JP7061134B2 - 薬剤負荷ナノ粒子が表面に結合したcar t細胞の養子移入およびその使用 - Google Patents
薬剤負荷ナノ粒子が表面に結合したcar t細胞の養子移入およびその使用 Download PDFInfo
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Description
本出願は、その開示が全体として参照によって本明細書に組み入れられる2017年3月20日に出願された米国仮特許出願番号62/473,594に対する優先権及びその利益を主張する。
本発明は、国立衛生研究所によって授与された助成金番号AI068978及びEB017206のもとでの政府の支援によって行われた。政府は本発明にて特定の権利を有する。
本発明の種々の実施形態はがんを治療するための組成物及び方法を提供する。
本明細書における出版物はすべて、各個々の出版物または特許出願が具体的に且つ個々に参照によって組み入れられるように指示されたのと同程度に参照によって組み入れられる。以下の記載は本発明を理解するのに有用であってもよい情報を含む。それは、本明細書で提供されている情報のいずれかが従来技術である、もしくは現在請求されている本発明に関連する、または具体的にもしくは暗に参照されている出版物が従来技術であると見なすべきではない。
[本発明1001]
操作された免疫エフェクター細胞であって、
(a)免疫エフェクター細胞と、
(b)前記免疫エフェクター細胞の表面に化学的に結合された粒子とを含み、
前記免疫エフェクター細胞は1以上のキメラ抗原受容体(CAR)をコードするポリヌクレオチドを含有するかまたはCARを発現し、
前記粒子に、アデノシンA 2A 受容体(A2AR)の阻害剤が封入されている、
前記操作された免疫エフェクター細胞。
[本発明1002]
前記免疫エフェクター細胞が、NK細胞、T細胞、B細胞、腫瘍特異的Tリンパ球及び造血幹細胞の1種以上を含む、本発明1001の操作された免疫エフェクター細胞。
[本発明1003]
前記免疫エフェクター細胞が自己由来である、本発明1002の操作された免疫エフェクター細胞。
[本発明1004]
前記A2AR阻害剤が、SCH58261、カフェイン、SYN115、FSPTP、ZM241385、PBS-509、ST1535、ST4206、トザデナント、V81444、またはイストラデフィリンを含む、本発明1001の操作された免疫エフェクター細胞。
[本発明1005]
前記A2A受容体阻害剤がSCH58261である、本発明1004の操作された免疫エフェクター細胞。
[本発明1006]
前記粒子が、リポソームを含むナノ粒子もしくはマイクロ粒子である、または高分子粒子である、本発明1001の操作された免疫エフェクター細胞。
[本発明1007]
前記粒子が、架橋された多重膜リポソーム(cMLV)である、本発明1005の操作された免疫エフェクター細胞。
[本発明1008]
前記免疫エフェクター細胞がT細胞であり、前記粒子がcMLVであり、A2ARの前記阻害剤がSCH58261である、本発明1001の操作された免疫エフェクター細胞。
[本発明1009]
前記CARが標的とする抗原が、4-1BB、5T4、腺癌抗原、アルファ-フェトプロテイン、BAFF、B-リンパ腫細胞、C242抗原、CA-125、炭酸脱水酵素9(CA-IX)、C-MET、CCR4、CD152、CD19、CD20、CD200、CD22、CD221、CD23(IgE受容体)、CD28、CD30(TNFRSF8)、CD33、CD4、CD40、CD44v6、CD51、CD52、CD56、CD74、CD80、CEA、CNTO888、CTLA-4、DR5、EGFR、EpCAM、CD3、FAP、フィブロネクチンエキストラドメイン-B、葉酸受容体1、GD2、GD3ガングリオシド、糖タンパク質75、GPNMB、HER2/neu、HGF、ヒト散乱因子受容体キナーゼ、IGF-1受容体、IGF-I、IgG1、L1-CAM、IL-13、IL-6、インスリン様増殖因子I受容体、インテグリンα5β1、インテグリンαvβ3、MORAb-009、MS4A1、MUC1、ムチンCanAg、N-グリコリルノイラミン酸、NPC-1C、PDGF-Rα、PDL192、ホスファチジルセリン、前立腺癌細胞、RANKL、RON、ROR1、SCH900105、SDC1、SLAMF7、TAG-72、テネイシンC、TGFベータ2、TGF-β、TRAIL-R1、TRAIL-R2、腫瘍抗原CTAA16.88、VEGF-A、VEGFR-1、VEGFR2、ビメンチン、及びそれらの組み合わせのいずれか1以上である、本発明1001の操作された免疫エフェクター細胞。
[本発明1010]
がんを治療する、がんを抑制する、またはがんの重症度もしくは可能性を軽減することを必要とする対象においてがんを治療する、がんを抑制する、またはがんの重症度もしくは可能性を軽減するための方法であって、
治療上有効な量の操作された免疫エフェクター細胞を前記対象に投与することを含み、
各操作された免疫エフェクター細胞は
(a)免疫エフェクター細胞と
(b)前記免疫エフェクター細胞の表面に化学的に結合された粒子とを含み、
前記免疫エフェクター細胞は1以上のキメラ抗原受容体(CAR)をコードするポリヌクレオチドを含有するかまたはCARを発現し、
前記粒子に、アデノシンA 2A 受容体(A2AR)の阻害剤が封入される、前記方法。
[本発明1011]
疾患を治療する、疾患を抑制する、または疾患の重症度もしくは可能性を軽減することを必要とする対象において疾患を治療する、疾患を抑制する、または疾患の重症度もしくは可能性を軽減するための方法であって、
治療上有効な量の操作された免疫エフェクター細胞を前記対象に投与することを含み、
各操作された免疫エフェクター細胞は
(a)免疫エフェクター細胞と
(b)前記免疫エフェクター細胞の表面に結合された、架橋された多重膜リポソーム(cMLV)とを含み、
前記免疫エフェクター細胞は1以上のCARをコードするポリヌクレオチドを含有するかまたはCARを発現し、
前記cMLVに、アデノシンA 2A 受容体の阻害剤が封入される、前記方法。
[本発明1012]
前記免疫エフェクター細胞が、NK細胞、T細胞、B細胞、腫瘍特異的Tリンパ球及び造血幹細胞の1種以上を含む、本発明1011の方法。
[本発明1013]
前記免疫エフェクター細胞がT細胞であり、前記粒子がcMLVであり、A2ARの前記阻害剤がSCH58261である、本発明1012の方法。
[本発明1014]
前記A2A受容体阻害剤が、SCH58261、カフェイン、SYN115、FSPTP、ZM241385、PBS-509、ST1535、ST4206、トザデナント、V81444、またはイストラデフィリンを含む、本発明1011の方法。
[本発明1015]
前記A2A受容体阻害剤がSCH58261である、本発明1011の方法。
[本発明1016]
前記疾患が、がんである、本発明1011の方法。
[本発明1017]
前記方法が、化学療法、放射線療法及びそれらの組み合わせから成る群から選択される既存の治療法を前記対象に施すことをさらに含む、本発明1011の方法。
[本発明1018]
前記既存の治療法が、前記操作された免疫エフェクター細胞と逐次的にまたは同時に施される、本発明1011の方法。
[本発明1019]
前記CARが標的とする抗原が、4-1BB、5T4、腺癌抗原、アルファ-フェトプロテイン、BAFF、B-リンパ腫細胞、C242抗原、CA-125、炭酸脱水酵素9(CA-IX)、C-MET、CCR4、CD152、CD19、CD20、CD200、CD22、CD221、CD23(IgE受容体)、CD28、CD30(TNFRSF8)、CD33、CD4、CD40、CD44v6、CD51、CD52、CD56、CD74、CD80、CEA、CNTO888、CTLA-4、DR5、EGFR、EpCAM、CD3、FAP、フィブロネクチンエキストラドメイン-B、葉酸受容体1、GD2、GD3ガングリオシド、糖タンパク質75、GPNMB、HER2/neu、HGF、ヒト散乱因子受容体キナーゼ、IGF-1受容体、IGF-I、IgG1、L1-CAM、IL-13、IL-6、インスリン様増殖因子I受容体、インテグリンα5β1、インテグリンαvβ3、MORAb-009、MS4A1、MUC1、ムチンCanAg、N-グリコリルノイラミン酸、NPC-1C、PDGF-Rα、PDL192、ホスファチジルセリン、前立腺癌細胞、RANKL、RON、ROR1、SCH900105、SDC1、SLAMF7、TAG-72、テネイシンC、TGFベータ2、TGF-β、TRAIL-R1、TRAIL-R2、腫瘍抗原CTAA16.88、VEGF-A、VEGFR-1、VEGFR2、ビメンチン、及びそれらの組み合わせのいずれか1以上である、本発明1011の方法。
[本発明1020]
前記対象が、前から存在する腫瘍浸潤リンパ球(TIL)を有するか、または以前にCAR-T細胞療法を受けたことがある、本発明1016の方法。
本明細書で引用されている参考文献はすべて、まるで完全に示されているかのように全体として参照によって組み入れられる。特に定義されない限り、本明細書で使用されている専門用語及び科学用語は本発明が属する当該技術の当業者によって一般に理解されるものと同じ意味を有する。Allen,et al.,Remington:The Science and Practice of Pharmacy 22nd ed.,Pharmaceutical Press,(September,15,2012);Hornyak,et al.,Introduction to Nanoscience and Nanotechnology,CRC Press,(2008);Singleton及びSainsbury,Dictionary of Microbiology and Molecular Biology 3rd ed.,revised ed.,J.Wiley & Sons,(New York,NY,2006);Smith,March’s Advanced Organic Chemistry Reactions,Mechanisms and Structure 7th ed.,J.Wiley & Sons,(New York,NY,2013);Singleton,Dictionary of DNA and Genome Technology 3rd ed.,Wiley-Blackwell,(November,28,2012);ならびにGreen and Sambrook,Molecular Cloning:A Laboratory Manual 4th ed.,Cold Spring Harbor Laboratory Press,
