JP2022512927A - 癌を処置するための組成物および方法 - Google Patents
癌を処置するための組成物および方法 Download PDFInfo
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Abstract
Description
本出願は、2018年11月8日出願の米国仮出願第62/757,383号の利益を主張する。先の出願の教示全体は、参照により本明細書に組み込まれる。
他に定義されない限り、本明細書で使用する全ての技術用語および科学用語は、本発明が属する技術分野の当業者によって一般的に理解されるのと同じ意味を有する。本明細書に説明されるものと類似のまたは同等の任意の方法および材料がまた、本発明の実施または試験において使用することもできるが、ここで好ましい方法および材料を説明する。
本発明は、PARP阻害剤を含むがこれに限定されない組み合わせDDR阻害剤における、およびテモゾロミド(TMZ)を含むがこれに限定されない化学療法薬とのさらなる組み合わせにおけるγδT細胞免疫療法のための組成物および方法を含む、患者における腫瘍を減少させ、癌を処置するための併用療法を提供する。好ましくは、癌の処置のためのγδT細胞免疫療法とPARP阻害剤との組み合わせにはさらに、免疫チェックポイント(ICP)遮断療法などの他の免疫療法および/または他の免疫刺激薬との組み合わせが含まれる。
1.5-メチルニコチンアミドおよびO-(2-ヒドロキシ-3-ピペリジノ-プロピル)-3-カルボン酸アミドオキシムなどのニコチンアミド、ならびにこれらの類似体および誘導体、
2.3-アミノベンズアミド、3-ヒドロキシベンズアミド 3-ニトロソベンズアミド、3-メトキシベンズアミドおよび3-クロロプロカインアミドなどの3置換ベンズアミド、ならびに4-アミノベンズアミドを含むベンズアミド、1,5-ジ[(3-カルバモイルフェニル)アミノカルボニルオキシ]ペンタン、ならびにこれらの類似体および誘導体、
3.2H-イソキノリン-1-オン、3H-キナゾリン-4-オン、5-ヒドロキシジヒドロイソキノリノン、5-メチルジヒドロイソキノリノン、および5-ヒドロキシイソキノリノンなどの5置換ジヒドロイソキノリノン、5-アミノイソキノリン-1-オン、5-ジヒドロキシイソキノリノン、3,4ジヒドロ-5-メトキシ-イソキノリン-1(2H)-オンおよび3,4ジヒドロ-5-メチル-1(2H)イソキノリノンなどの3,4ジヒドロイソキノリン-1(2H)-オン、イソキノリン-1(2H)-オン、4,5-ジヒドロ-イミダゾ[4,5,1-ij]キノリン-6-オン、1,6,-ナフチリジン-5(6H)-オン、4-アミノ-1,8-ナフタルイミドなどの1,8-ナフタルイミド、イソキノリノン、3,4-ジヒドロ-5-[4-1(1-ピペリジニル)ブトキシ]-1(2H)-イソキノリノン、2,3-ジヒドロベンゾ[デ]イソキノリン-1-オン、1-11b-ジヒドロ-[2H]ベンゾピラノ[4,3,2-デ]イソキノリン-3-オン、ならびにベンゾピラノ[4,3,2-デ]イソキノリノンなどのベンズピラノイソキノリノンをはじめとする四環式ラクタム、ならびにこれらの類似体および誘導体、
4.ベンズオキサゾール-4-カルボキサミド、2置換ベンズオキサゾール4-カルボキサミドなどのベンズイミダゾール-4-カルボキサミドおよび2-アリールベンズイミダゾール4-カルボキサミドなどの2置換ベンズイミダゾール4-カルボキサミドをはじめとするベンズイミダゾールおよびインドール、ならびに2-(4-ヒドロキシフェニルベンズイミダゾール4-カルボキサミドをはじめとする2-シクロアルキルベンズイミダゾール-4-カルボキサミド、キノキサリンカルボキサミド、イミダゾピリジンカルボキサミド、2-フェニルインドール、2-フェニルベンズオキサゾールおよび2-(3-メトキシフェニル)ベンズオキサゾールなどの2置換ベンズオキサゾール、2-フェニルベンズイミダゾールおよび2-(3-メトキシフェニル)ベンズイミダゾールなどの2置換ベンズイミダゾール、1,3,4,5テトラヒドロ-アゼピノ[5,4,3-cd]インドール-6-オン、1,5ジヒドロ-アゼピノ[4,5,6-cd]インドリン-6-オンおよびジヒドロジアザピノインドリノンなどのアゼピノインドールおよびアゼピノインドロン、3-(4-トリフルオロメチルフェニル)-ジヒドロジアザピノインドリノンなどの3置換ジヒドロジアザピノインドリノン、テトラヒドロジアザピノインドリノンおよび5,6,-ジヒドロイミダゾ[4,5,1-j,k][1,4]ベンゾジアゾピン-7(4H)-オン、2-フェニル-5,6-ジヒドロ-イミダゾ[4,5,1-jk][1,4]ベンゾジアゼピン-7(4H)-オンおよび2,3,ジヒドロ-イソインドール-1-オン、ならびにこれらの類似体および誘導体、
5.4-ヒドロキシキナゾリン、フタラジノン、5-メトキシ-4-メチル-1(2)フタラジノン、4置換フタラジノン、4-(1-ピペラジニル)-1(2H)-フタラジノン、四環式ベンゾピラノ[4,3,2-デ]フタラジノンおよび四環式インデノ[1,2,3-デ]フタラジノンなどのフタラジン-1(2H)-オンおよびキナゾリノン、ならびに8-ヒドロキシ-2-メチルキナゾリン-4-(3H)オンなどの2置換キナゾリン、三環式フタラジノンならびに2-アミノフタルヒドラジド、ならびにこれらの類似体および誘導体、
6.イソインドリノンならびにこの類似体および誘導体、
7.5[H]フェナントリジン-6-オン、置換5[H]フェナントリジン-6-オンなどのフェナントリジンおよびフェナントリジノン、特に2置換5[H]フェナントリジン-6-オン、3置換5[H]フェナントリジン-6-オン、ならびに6(5H)フェナントリジノンのスルホンアミド/カルバミド誘導体、9-アミノチエノ[2,3-c]イソキノロンおよび9-ヒドロキシチエノ[2,3-c]イソキノロンなどのチエノ[2,3-c]イソキノロン、9-メトキシチエノ[2,3-c]イソキノロン、ならびにN-(6-オキソ-5,6-ジヒドロフェナントリジン-2-イル]-2-(N,N-ジメチルアミノ}アセトアミド、置換4,9-ジヒドロシクロペンタ[lmn]フェナントリジン-5-オン、ならびにこれらに類似体および誘導体、
8.1,2-ベンゾピロン6-ニトロソベンゾピロン、6-ニトロソ1,2-ベンゾピロン、および5-ヨード-6-アミノベンゾピロンなどのベンゾピロン、ならびにこれらの類似体および誘導体、
9.O-(3-ピペリジノ-2-ヒドロキシ-1-プロピル)ニコチンアミドオキシムなどの不飽和ヒドロキシム酸誘導体、ならびにこれらの類似体および誘導体、
10.縮合ピリダジンをはじめとするピリダジン、ならびにこれらの類似体および誘導体、ならびに
11.カフェイン、テオフィリン、およびチミジンなどの他の化合物、ならびにこれらの類似体および誘導体。
好ましくは、処置投与計画としてのγδT細胞免疫療法とDDR阻害剤療法との組み合わせにはさらに、化学療法薬との組み合わせを含み、この場合、γδT細胞は、薬剤耐性免疫療法(DRI)として公知の化学療法薬に対する耐性を付与するように遺伝子改変されている。好ましくは、γδT細胞を化学療法薬の作用に対して耐性にするためのγδT細胞の遺伝子改変は、化学療法薬の存在下または非存在下での標的癌細胞を死滅させるγδT細胞の能力に影響を及ぼさない。γδT細胞は、例、ならびに国際公開第2011/053750号およびLamb et al.,PloS ONE 8(1):e51805.doi:10.1371/journal.pone.0051805)において説明されているものなど、標準的な組換え技術を用いて遺伝子改変される。
