JP7467414B2 - 改良したt細胞治療方法 - Google Patents
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Description
(b)対象に癌関連抗原を発現させた細胞を投与するステップ。
先行の臨床試験は既に、CAR-T免疫療法の癌治療、特にB細胞の悪性腫瘍における有効性を決定している。CAR-T細胞により癌を治療することの次のステップは寛解の継続時間を延長させることである。
(a)前記対象に癌関連抗原を特異的に標的化した治療用T細胞を投与するステップ、及び
(b)前記対象に前記癌関連抗原を発現させた細胞を投与するステップ。
CRISPR/Cas9媒介B-NDGマウスの産生
CRISPR/Cas9媒介B-NDGマウスはBeijing Biocytogen Co.,Ltd.により生成された。簡単に言えば、Il2rg遺伝子座の最初及び最後のエクソンの側部に位置する標的領域のsgRNA標的化に関する。各標的部位に対して、CRISPR設計ツール(http://crispr.mit.edu/)により4種類の候補sgRNAを決定し、且つUCAキット(北京Biocytogen)を用いて標的活性をスクリーニングした。2種のsgRNAを選択してマウスの受精卵中に注射した。生体外転写されたCas9 mRNAとsgRNAを異なる濃度で混合し、且つNOD-scidマウスの受精卵中に同時に注射した。注射後、生存した受精卵をKM偽妊娠雌性の卵管に移した。F0初代修飾マウスにおいて、Il2rg欠損ヘテロ接合及びホモ接合マウス(B-NDGマウス)をさらに産生した。すべてのマウスはいずれも特定の病原体フリーの施設に保持されている。
293-T細胞(ATCC、CRL-3216)を、10%FBS及び100U/mlペニシリン/ストレプトマイシンが補充されたDMEM(Hyclone、Logan、Utah、USA)中に培養した。Raji(ATCC、CCL-86)、Raji-Fluc(軍事医学科学院、北京;エンコードされたフルオレセイン及びプロマイシンレンチウイルスベクターをトランスフェクションすることによりRaji細胞から誘導する)、CD19-K562及びK562細胞(Genomeditech、上海)を、10%FBS及び100U/mlペニシリン/ストレプトマイシンが補充されたRPMI1640中に培養した。細胞を40Gyコバルト照射に晒すことにより、照射されたRaji-Fluc細胞を得た。すべての培地及び抗生物質はいずれもGibco Life Technologies(Carlsbad、CA、USA)から購入する。
抗CD19 CARは、CD19特異的FMC63 mAbのscFv、CD8のヒンジと膜貫通領域、4-1BB共刺激ドメイン、及びTCR複合体の細胞内CD3ζ鎖を含む。抗CD19 CAR遺伝子はレンチウイルスベクターpPVLV2(Pharosvaccine Inc.、Gyeonggi、Republic of Korea)中にクローンされた。該ベクターはCAR-T-19細胞の産生に用いられる。
健康なボランティアから収集した血液から新鮮な末梢血単核細胞(PBMC)を得た。直ちにPBMCを、90%ヒトAB血清+10%ジメチルスルホキシドを含有する培地中に使用し、又は前記培地中に冷凍保存して将来の使用に供した。PBMCを、抗CD3及び抗CD28モノクローナル抗体が被覆された常磁性ビーズ(Invitrogen、Carlsbad、CA、USA)を用いて、3:1の比率で24時間刺激した。T細胞活性化後、細胞を1×106/mLでIMSF100培地中に重懸濁させ、8μg/mlポリブレン(SIGMA、セントルイス、MO、USA)の存在下、レンチウイルスベクターと混合した。多重感染度(MOI)は0.5~2であり、且つ12ウェルプレート中に移した。プレートを、環境温度下で、水平ローター遠心分離機を用いて1200gで2時間遠心分離し、続いて37℃、5%CO2のインキュベータ中に移した。24時間インキュベートした後、形質導入された細胞を収集し、且つIMSF100培地で洗浄し、次に細胞を、500IU/mL IL-2(BMI、韓国)が補充された培地中にインキュベートした。その後、2又は3日ごとに培地及びIL-2(300IU/mL)を交換し、マウスに注射するまで培養物を37℃/5%CO2に維持した。ここでCAR-T-19細胞は抗CD19 CARを発現させたT細胞である。aT19細胞はCD19を発現させたT細胞である。
マウス中のT、B及びNK細胞とCAR-T細胞を検出するために、Becton Dickinson(BD)蛍光活性化セルソーティング(FACS)標準を使用して、メーカーのプロトコルに従って多色フローサイトメトリー分析を行った。右心室から末梢血を収集した。BD細胞ストレーナーにより脾臓細胞を収集して濾過した。血液中の赤血球と脾臓細胞を分解溶液で枯渇した。PerCP-CD3、FITC-CD4、PE-CD8、FITC-CD19及びAPC-CD49を含む抗体を用いて一重染色又は二重染色を行うことで白血球を検出した。すべての抗体はBiolegendから購入する。