(Cold Spring Harbor,NY,2012)は当業者に本出願で使用されている用語の多くに対する一般的な指針を提供する。抗体を調製する方法に関する参考文献については、Greenfield,Antibodies A Laboratory Manual 2nd ed.,Cold Spring Harbor Press,(Cold Spring Harbor,NY,2013);Kohler及びMilstein,Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion,Eur.J.Immunol.1976,Jul,6(7):511-9;Queen及びSelick,Humanized immunoglobulins,U.S.Patent No.5,585,089 (1996 Dec);ならびにRiechmann et al., Reshaping human antibodies for therapy,Nature,1988,Mar.24,332(6162):323-7を参照のこと。
種々の実施形態では、本発明は医薬組成物を提供する。医薬組成物はA2A受容体阻害剤を封入している架橋された多重膜リポソーム(CMLV)を含む免疫エフェクター細胞を含む。一部の実施形態では、免疫エフェクター細胞には、NK細胞、T細胞(CARを発現しているT細胞を含む)、腫瘍特異的Tリンパ球、及び/または造血幹細胞が挙げられる。一部の実施形態では、A2A受容体阻害剤はSCH58261、カフェインまたはZM241385である。
実験方法
材料
ヒト卵巣癌細胞株SKOV3及びヒト骨髄性白血病細胞株K562はATCCから入手し、10%の熱非働化FBSを伴ったRPMI-1640で維持した。CD19+K562細胞及びCD19+SKOV3細胞は親のK562細胞及びSKOV3細胞にFUW-CD19レンチウイルスで形質導入し、蛍光活性化細胞選別(FACS)によってCD19+細胞を選別することによって生成した。SCH58261はSigma-Aldrich(St.Louis,MO)から購入した。脂質:1,2-ジオレオイル-sn-グリセロ-3-ホスホコリン(DOPC)、1,2-ジオレオイル-sn-グリセロ-3-ホスホ-(10-rac-グリセロール)(DOPG)及び1,2-ジオレオイル-sn-グリセロ-3-ホスホエタノールアミン-N-[4-(p-マレイミドフェニル)ブタ-イラミド(マレイミド-頭基脂質、MPB-PE)はすべてNOF Corporation(日本)から購入した。
FUWレンチウイルスベクターを構築してHAタグ付き抗CD19第2世代CARタンパク質を発現させた。抗CD19単鎖可変断片(scFv)の配列はCarl June(特許番号US2013/0287748A1,2013)によって開発された。ヒトCD8ヒンジ領域(aa138~184)がその後に続くこの配列をコドンで最適化し、IDT DNAによって構築した。PCRを用いて、抗CD19/CD8ヒンジの遺伝子ブロックをヒトCD28の膜貫通ドメイン及び細胞内ドメイン(aa153~220)及びヒトCD3ζの細胞内ドメイン(aa52~164)と組み合わせた。HAタグを抗CD19scFv(配列:tacccatacgatgttccagattacgct)の上流に挿入し、CARを発現する細胞の標識を可能にした。コザック配列及びヒトCD8リーダー配列もCAR構築物の上流に挿入した。レンチウイルスベクターを作るために、Gibsonアセンブリを用いて、この配列をレンチウイルスプラスミドFUWにおけるヒトユビキチン-Cプロモーターの下流に挿入した。
標準のリン酸カルシウム沈殿法を用いて293T細胞に一時的に形質移入することによってレンチウイルスベクターを作製した。293T細胞を15cmのプレートに播き、14~18時間後、80~90%の集密度に達したらすぐに形質移入した。形質移入については、40μgのFUW-CARプラスミドをパッケージングプラスミドpMDLg/pRRE及びpRSV-RevならびにpVSVgエンベローププラスミドのそれぞれ20μgと組み合わせた。細胞の形質移入の4時間後、培地を取り除き、細胞をPBSで洗浄し、新しい培地を加えた。形質移入の48時間後、ウイルス上清を回収した。