好ましくは、処置投与計画としてのγδT細胞DRIとDDR阻害剤との併用療法にはさらに、ICP阻害剤との組み合わせが含まれる。好ましくは、チェックポイント阻害剤は、PD-1阻害剤またはCTLA-4阻害剤である。好ましくは、免疫チェックポイント阻害剤は、生物学的治療薬または小分子であってよい。好ましくは、チェックポイント阻害剤は、モノクローナル抗体、ヒト化抗体、完全ヒト抗体、融合タンパク質、抗原結合断片またはこれらの組み合わせである。
好ましくは、本明細書に開示される併用療法は、例えば経口でまたは非経口でをはじめとするさまざまな経路によって患者に投与されてよく、静脈内、筋肉内、皮下、眼窩内、嚢内、腹腔内、直腸内、大槽内、腫瘍内、血管内、皮内、膣内(例えば、膣坐剤)、または局所的に(例えば、散剤、軟膏経皮パッチ)、または例えば、それぞれ皮膚パッチもしくは経皮イオン導入を使用する皮膚を通した受動的吸収もしくは促進された吸収を含むことができるが、これらに限定されない。
本明細書に説明する併用処置方法は、癌の処置に特に適している。癌細胞は、近くの組織に浸潤することができ、血流およびリンパ系を経て身体の他の部分に広がることができる。癌にはいくつかの主な種類があり、例えば、癌腫とは、内臓を裏打ちするかまたは覆う皮膚または組織において発生する癌である。肉腫とは、骨、軟骨、脂肪、筋肉、血管、または他の結合組織もしくは支持組織において発生する癌である。白血病とは、骨髄などの血液形成組織において発生し、多数の異常な血球が産生されて血流に入る癌である。リンパ腫とは、免疫系の細胞内で発生する癌である。
本明細書に説明される本発明の併用療法において使用される治療有効量の1つ以上の作用薬を典型的に含む医薬組成物を含むキットも提供される。キットは、典型的には、キットの内容物の意図する用途を示すラベルおよび使用説明書を含む。
次の例は例示として提供されるのであって、決して特許請求される本発明を制限するものと解釈されるべきではない。
化学療法薬、薬剤耐性γδ-T細胞、PARP-1阻害剤、および免疫チェックポイント阻害剤(複数可)を含む併用療法は、癌患者を処置するために使用される。卵巣癌の処置のために、ニラパリブ、オラパリブ、またはルカパリブがPARP阻害剤として使用される。膠芽腫の処置のために、オラパリブまたはニラパリブがPARP阻害剤として使用される。化学療法薬は、アルキル化薬(例えば、シクロホスファミド、イホスファミド)、代謝拮抗薬(例えば、メトトレキサート(MTX)、5-フルオロウラシルまたはその誘導体)、抗腫瘍抗生物質(例えば、マイトマイシン、アドリアマイシン)、植物由来の抗腫瘍薬(例えば、ビンクリスチン、ビンデシン、TAXOL(登録商標)、パクリタキセル、アブラキサン)、シスプラチン、カルボプラチン、エトポシドなどから選択される。このような作用薬にはさらに、抗癌薬トリメトトレキサート(TMTX)、テモゾロミド、ラルチトレキセド、S-(4-ニトロベンジル)-6-チオイノシン(NBMPR)、6-ベンジグアニジン(6-BG)、ビス-クロロニトロソ尿素(BCNU)、シタラビン、およびカンプトテシン、またはこれらのいずれかの治療用誘導体が含まれてよいが、それらに限定されない。薬剤耐性γδ-T細胞は、化学療法薬に対して耐性がある。免疫チェックポイント阻害剤は、単独でまたは他の免疫チェックポイント阻害剤と組み合わせて使用され、免疫チェックポイントタンパク質の阻害剤であるCTLA-4、PDL1(B7-H1、CD274)、PDL2(B7-DC、CD273)、PD1、B7-H3(CD276)、B7-H4(B7-S1、B7x、VCTN1)、BTLA(CD272)、HVEM、TIM3(HAVcr2)、GAL9、LAG3(CD223)、VISTA、KIR、2B4(CD244、CD2分子ファミリーに属し、NK細胞、γδ細胞、および記憶CD8+(αβ)T細胞の全てにおいて発現する)、CD160(BY55とも称される)、CGEN-15049、CHK1キナーゼおよびCHK2キナーゼ、OX40、A2aRならびにさまざまなB-7ファミリーリガンドから選択される。
