前立腺癌、及び卵巣癌から選択される、請求項1又は請求項2に記載の免疫調節薬。
- 前記がんが転移性である、請求項1~請求項3のいずれか一項に記載の免疫調節薬。
- 前記非病原性加熱殺菌全細胞Mycobacterium obuense及び/又は前記遮断薬が、非経口経路、経口経路、舌下経路、経鼻経路、又は肺経路を介して投与されるものである、請求項1~請求項4のいずれか一項に記載の免疫調節薬。
- 前記非経口経路が、皮下(subcutaneous)、皮内、皮下(subdermal)、腹腔内、又は静脈内から選択される、請求項5に記載の免疫調節薬。
- 前記非経口経路が腫瘍内注射、又は腫瘍の近傍若しくはリンパ節の近傍への投与を含む、請求項5又は請求項6に記載の免疫調節薬。
- 前記免疫調節薬の投与が、前記チェックポイント阻害処置の前及び/又は後である、請求項1~請求項7のいずれか一項に記載の免疫調節薬。
- 前記免疫調節薬の投与が、2以上の反復投与で投与される、請求項1~請求項8のいずれか1項に記載の免疫調節薬。
- 1回当たりに投与される前記非病原性加熱殺菌全細胞Mycobacterium obuenseの量が107細胞~109細胞である、請求項1~請求項9のいずれか一項に記載の免疫調節薬。
- 1回当たりに投与される前記非病原性加熱殺菌全細胞Mycobacterium obuenseの量が0.1mg~1mgである、請求項1~請求項10のいずれか一項に記載の免疫調節薬。
- 前記使用により、前記遮断薬又は前記免疫調節薬の単独投与と比べて治療有効性が増大する、請求項1~請求項10のいずれか一項に記載の免疫調節薬。
- 治療有効性の増大が、全生存期間の延長;無増悪生存期間の延長;腫瘍サイズの減少又は安定化;又は全奏効率の改善及び/若しくは生活の質の向上により測定される、請求項12に記載の免疫調節薬。
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CN107847598A (zh) | 2018-03-27 |
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PT3319635T (pt) | 2021-07-07 |
WO2016207646A1 (en) | 2016-12-29 |
AU2016281765A1 (en) | 2018-01-18 |
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US20220111046A1 (en) | 2022-04-14 |
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RU2018102547A3 (ja) | 2019-12-24 |
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CN107847598B (zh) | 2022-01-25 |
KR20180015269A (ko) | 2018-02-12 |
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