健常ドナーに由来する解凍した末梢血単核細胞(PBMC)を、X-vivo15無血清培地(Lonza)と5%(vol/vol)のGemCellヒト血清抗体AB(Gemini bio-products、West Sacramento CA)と1%(vol/vol)のGlutamax-100x(Gibco Life Technologies)と10mMのHEPES緩衝液(Corning)と1%(vol/vol)のペニシリン/ストレプトマイシン(Corning)と12.25mMのN-アセチル-L-システイン(Sigma)とを含有するT細胞培地(TCM)で培養した。培養物に10ng/mLのヒトIL-2を補完した。10e+6個の細胞/mLの密度にてDynabeads CD3/CD28ビーズT細胞エキスパンダー(細胞当たり3個のビーズ;Invitrogen)を用いてPBMCを活性化し、活性化の2日後、レンチウイルスで形質導入した。生体外増殖の間、培養培地を補給し、T細胞の密度は0.5~1×106個/mLの間で維持した。形質導入した細胞を増やし、活性化後13日目に回収した。
HAタグ付きCD19scFv-28-ζ CAR-T細胞をPBSで洗浄し、ウサギ抗HAとその後、CAR検出のためのAlex647を結合した抗ウサギ抗体で染色した。レトロウイルスで形質導入した細胞をtEGFR検出のためのAPCを結合した抗ヒトEGFRで染色した。MACS Quantフローサイトメトリーアナライザー(Miltenyi Biotec,Inc.,San Diego,CA)を用いて受容体の発現を解析した。
リポソームは、Joo,et al(2013)で報告された従来の脱水・再水和法に基づいて調製した。SCH-58261をcMLVに封入するために、有機溶媒中の1mgのSCHを脂質混合物と混合して乾燥させた脂質薄膜を形成した。DiD脂溶性色素でリポソーム粒子を標識するために、0.01:1(DiD:脂質)の比でDiD色素をクロロホルムにおける脂質混合物に加えた。架橋した多重膜リポソームはクロロホルム中に混合した1.5マイクロモルの脂質DOPC:DOPG:MPE-PE=40:10:50から調製し、アルゴン気体のもとで蒸発させた後、真空下で一晩乾燥させて乾燥脂質膜を形成した。脂質膜はpH7.0での10mMのBis-Trisプロパンに再水和した。SCH58261の有無にかかわらず、10分毎での1時間の激しいボルテックス撹拌を介して脂質を混合した後、それらは4サイクルの15秒間の超音波処理(Misonix Microson XL2000,Farmingdale,NY)を受け、各サイクルの後1分間間隔で氷上にて静置した。最終濃度10mMのMgCl2を加えて二価誘発性の小胞融合を誘導した。多重膜小胞の架橋(cMLV)は37℃にて1時間1.5mMの最終濃度でジチオスレイトール(DTT、Sigma-Aldrich)を加えることによって行った。架橋された多重膜小胞は14,000gでの4分間の遠心分離によって回収し、PBSで2回洗浄した。小胞の多重膜構造の形態的分析を行い、以前の研究での低温電子顕微鏡によって確認した。cMLVの流体力学的サイズは動的光散乱(Wyatt Technology,Santa Barbara,CA)によって測定した。粒子は濾過水に浮遊させ、ボルテックス撹拌し、分析に先立って超音波処理した。放出動態と同様に小分子負荷の効率に関する詳細な情報は補足方法に含まれる。
ナノ粒子の細胞への化学結合はStephan et al(2010)で提供された方法に基づいて行った。発明者らは、無血清X-vivo15培地(Lonza)に10×106個の細胞/mLを再浮遊させた。次いで、ナノ粒子のT細胞に対する様々な結合比でヌクレアーゼを含まない水に等体積のナノ粒子を再浮遊させ、37℃でインキュベートした。10分毎に合計30分間、細胞及びナノ粒子を混合した。未結合のナノ粒子を細胞から離すためのPBS洗浄の後、我々は1mL当たり10×106個の細胞をTCM中で1mg/mLのチオール末端の2kDaのPEGと共に37℃で30分間インキュベートして細胞に結合した粒子上で残りのマレイミド基の反応を止めた。発明者らは2回のPBS洗浄を行って未結合のPEGを除いた。
改変型の細胞傷害性アッセイを以前記載されたKochenderfer,et al(2009)のように行った。SKOV3細胞及びK562細胞(非標的)を1.5×106個/mLの濃度でTCMに浮遊させ、5μMの濃度での蛍光色素5-(及び-6)-(((4-クロロメチル)ベンゾイル)アミノ)テトラメチルローダミン(CMTMR)(Invitrogen)で染色した。細胞を混合し、37℃で30分間インキュベートした。細胞を洗浄し、TCMに再浮遊させ、37℃で60分間インキュベートした。次いで、細胞を2回洗浄し、TCMに再浮遊させた。標的細胞(SKOV3-CD19+細胞及びK562-CD19+細胞)を1×106個/mLでPBS+0.1%BSAに浮遊させ、1μMの濃度でのカルボキシフルオレセインジアセテートスクシンイミドエステル(CFSE)(Invitrogen)で染色した。細胞を37℃で10分間インキュベートし、RTにて細胞浮遊液の容量と同じ容量のFBSを2分間加えることによって標識反応を止めた。細胞を洗浄し、TCMに再浮遊させた。
直径24mmで3μmの孔サイズのトランスウェルプレート(Costar)でT細胞遊走アッセイを行った。cMLVを結合した及び未結合のCAR T細胞(0.5×106個/ウェル)を上側ウェルに入れ、TCMを下側ウェルに加えた。T細胞の化学誘引物質CXCL-9(0.1mg/mL、Preprotech)を下側ウェルに加えた。37℃で6時間インキュベートした後、下側チャンバーに移動したT細胞を数えた。