応答評価基準には、固形腫瘍応答評価基準(WHO;世界保健機構オフセット公開第48号、1979年)、RECIST(固形腫瘍における応答評価基準、J Natl Cancer Inst 2000;92:205-16、Eisenhauer EA et al.,Eur J Cancer 2009;45:228-47)、免疫関連応答基準(Jedd WE et al.,Clin Cancer Res 2009;15(23),7412-7420)、およびiRANO(神経癌学における免疫療法応答評価)(Okada H et al.,Lancet Oncol 2015 Nov;16(15):e534-42)に基づく評価がある。
薬剤耐性γδ-T細胞(および/または薬剤耐性ナチュラルキラー細胞)と、PARP-1阻害剤と、免疫チェックポイントタンパク質の阻害剤(複数可)とを追加で含む併用療法としての化学療法は結果として、抗腫瘍応答の増強または長期化、;医学的に有益な応答、化学療法単独、または薬剤耐性γδ-T細胞(および/または薬剤耐性ナチュラルキラー細胞)と組み合わせた化学療法と比較したときの相加的または相乗的な抗腫瘍活性、新たな病変を伴わないベースライン病変の縮小、;腫瘍退縮、総腫瘍量の着実な減少の可能性を伴う永続的な安定した疾患、総腫瘍量の増加後の応答、および新たな病変の存在下での応答をもたらす。他の臨床所見には、腫瘍の大きさの増加によって測定される腫瘍浸潤リンパ球の増加、および長期生存促進が含まれることがある。
γδT細胞のエクスビボでの増殖
健常なドナーからのヒト分離交換産物の収集。静的培養の場合:全ての操作は、ISO-7に分類された無菌室環境に囲まれたISO-5層流フード内で行った。生成物をHBSS(Hankの平衡塩溶液)で体積/体積で希釈し、単核細胞をFicoll(Sigma-Aldrich、ミズーリ州セントルイス市)での密度勾配分離によって単離した。間期を収集し、HBSS中で2回洗浄した。細胞ペレットを、2mMのゾレドロン酸(Novartis、バーゼルHV)および100u/mLのIL2(Miltenyi Biotec Ltd、ドイツ国ベルギッシュ・グラートバッハ市)を補充したCTS(商標)OpTmizer(商標)T細胞増殖無血清培地(ThermoFisher Scientific、マサチューセッツ州ウォルサム市)中に再懸濁した。細胞を標準的なT150フラスコまたはT75フラスコ内で培養した。閉鎖系培養の場合:培地、原液および緩衝液の調製をはじめとする全ての操作を、GMP等級の試薬を使用してバイオセーフティキャビネットイオンおよびISO-t無菌室環境下でISO7無菌室内で行った。生成物の自動Ficoll分離および培養は、個別化された細胞加工プログラムおよびTS520細管セットを使用して、CLINIMACS PRODIGY(登録商標)(Miltenyi Biotec Ltd、ドイツ国ベルギッシュ・グラートバッハ市)バイオリアクタ内で行った。次いで、OpTmizer無血清培養(Thermo Fisher Scientific、マサチューセッツ州ウォルサム市)で、ゾレドロナート(Zometa;Novartis、バーゼル)とインターロイキン2(Miltenyi Biotec Ltd;ドイツ国ベルギッシュ・グラートバッハ市)(ZOL/IL-2)との組み合わせを使用して、CLINIMACS PRODIGY(登録商標)のCentriCult-Unit内で細胞を増殖させた。培養物を1~2×106個の細胞/mlの密度で維持し、13日目に細胞が収集されるまで、IL-2 100u/mLを1日おきに補充した。一定の間隔でフラスコ内での小規模培養と比較して、増殖および表現型の動態を決定するために、プロセスを連続的に監視した。9~14日間の培養後、増殖したγδT細胞を表現型分類し、細胞毒性を標準的な白血病細胞株および神経膠腫腫瘍細胞に対して決定した。
材料および方法
細胞収集方法/加工/培養条件:
処置投与計画を作成するための全体的な戦略を以下に概説する。目標は、新たに調製した細胞集団として投与される初回用量で患者を処置するのに必要なγδT細胞の総数を求めることとした。