上記に記載されているように、SKOV3.CD19腫瘍をNSGマウスに移植した。腫瘍が生着した後、マウスを各処置群に無作為に割り当てた。腫瘍増殖を、測径器を用いて測定し、式(幅2×長さ)/2を用いて算出した。各群から3匹のマウスを処置後2日目及び14日目に屠殺した。さらなる生体外分析のために各マウスから腫瘍及び脾臓を摘出した。
上記に記載されているように、SKOV3.CD19腫瘍をNSGマウスに移植した。腫瘍が生着した後、マウスすべてに3×106個のCART.tEGFR細胞を注射した。最初の養子CAR T細胞移入の10日後、マウスは無作為に割り当てられ、以下の処置:(1)PBS;(2)CAR-T細胞;(3)空のcMLVsに結合されたCAR-T細胞(CART.cMLV);(4)CAR-T細胞とcMLV(SCH)との混合物(CART+cMLV(SCH));及び(5)SCHを負荷したcMLVsに結合されたCAR-T細胞(CART.cMLV(SCH))を受けた。各マウスに2.5×106個のCAR陽性T細胞を注射した。未結合のcMLVで処置したマウスについては、109の薬剤負荷cMLVをCAR-T細胞と共に同時注入した。2回目の養子T細胞移入の48時間後、マウスを屠殺した。生体外アッセイのために脾臓及び腫瘍を摘出した。
3つの分析:(1)抗CD3/抗CD28が誘導する細胞内IFN-γサイトカイン染色、(2)ホスホ-CREB及び(3)CAR-T細胞におけるKi-67の発現を行った。細胞内IFN-γ染色については、合計0.5×106個の細胞をヒトCD3/CD28抗体及び10ng/mLのブレフェルジンAで刺激した。96穴丸底プレートにおいて培養物を37℃で6時間インキュベートした。蛍光色素分子を結合したヒトCD3、CD45、CD4及びCD8の抗体を免疫染色に使用した。Cytofix/Cytoperm溶液(BD Bioscience)を用いて細胞膜を透過化し、製造元の指示書に従って細胞内染色を行った。
生体内でのナノ粒子の生体分布試験については、異種移植腫瘍モデルを使用した。腫瘍を生着させるために、PBS溶液中のSKOV3.CD19細胞をNOD/scid/IL2Rγ-/-(NSG)マウスの脇腹に皮下注射した。DiD標識したcMLVs(cMLV)、DiD標識したcMLVと混合したCD19CART細胞(5×106)(CART+cMLV)、DiD標識したcMLVsと表面結合したCD19CAR-T細胞(5×106)(CART.cMLV)、またはPBSを担癌マウスに静脈内注射した。24及び48時間後、示した組織を取り出し、秤量し、ハサミでくずした。Xenogen IVISスペクトル画像化システムを用い、群について盲検化されたUSC Imaging Coreの科学者によってDiD特異的な組織蛍光(Abs644nm、Em665nm)が各臓器について定量され、組織1グラム当たりの注射した用量の比率(%ID/g)が算出された。
上記に記載されているように、SKOV3.CD19腫瘍をNSGマウスに移植した。CFSE標識したCAR-T細胞及びDiD標識したcMLVを担癌マウスに注射した。示した時間に、腫瘍を摘出し、固定し、凍結し、凍結切片を作製し、ガラススライド上で標本にした。Zeiss 700共焦点レーザー走査顕微鏡(倒立)(Carl Zeiss,Germany)を用いてCFSE標識したCAR-T細胞及びDiD標識したcMLVを可視化した。Zeiss Zen顕微鏡ソフトウェアを用いて定量分析を行った。
高速液体クロマトグラフィー(HPLC)を用いて、以前詳述された(35)ように、凍結腫瘍組織においてPTXの濃度を定量した。手短には、解凍した腫瘍組織を酢酸エチルにホモジネートし、既知の濃度の対照薬剤を内部標準として各試料に加えた。試料を遠心分離し、有機層をきれいな試験管に移した。有機層をアルゴンの流れのもとで蒸発させ、希釈したアセトニトリルで再水和した。試料をHPLCにかけた後、ピークの高さを解析して腫瘍内のSCH濃度を決定した。
2群間の差異はスチューデントのt検定で判定した。3以上の群間での差異は一元配置分散分析(ANOVA)で判定した。
cMLV(SCH)に封入されたSCHの量はC-18RP-HPLCクロマトグラフィー(Backman)によって決定した。0.5mLの合計容量まで水及びアセトニトリルを加えることによってcMLV(SCH)の浮遊液を希釈した。SCHの抽出は、5mLのtert-ブチルメチルエーテルを加え、試料を1分間ボルテックスで混合することによって達成した。次いで、混合物を遠心分離し、有機層をガラス試験管に移し、アルゴンのもとで乾燥するまで蒸発させた。緩衝液A(95%水、5%アセトニトリル)を用いて乾燥した有機層を再水和した。SCHの濃度を決定するために、1mLの溶液をC18カラムに注入し、392nmでSCHを検出した(流速:1mL/分)。10%ウシ胎児血清(FBS)を含有する培地で37℃にてインキュベートされたcMLVから放出培地を取り出し、毎日新鮮な培地で置き換えることによってcMLVからのSCHの放出動態を検討した。取り出した培地は毎日、(HPLCによって)SCHの蛍光について定量した。細胞への結合の前及び後でのcMLVからのSCHの放出動態を得るために、cMLV(SCH)及びCART.cMLV(SCH)を10%FBS含有の培地おいて37℃でインキュベートし、毎日遠沈し、新鮮な培地で再浮遊させた。回収した培地から毎日HPLCによってSCHを定量した。