培養物が対数増殖期、通常は>20%のγδT細胞に到達すると、MGMTレンチウイルス(Miltenyi Lentigen:メリーランド州ボルチモア市)を用いた細胞形質導入を行った。培養物を10×2のMOIでスピノキュレーションによって形質導入した。
PARPiに対するGBM+テモゾロミド(TMZ)の推定上の差次的感受性を測定するために、標準化GBM細胞株LN229、U87MGおよびU251MG細胞(96ウェルプレートのウェルあたり6000個の細胞、三つ組で播種)を、オラパリブ(5または10mM)単独、オラパリブ(例示的なPARP阻害剤)+200mg/mL TMZまたは培地単独(RPMI+10%FBS培地)に4時間曝露し、標準化MTT生存度アッセイと、懸濁液フローサイトメトリーアッセイにおける7-AADの組み込みとを用いて、開始時ならびに処置の8、16、24、および36時間後に測定される生存度を測定した。
図1~図3のデータは、PARP阻害剤とテモゾロミド(TMZ)との組み合わせが、3つの高度悪性神経膠腫細胞株上の選択されたナチュラルキラー基2D(NKG2D)リガンドを上方調節するために相乗的に作用することを示す。
Claims (45)
- 癌の処置を必要とする患者における癌の処置のための方法であって、
i)少なくとも1つの化学療法薬に対して耐性であるように遺伝子操作された治療有効量のγδT細胞を含む組成物を患者に投与することと、
ii)治療有効量の化学療法薬を患者に投与することと、
iii)治療有効量のDDR阻害剤を患者に投与することと、
を含む、方法。 - 前記DDR阻害剤がPARP阻害剤である、請求項1に記載の方法。
- 前記PARP阻害剤が、前記化学療法薬を投与する前、および前記遺伝子操作されたγδT細胞を含む組成物を投与する前に投与される、請求項2に記載の方法。
- 前記PARP阻害剤が、前記化学療法薬を投与する約1日~約21日前に投与される、請求項3に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記化学療法薬の投与の約8~約72時間後に投与される、請求項4に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記化学療法薬の投与の約12時間後~約36時間後に投与される、請求項4に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記化学療法薬の投与の約24時間後に投与される、請求項4に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記化学療法薬の投与の約8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、または36時間後に投与される、請求項4に記載の方法。
- 前記化学療法薬が、アルキル化薬、代謝拮抗薬、DNA脱メチル化薬、置換ヌクレオチド、置換ヌクレオシド、抗腫瘍抗生物質、植物由来の抗腫瘍薬またはニトロソ尿素である、請求項1に記載の方法。
- 前記化学療法薬が、シスプラチン、カルボプラチン、エトポシド、メトトレキサート(MTX)、トリメトトレキサート(TMTX)、テモゾロミド、ダカルバジン(DTIC)、ラルチトレキセド、S-(4-ニトロベンジル)-6-チオイノシン(NBMPR)、6-ベンジグアニジン(6-BG)、ニトロソ尿素(ラビノピラノシル-N-メチル-N-ニトロソ尿素(アラノース)、カルムスチン(BCNU、BiCNU)、クロロゾトシン、エチルニトロソ尿素(ENU)、ホテムスチン、ロムスチン(CCNU)、ニムスチン、N-ニトロソ-N-メチル尿素(NMU)、ラニムスチン(MCNU)、セムスチン、ストレプトゾシン(ストレプトゾトシン))、シタラビン、カンプトテシン、およびこれらのいずれかの治療用誘導体から選択される、請求項1に記載の方法。