細胞表面への安定なナノ粒子の連結
CAR操作したT細胞療法の有効性を改善するために、発明者らはTMEにおける免疫抑制性のメカニズムを阻害することができる薬剤であるSCH-58261を負荷したナノ粒子を運ぶシャペロンとしてCAR-T細胞を使用した。T細胞上でCARを発現させるために、活性化したヒトPBMCにレンチウイルスで形質導入し、CD28及びCD3ζの細胞内シグナル伝達ドメインから成る抗CD19 CARを作り出した。表面CAR発現のFACS解析は50%の形質導入効率を示した(図9)。
発明者らは次に表面に結合したcMLVが、たとえば、細胞のサイトカイン分泌、細胞傷害性、及び移動のようなCAR-T細胞の重要な細胞性の機能に影響を与え得るかどうかを調べようとした。cMLV結合を有するまたは有さないCART細胞をSKOV3.CD19またはK562.CD19標的細胞と共に4時間共培養した。SKOV3.CD19標的細胞で刺激したCART及びCART.cMLVがそれぞれ17.05±0.07%及び19.15±1.63%のIFN-γ+のT細胞集団を誘導したということは、CART及びCART.cMLVの双方が類似の効率でIFN-γを分泌することができたことを示している(図2A及び2B)。cMLVをDiD色素で標識した場合、IFN-γは表面結合したcMLVの有無にかかわらず双方の細胞から分泌された(図10)。さらに、cMLVの表面結合はSKOV3.CD19細胞(図2D)またはK562.CD19細胞(図2C)に対するCAR-T細胞の細胞傷害性を低下させなかった。最後に、発明者らは試験管内でのCAR-T細胞の遊走の能力を評価した。同等の比率の結合した細胞及び未結合の細胞がトランスウェル共培養系の下側チャンバーに移動したということは、CART.cMLV細胞がその遊走の能力を維持していることを示している(図2E、2F)。したがって、cMLVの細胞表面結合は標的細胞の認識、IFN-γの分泌、細胞の細胞傷害性、または移動を妨害しない。
cMLVのCAR T細胞への結合がナノ粒子の腫瘍部位での蓄積を改善し得るかどうかを判定するために、発明者らは、DiD色素を含有するcMLVを合成することによって生体分布アッセイを行った。DiDで標識したcMLVのみ(cMLV(DiD))、CAR-T細胞と混合したDiDで標識したcMLV(CART+cMLV(DiD))、またはCAR-T細胞に結合したDiDで標識したcMLV(CART.cMLV(DiD))をSKOV3.CD19腫瘍のNSG担癌マウスに静脈内注射し、DiDでタグをつけたcMLVの蓄積を様々な臓器でモニターした。24時間で、腫瘍(p<0.001)、脾臓(p<0.001)、リンパ節(p<0.01)及び肺(p<0.01)においてcMLV群及びCART+cMLV群と比べてCART.cMLV(DiD)群から有意に高いcMLVの蓄積が検出された。いずれの組織においてもcMLV(DiD)群とCART+cMLV(DiD)群との間ではcMLVの蓄積に有意差は指摘されなかった。さらに、任意の群における循環血では24時間でDiDのシグナルに有意差は検出されなかった(図3A)。48時間では、cMLV(DiD)群及びCART+cMLV(DiD)群の双方と比べてCART.cMLV(DiD)は血液(p<0.05)、腫瘍(p<0.05)、脾臓(p<0.05)及び肺(p<0.05)において高いcMLVの蓄積を明らかにした(図3B)。特に、cMLVへのCAR-T細胞の結合は、24時間(p<0.05)及び48時間(p<0.001)でcMLV(DiD)群及びCART+cMLV(DiD)群の双方と比べて肝臓において有意に低いcMLVの蓄積を生じた。
発明者らは次に、cMLVを結合したまたは未結合の蛍光で標識したCAR-T細胞で処置したSKOV3.CD19腫瘍の組織切片の共焦点画像化によって、キャリアCAR-T細胞の腫瘍浸潤特性を評価した。代表的な共焦点画像は、cMLVの表面結合は腫瘍内CAR-T細胞の移動を妨げないことを実証している。CART.cMLV及びCART+cMLVの双方がT細胞の同等の浸潤を有した(図4A、4B)。CART.cMLV及びCART+cMLVで処置した腫瘍におけるCAR-T細胞の密度はそれぞれ0.26±0.1個/mm2及び0.35±0.2個/mm2だった。しかしながら、CAR-T細胞とcMLVの共局在化はCART.cMLVで処置した腫瘍の内部でしか観察されなかった。CART+cMLVで処置した腫瘍で検出できなかったことと比べてCART.cMLVで処置した腫瘍では共局在化の比率は78.57±26.7%だった(図4C、4D)。これらの結果は、CAR-T細胞へのcMLVの結合がT細胞の移動を妨害することなく腫瘍に送達されるcMLVの量を増やすことができることを示している。
A2a受容体(A2aR)の薬理学的な阻害が、アデノシンの豊富なTMEにおいてCAR-T細胞の機能低下を防ぐかどうかを調べるために、発明者らは、生体内での腫瘍増殖及びT細胞増殖をモニターした。SKOV3.CD19担癌マウスを図5Aで示すように6つの異なる群に割り当てた。処置群すべてにおいて動物は腫瘍の進行を示した。CART、CART.cMLV、CART+cMLV(SCH)及びCART.cMLV(SCH)の処置群は、PBS処置群と比べると、ACT後の2日目から17日目までで統計的に有意な腫瘍の増殖制御を示した(図5B及び表2)。他の処置群に比べて、CART.cMLV(SCH)処置は、ACTの後、調べたすべての日について有意に小さな腫瘍を生じる最も際立った腫瘍増殖の抑制を実証した(図5B)。その結果、CART.cMLV(SCH)処置はCART(p<0.0001、ログ・ランク検定)、CART.cMLV(p<0.0001、ログ・ランク検定)、及びCART+cMLV(SCH)(p=0.0008、ログ・ランク検定)の処置群と比べてマウスの生存率を顕著に改善した。CART、CART.cMLV、CART+cMLV(SCH)及びCART.cMLV(SCH)はそれぞれ処置後、22、22、24及び36日の生存期間の中央値を有した(図5C)。PBS及びcMLVの処置は22日の生存期間の中央値を有した。CART.cMLV(SCH)処置のみが、PBS群及びcMLV群と比べて生存期間の中央値を有意に改善した(PBSについてはp=0.0003及びcMLVについてはp=0.0002、ログ・ランク検定)。
腫瘍に浸潤したCAR-T細胞は腫瘍塊に移動することはできるが、それらはアデノシンが豊富な腫瘍微小環境に入った後、腫瘍殺傷能力及び炎症性サイトカイン分泌能力を徐々に失う傾向がある。発明者らは、腫瘍に存在する機能低下したT細胞がSCHによるA2aRシグナル伝達の遮断の状態で、そのエフェクター機能を取り戻し得るという仮説を立てた。本出願における発明者らの結合システムの潜在力を実証するために、発明者らは、切断型表皮増殖因子受容体(tEGFR)を発現しているCD19CAR-T細胞の担癌マウスへの最初の静脈内注入によって、TMEにおいて腫瘍に存在する機能低下したCAR-T細胞を伴う生体内モデルを確立した(図11A);これらのCAR-T細胞をCART.tEGFRと名付ける。EGFR表面マーカーを用いて腫瘍に存在する機能低下したCAR-T細胞の当初の集団を追跡し、EGFRを欠く表面操作したCAR-T細胞のその後の処置投与からそれらを区別できるようにした。当初のCART.tEGFR細胞移入の10日後、5つの異なる群において救済処置がマウスに注入された(図6A)。
Claims (22)
- 操作された免疫エフェクター細胞であって、
(a)免疫エフェクター細胞と、
(b)前記免疫エフェクター細胞の表面に化学的に結合された粒子とを含み、
前記免疫エフェクター細胞は1以上のキメラ抗原受容体(CAR)をコードするポリヌクレオチドを含有するかまたはCARを発現し、
前記粒子に、アデノシンA2A受容体(A2AR)の阻害剤が封入されている、
前記操作された免疫エフェクター細胞。 - 前記免疫エフェクター細胞が、NK細胞、T細胞、B細胞、腫瘍特異的Tリンパ球及び造血幹細胞の1種以上を含む、請求項1に記載の操作された免疫エフェクター細胞。
- 前記免疫エフェクター細胞が自己由来である、請求項2に記載の操作された免疫エフェクター細胞。
- 前記A2AR阻害剤が、SCH58261、カフェイン、SYN115、FSPTP、ZM241385、PBS-509、ST1535、ST4206、トザデナント、V81444、またはイストラデフィリンを含む、請求項1~3のいずれか一項に記載の操作された免疫エフェクター細胞。
- 前記A2A受容体阻害剤がSCH58261である、請求項4に記載の操作された免疫エフェクター細胞。
- 前記粒子が、リポソームを含むナノ粒子もしくはマイクロ粒子である、または高分子粒子である、請求項1~5のいずれか一項に記載の操作された免疫エフェクター細胞。
- 前記粒子が、架橋された多重膜リポソーム(cMLV)である、請求項5に記載の操作された免疫エフェクター細胞。
- 前記免疫エフェクター細胞がT細胞であり、前記粒子がcMLVであり、A2ARの前記阻害剤がSCH58261である、請求項1に記載の操作された免疫エフェクター細胞。
- 前記CARが標的とする抗原が、4-1BB、5T4、腺癌抗原、アルファ-フェトプロテイン、BAFF、B-リンパ腫細胞、C242抗原、CA-125、炭酸脱水酵素9(CA-IX)、C-MET、CCR4、CD152、CD19、CD20、CD200、CD22、CD221、CD23(IgE受容体)、CD28、CD30(TNFRSF8)、CD33、CD4、CD40、CD44v6、CD51、CD52、CD56、CD74、CD80、CEA、CNTO888、CTLA-4、DR5、EGFR、EpCAM、CD3、FAP、フィブロネクチンエキストラドメイン-B、葉酸受容体1、GD2、GD3ガングリオシド、糖タンパク質75、GPNMB、HER2/neu、HGF、ヒト散乱因子受容体キナーゼ、IGF-1受容体、IGF-I、IgG1、L1-CAM、IL-13、IL-6、インスリン様増殖因子I受容体、インテグリンα5β1、インテグリンαvβ3、MORAb-009、MS4A1、MUC1、ムチンCanAg、N-グリコリルノイラミン酸、NPC-1C、PDGF-Rα、PDL192、ホスファチジルセリン、前立腺癌細胞、RANKL、RON、ROR1、SCH900105、SDC1、SLAMF7、TAG-72、テネイシンC、TGFベータ2、TGF-β、TRAIL-R1、TRAIL-R2、腫瘍抗原CTAA16.88、VEGF-A、VEGFR-1、VEGFR2、ビメンチン、及びそれらの組み合わせの1以上を含む、請求項1~8のいずれか一項に記載の操作された免疫エフェクター細胞。