- 前記γδT細胞が、アルキルグアニントランスフェラーゼ(AGT)、P140KMGMT、O6メチルグアニンDNAメチルトランスフェラーゼ(MGMT)、L22Y-DHFR、チミジル酸シンターゼ、ジヒドロ葉酸レダクターゼ、または多剤耐性1型タンパク質(MDR1)をコードするように遺伝子改変されている、請求項1に記載の方法。
- 前記γδT細胞が、アルキル化薬、代謝拮抗薬、DNA脱メチル化薬、置換ヌクレオチド、置換ヌクレオシド、抗腫瘍抗生物質、植物由来の抗腫瘍薬、およびニトロソ尿素から選択される少なくとも2つの化学療法薬に対して耐性となるように遺伝子改変されている、請求項1に記載の方法。
- 前記γδT細胞が、シスプラチン、カルボプラチン、エトポシド、メトトレキサート(MTX)、トリメトトレキサート(TMTX)、テモゾロミド、ダカルバジン(DTIC)、ラルチトレキセド、S-(4-ニトロベンジル)-6-チオイノシン(NBMPR)、6-ベンジグアニジン(6-BG)、ニトロソ尿素(ラビノピラノシル-N-メチル-N-ニトロソ尿素(アラノース)、カルムスチン(BCNU、BiCNU)、クロロゾトシン、エチルニトロソ尿素(ENU)、ホテムスチン、ロムスチン(CCNU)、ニムスチン、N-ニトロソ-N-メチル尿素(NMU)、ラニムスチン(MCNU)、セムスチン、ストレプトゾシン(ストレプトゾトシン))、シタラビン、カンプトテシン、およびこれらのいずれかの治療用誘導体から選択される少なくとも2つの化学療法薬に対して耐性となるよう遺伝子改変されている、請求項1に記載の方法。
- 前記化学療法薬が、TMZ、メトトレキサート、DTIC、BCNU、CCNU、MCNU、NMUまたはENUである、請求項1に記載の方法。
- 免疫チェックポイント阻害剤(ICP)を投与するステップをさらに含む、請求項1に記載の方法。
- 前記免疫チェックポイント阻害剤が、CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160(BY55とも称される)、CGEN-15049、CHK1キナーゼ、CHK2キナーゼ、A2aR、OX40、またはB-7ファミリーリガンドを標的とする、請求項15に記載の方法。
- 前記チェックポイント阻害剤が、PD-1、PDL1、PDL2またはCTLA-4を標的とする、請求項16に記載の方法。
- 前記癌が、中枢神経系(CNS)腫瘍、黒色腫、ぶどう膜黒色腫、神経内分泌腫瘍、副腎腫瘍、非ホジキンリンパ腫、軟部組織肉腫、骨癌、子宮肉腫、卵巣癌、小肺癌(SCLC)およびゾリンジャー・エリソン症候群から選択される、請求項1に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、約60%を超えるγδT細胞と、約5%未満のαβT細胞と、約25%未満のナチュラルキラー(NK)細胞と、を含む、請求項1に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記患者の体重1kg当たり約5×108個以下のγδT細胞、前記患者の体重1kg当たり約1×107個以下のγδT細胞、または前記患者の体重1kg当たり約5×106個以下のγδT細胞を含む、請求項1に記載の方法。
- 癌の処置を必要とする患者における癌を処置するための方法であって、
i)少なくとも1つの化学療法薬に対して耐性であるように遺伝子操作された治療有効量のγδT細胞を含む組成物を患者に投与することと、
ii)治療有効量の化学療法薬を患者に投与することと、
iii)治療有効量のDDR阻害剤を患者に投与することと、
を含む、方法であって、
前記DDR阻害剤が、PARP阻害剤であり、前記化学療法薬の投与の約1~21日前に投与され、遺伝子操作されたγδT細胞を含む組成物が、前記化学療法薬の投与の約8~約36時間後に投与される、方法。 - 前記遺伝子操作されたγδT細胞を含む組成物が、前記化学療法薬の投与の約8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29、30、31、32、33、34、35、または36時間後に投与される、請求項21に記載の方法。