- 操作された免疫エフェクター細胞を含む、がんを治療する、がんを抑制する、またはがんの重症度もしくは可能性を軽減するための医薬であって、
各操作された免疫エフェクター細胞は
(a)免疫エフェクター細胞と
(b)前記免疫エフェクター細胞の表面に化学的に結合された粒子とを含み、
前記免疫エフェクター細胞は1以上のキメラ抗原受容体(CAR)をコードするポリヌクレオチドを含有するかまたはCARを発現しており、
前記粒子に、アデノシンA2A受容体(A2AR)の阻害剤が封入されている、
前記医薬。 - 操作された免疫エフェクター細胞を含む、対象において疾患を治療する、疾患を抑制する、または疾患の重症度もしくは可能性を軽減するための医薬であって、
各操作された免疫エフェクター細胞は
(a)免疫エフェクター細胞と
(b)前記免疫エフェクター細胞の表面に結合された、架橋された多重膜リポソーム(cMLV)とを含み、
前記免疫エフェクター細胞は1以上のCARをコードするポリヌクレオチドを含有するかまたはCARを発現し、
前記cMLVに、アデノシンA2A受容体の阻害剤が封入されている、
前記医薬。 - 前記免疫エフェクター細胞が、NK細胞、T細胞、B細胞、腫瘍特異的Tリンパ球及び造血幹細胞の1種以上を含む、請求項11に記載の医薬。
- 前記免疫エフェクター細胞がT細胞を含み、前記粒子がcMLVであり、A2ARの前記阻害剤がSCH58261である、請求項12に記載の医薬。
- 前記A2A受容体阻害剤が、SCH58261、カフェイン、SYN115、FSPTP、ZM241385、PBS-509、ST1535、ST4206、トザデナント、V81444、またはイストラデフィリンを含む、請求項11または12に記載の医薬。
- 前記A2A受容体阻害剤がSCH58261である、請求項11または12に記載の医薬。
- 前記疾患が、がんである、請求項11~15のいずれか一項に記載の医薬。
- 化学療法、放射線療法及びそれらの組み合わせから成る群から選択される既存の治療法と併用するための、請求項11~16のいずれか一項に記載の医薬。
- 前記既存の治療法が、前記操作された免疫エフェクター細胞の投与と逐次的にまたは同時に施されるように用いられることを特徴とする、請求項17に記載の医薬。
- 前記CARが標的とする抗原が、4-1BB、5T4、腺癌抗原、アルファ-フェトプロテイン、BAFF、B-リンパ腫細胞、C242抗原、CA-125、炭酸脱水酵素9(CA-IX)、C-MET、CCR4、CD152、CD19、CD20、CD200、CD22、CD221、CD23(IgE受容体)、CD28、CD30(TNFRSF8)、CD33、CD4、CD40、CD44v6、CD51、CD52、CD56、CD74、CD80、CEA、CNTO888、CTLA-4、DR5、EGFR、EpCAM、CD3、FAP、フィブロネクチンエキストラドメイン-B、葉酸受容体1、GD2、GD3ガングリオシド、糖タンパク質75、GPNMB、HER2/neu、HGF、ヒト散乱因子受容体キナーゼ、IGF-1受容体、IGF-I、IgG1、L1-CAM、IL-13、IL-6、インスリン様増殖因子I受容体、インテグリンα5β1、インテグリンαvβ3、MORAb-009、MS4A1、MUC1、ムチンCanAg、N-グリコリルノイラミン酸、NPC-1C、PDGF-Rα、PDL192、ホスファチジルセリン、前立腺癌細胞、RANKL、RON、ROR1、SCH900105、SDC1、SLAMF7、TAG-72、テネイシンC、TGFベータ2、TGF-β、TRAIL-R1、TRAIL-R2、腫瘍抗原CTAA16.88、VEGF-A、VEGFR-1、VEGFR2、ビメンチン、及びそれらの組み合わせの1以上を含む、請求項11~18のいずれか一項に記載の医薬。
- 前記対象が、前から存在する腫瘍浸潤リンパ球(TIL)を有するか、または以前にCAR-T細胞療法を受けたことがある、請求項16に記載の医薬。
- A2ARの阻害剤が、免疫エフェクター細胞に結合されていない点を除き同一であるcMLVより遅い速度で、免疫エフェクター細胞の表面に結合されたcMLVから放出される、請求項7に記載の操作された免疫エフェクター細胞。
- A2ARの阻害剤が、免疫エフェクター細胞に結合されていない点を除き同一であるcMLVより遅い速度で、免疫エフェクター細胞の表面に結合されたcMLVから放出される、請求項11に記載の医薬。
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