- 前記化学療法薬が、アルキル化薬、代謝拮抗薬、DNA脱メチル化薬、置換ヌクレオチド、置換ヌクレオシド、抗腫瘍抗生物質、植物由来の抗腫瘍薬またはニトロソ尿素である、請求項21に記載の方法。
- 前記化学療法薬が、シスプラチン、カルボプラチン、エトポシド、メトトレキサート(MTX)、トリメトトレキサート(TMTX)、テモゾロミド、ダカルバジン(DTIC)、ラルチトレキセド、S-(4-ニトロベンジル)-6-チオイノシン(NBMPR)、6-ベンジグアニジン(6-BG)、ニトロソ尿素(ラビノピラノシル-N-メチル-N-ニトロソ尿素(アラノース)、カルムスチン(BCNU、BiCNU)、クロロゾトシン、エチルニトロソ尿素(ENU)、ホテムスチン、ロムスチン(CCNU)、ニムスチン、N-ニトロソ-N-メチル尿素(NMU)、ラニムスチン(MCNU)、セムスチン、ストレプトゾシン(ストレプトゾトシン))、シタラビン、カンプトテシン、およびこれらのいずれかの治療用誘導体から選択される、請求項21に記載の方法。
- 前記γδT細胞が、アルキルグアニントランスフェラーゼ(AGT)、P140KMGMT、O6メチルグアニンDNAメチルトランスフェラーゼ(MGMT)、L22Y-DHFR、チミジル酸シンターゼ、ジヒドロ葉酸レダクターゼ、または多剤耐性1型タンパク質(MDR1)をコードするように遺伝子改変されている、請求項21に記載の方法。
- 前記γδT細胞が、アルキル化薬、代謝拮抗薬、DNA脱メチル化薬、置換ヌクレオチド、置換ヌクレオシド、抗腫瘍抗生物質、植物由来の抗腫瘍薬、およびニトロソ尿素から選択される少なくとも2つの化学療法薬に対して耐性となるように遺伝子改変されている、請求項21に記載の方法。
- 前記γδT細胞が、シスプラチン、カルボプラチン、エトポシド、メトトレキサート(MTX)、トリメトトレキサート(TMTX)、テモゾロミド、ダカルバジン(DTIC)、ラルチトレキセド、S-(4-ニトロベンジル)-6-チオイノシン(NBMPR)、6-ベンジグアニジン(6-BG)、ニトロソ尿素(ラビノピラノシル-N-メチル-N-ニトロソ尿素(アラノース)、カルムスチン(BCNU、BiCNU)、クロロゾトシン、エチルニトロソ尿素(ENU)、ホテムスチン、ロムスチン(CCNU)、ニムスチン、N-ニトロソ-N-メチル尿素(NMU)、ラニムスチン(MCNU)、セムスチン、ストレプトゾシン(ストレプトゾトシン))、シタラビン、カンプトテシン、およびこれらのいずれかの治療用誘導体から選択される少なくとも2つの化学療法薬に対して耐性となるよう遺伝子改変されている、請求項21に記載の方法。
- 前記化学療法薬が、TMZ、メトトレキサート、DTIC、BCNU、CCNU、MCNU、NMUまたはENUである、請求項21に記載の方法。
- 免疫チェックポイント阻害剤(ICP)を投与するステップをさらに含む、請求項21に記載の方法。
- 前記免疫チェックポイント阻害剤が、CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160(BY55とも称される)、CGEN-15049、CHK1キナーゼ、CHK2キナーゼ、A2aR、OX40、またはB-7ファミリーリガンドを標的とする、請求項29に記載の方法。
- 前記チェックポイント阻害剤が、PD-1、PDL1、PDL2またはCTLA-4を標的とする、請求項30に記載の方法。
- 前記癌が、中枢神経系(CNS)腫瘍、黒色腫、ぶどう膜黒色腫、神経内分泌腫瘍、副腎腫瘍、非ホジキンリンパ腫、軟部組織肉腫、骨癌、子宮肉腫、卵巣癌、小肺癌(SCLC)およびゾリンジャー・エリソン症候群から選択される、請求項21に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、約60%を超えるγδT細胞と、約5%未満のαβT細胞と、約25%未満のナチュラルキラー(NK)細胞と、を含む、請求項21に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記患者の体重1kg当たり約5×108個以下のγδT細胞、前記患者の体重1kg当たり約1×107個以下のγδT細胞、または前記患者の体重1kg当たり約5×106個以下のγδT細胞を含む、請求項21に記載の方法。
- 癌の処置を必要とする患者における癌の処置のための方法であって、
i.場合により濃縮されたおよび/または場合により増殖されたγδT細胞集団を含む組成物を得ることと、
ii.場合により濃縮されたおよび/または場合により増殖されたγδT細胞集団を含む組成物を前記患者に投与することと、
iii.有効量の少なくとも1つのDNA損傷修復(DDR)阻害剤を前記患者に投与することと、
iv.有効量の化学療法薬を前記患者に投与することと、
を含む、方法。 - 前記DDR阻害剤がPARP阻害剤である、請求項35に記載の方法。
- 前記化学療法薬が、アルキル化薬、代謝拮抗薬、DNA脱メチル化薬、置換ヌクレオチド、置換ヌクレオシド、抗腫瘍抗生物質、植物由来の抗腫瘍薬およびニトロソ尿素から選択される、請求項35に記載の方法。
- 前記化学療法薬が、シスプラチン、カルボプラチン、エトポシド、メトトレキサート(MTX)、トリメトトレキサート(TMTX)、テモゾロミド、ダカルバジン(DTIC)、ラルチトレキセド、S-(4-ニトロベンジル)-6-チオイノシン(NBMPR)、6-ベンジグアニジン(6-BG)、ニトロソ尿素(ラビノピラノシル-N-メチル-N-ニトロソ尿素(アラノース)、カルムスチン(BCNU、BiCNU)、クロロゾトシン、エチルニトロソ尿素(ENU)、ホテムスチン、ロムスチン(CCNU)、ニムスチン、N-ニトロソ-N-メチル尿素(NMU)、ラニムスチン(MCNU)、セムスチン、ストレプトゾシン(ストレプトゾトシン))、シタラビン、カンプトテシン、およびこれらのいずれかの治療用誘導体から選択される、請求項35に記載の方法。
- 前記化学療法薬が、TMZ、メトトレキサート、DTIC、BCNU、CCNU、MCNU、NMUまたはENUである、請求項35に記載の方法。
- 免疫チェックポイント阻害剤(ICP)を投与するステップをさらに含む、請求項35に記載の方法。
- 前記免疫チェックポイント阻害剤が、CTLA-4、PDL1、PDL2、PD1、B7-H3、B7-H4、BTLA、HVEM、TIM3、GAL9、LAG3、VISTA、KIR、2B4、CD160(BY55とも称される)、CGEN-15049、CHK1キナーゼ、CHK2キナーゼ、A2aR、OX40、またはB-7ファミリーリガンドを標的とする、請求項40に記載の方法。
- 前記チェックポイント阻害剤が、PD-1、PDL1、PDL2またはCTLA-4を標的とする、請求項41に記載の方法。
- 前記癌が、中枢神経系(CNS)腫瘍、黒色腫、ぶどう膜黒色腫、神経内分泌腫瘍、副腎腫瘍、非ホジキンリンパ腫、軟部組織肉腫、骨癌、子宮肉腫、卵巣癌、小肺癌(SCLC)およびゾリンジャー・エリソン症候群から選択される、請求項35に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、約60%を超えるγδT細胞と、約5%未満のαβT細胞と、約25%未満のナチュラルキラー(NK)細胞と、を含む、請求項35に記載の方法。
- 前記遺伝子操作されたγδT細胞を含む組成物が、前記患者の体重1kg当たり約5×108個以下のγδT細胞、前記患者の体重1kg当たり約1×107個以下のγδT細胞、または前記患者の体重1kg当たり約5×106個以下のγδT細胞を含む、請求項35に記載の方法。
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