本研究におけるマウスに対しては、実験動物管理評価認証協会により制定されたガイドラインに基づき飼育及び操作を行った。研究はNIFDC動物実験委員会による承認を受けた。4週齢の雌BALB/c、C57BL/6、NOD-scid、及びB-NDGマウスはNIFDC実験動物資源研究所(中国北京)から得た。D0に、マウスに尾静脈注射を介して5×105個のRaji-Fluc細胞を移植し、続いて、5日(D5)目又は6日(D6)目に2×107個のCAR-T-19細胞をインプラントした。CAR-Tメモリー実験において、D10又はD11に異なる用量のRaji-Fluc細胞、照射されたRaji-Fluc細胞又はaT19細胞を注射した。指定の時点にすべてのマウスの生物発光シグナルを観察した。所定の時点に血液サンプルを取得し、蛍光活性化セルソーティング、及び定量的リアルタイムPCR(qPCR)分析を行った。
簡単に言えば、IVIS-Lumina IIイメージングシステム(PerkinElmer、Baltimore、MD)を使用してマウスの生物発光イメージングを得た。ペントバルビタールナトリウム(75mg/kg体重)を腹腔内注射することでマウスを麻酔した。次に10分間後、それにD-フルオレセイン(75mg/kg体重;PE)を腹腔内注射した。Living Imageソフトウェア(Caliper Life Sciences)を用いて画像を分析し、且つデータを総フラックス(光子/s)として示した。生じた最大生物発光値が1×106フラックスを超え、且つ生物発光面積が次の時点に1×106フラックス未満ではない場合、該時点を腫瘍再発時間として記録した。
フローサイトメトリーにより、CAR-T-19細胞のK562、CD19-K562、aT19、及びRaji-Fluc細胞死滅能力を測定した。簡単に言えば、標的細胞(K562、CD19-K562、Raji-Fluc又はaT19)を遠心分離管中に移し、且つCFSEで染色した。次に、標的細胞:CAR-T-19細胞の比率を調整し、且つそれぞれ異なる比で細胞(K562又はCD19-K562:CAR-T-19=1:1、1:3又は1:6;aT19又はRaji-Fluc:CAR-T-19=1:0.3、1:1又は1:3)を接種した。形質導入されていないT細胞をNC(陰性対照)として記録した。20~24時間インキュベートした後、フローサイトメトリーによりCFSE+7-AAD+細胞の百分率を分析した。
qPCRにより、マウス末梢血及び脾臓中から分離したCAR-T-19細胞中のCAR遺伝子の存在を検出した。簡単に言えば、QIAamp DNA Mini Kit(Qiagen、GER)でDNAを抽出し、且つIMPLEN N50ウルトラマイクロ紫外線分光光度計(IMPLEN、N80TOUCH)中で定量化した。使用が必要になるまで抽出したDNAを-20℃に保存した。4-1BBプライマー(Invitrogen)及びプローブ(Thermo Fisher Scientific)を用いてDNA(100ng)にPCR増幅を行うことで、CAR遺伝子の発現(CD19 4-1BB Fプライマー、5’-TGCCGATTTCCAGAAGAAGAAGAAG-3’;CD19 4-1BB Rプライマー、5’-GCGCTCCTGCTGAACTTC-3’;CD19 4-1BB MGBプローブ、5’-ACTCTCAGTTCACATCCTC-3’))を検出した。
すべてのグラフはいずれもGraphPad Prism 6.0ソフトウェアを使用して生成され、すべての統計学的比較はいずれもノンパラメトリック一元配置分散分析又はStudent’t検定を用いて行われ、P値<0.05は、統計学的有意(*)であり、P<0.01(**)は非常に有意であった。
非活性化Il2rgを有する非肥満糖尿病重症複合免疫不全(NOD-scid)マウスには、成熟T細胞、B細胞及びナチュラルキラー(NK)細胞が欠損し、且つサイトカインシグナル伝達が欠損しており、その結果、複数種の癌タイプがよりよくインプラントできる。本実施例では、CRISPR/Cas9ゲノム編集技術を用いて、NOD-scidマウスからIl2rg遺伝子を欠失させ、それによりB-NDGマウス(図1A)を製造した。B-NDGマウスが生存、繁殖することができ、且ついずれの顕著な体の異常も示されないことが観察された。NOD-scidマウスに比べて、FACS分析を行ったところ、B-NDGマウスの脾臓及び末梢血に少量のCD19+B細胞、CD4+、及びCD8+T細胞(図1B)があることを示した。NOD-scidマウスは高百分率のCD49b+NK細胞(脾臓20.90%、末梢血24.10%)を有し、一方、B-NDGマウスは機能的NK細胞(脾臓1.45%、末梢血5.95%)を有さなかった。したがって、ゲノム編集により生じたB-NDGマウスは表現型に関してはNSGマウスと類似した。
CAR-T細胞の効果が良好であるものの、B-NDGマウスは最終的に腫瘍により死亡した。Raji細胞の再発ソースを見つけるために、マウスのすべての主要な器官の生物発光をテストした。結果から明らかなように、Raji細胞は、脾臓、心臓や皮膚においてCD19 CAR-T細胞により明らかに除去された。たとえば、脾臓には、CAR-T細胞処理後生物発光が1000倍減少した(図3A)。しかしながら、CD19 CAR-Tは、他の器官、特に肝臓及び脳でそれほど有効ではなかった(図3A)。これらの器官中に隠されたCAR-Tにより効果的に除去できない残留Raji細胞は腫瘍再発の原因である可能性がある。
CAR-T細胞が腫瘍の微環境に応じて変化し、その結果、それがRaji細胞を認識して死滅できず、疾患の再発を引き起こすか否かをテストするために、PI後のD10に生物発光が検出されなかった場合、CD19 CAR-T処理後のマウス中に異なる量のRaji-Fluc細胞(A1:5×104、A2:5×105、A3:5×106)に改めてインプラントした。Raji-Fluc細胞を再度接種していないマウスを対照(SNT)として用いた。SNT群には、すべてのマウスが死亡するまで生物発光が連続的に観察できた。再インプラントしてから1日後、すべてのマウスには疾患が素早く発症した。意外なことに、再インプラントしてから9日後、ほぼすべてのRaji細胞が除去された(図3A)。再インプラント群の生存はSNT群よりも好ましい(P<0.05、図3A及びB)。A1群の3匹のマウスは200日を超えて生存した。ある時点にマウスの最大生物発光値が1×106フラックスを超え、且つ次の時点に生物発光面積が1×106フラックス未満ではない場合、該時点を腫瘍再発時間として記録した。他の各群に比べて、低用量Raji-Fluc細胞を再度接種することにより無再発時間を延長できた(図3A及びC)。次に、異なる時点で異なる群の平均生物発光強度を分析した。低用量再インプラント群のシグナルは空白対照群のシグナルに近く(図3D)、一方、他の群のシグナルは異なる程度で増加しており、このことから明らかなように、再発はCARの能力不足ではなく、その不良な持続性によるものであり、且つ低用量腫瘍細胞の抗原刺激はCAR-T細胞の免疫メモリーの発生を促進した。
臨床的には腫瘍生細胞の注射は実現できないことであり、したがって、照射後死亡した腫瘍細胞がCAR-T細胞の免疫メモリーを刺激できるか否かをテストした。現在、本分野ではCAR-T細胞を複数回注入することは、その持続性不足を解決するための主要な戦略であり、CAR-T治療を繰り返したマウスモデルは設計された。図4に示すように、5日(D5)目にCAR-T細胞治療を行った後、Raji-B-NDGマウスに、D10に異なる用量の照射されたRaji-Fluc細胞(rRaji-Fluc、A1:5×104、A2:5×105、A3:5×106)を注射した。同一用量のrRaji-Flucを接種した3群のB-NDGマウスを照射済み細胞対照群(PA1/PA2/PA3)とした。rRaji-FLucインプラント無しマウスを単回処理群(SNT)とした。2重処理群(DNT)のマウスに、D10に2×107個のCAR-T細胞を注射した。SNT群のすべてのマウスが死亡するまでマウスに生物発光シグナルが観察できた。SNT群に比べて、rRaji-Fluc細胞の再インプラントは、マウスの全生存期間及び無再発生存期間を延長できなかった(図4B及びC)。SNT群及びDNT群には有意差がなく、これは、2重処理が無効であることを示した。A1/A2/A3/SNT群のマウスの末梢血中のCAR-T細胞の数量は、類似した時間にピークに達した(図4D)。CAR-T細胞を2回注射するため、DNT群のピーク時間は他の群よりも遅い。A1群のCAR-T細胞の減少速度はA2/A3/SNT群よりも低く、このことから明らかなように、低用量rRaji-Fluc細胞による刺激はCAR-T細胞の維持を促進する傾向がある。
CAR遺伝子構築体は、CD19特異的FMC63 mAbに由来するscFv、CD8のヒンジと膜貫通領域、並びに4-1BB細胞質ドメイン、及びTCR複合体の細胞内CD3ζ鎖を含む(図5A)。pEF1αはCAR遺伝子プロモータである。ヒトCD19を用いてCAR導入遺伝子を置換してaT19構築体を生成した(図5B)。CAR-19又はCD19構築体(aT19)を用いて健康なボランティアから得たPBMCから分離したT細胞を形質導入した。表1は、実験中に使用されているCAR-T-19、生Raji-Fluc、照射されたRaji-Fluc、及びaT19細胞の表現型及び数量を示す。次に、細胞毒性測定を行うことで、CAR-T-19細胞の死滅能力を検査した。CD19+Raji又はaT19細胞と生体外で共培養した後、CAR-T-19細胞は、>3:1のエフェクター/標的比で、50%超えのRaji-Fluc細胞又はaT19を死滅させるのに対して、T細胞を対照K562細胞と共培養した場合、細胞毒性作用がほぼ観察されなかった(図5C)。
陽性群及びNC群中のマウスは、単独で腫瘍細胞を受ける、又はPBSだけを受け、且つそれぞれP群又はN群(n=3/群)として記録された。NT群中のマウスは、刺激がない場合、CAR-T-19細胞(n=5/群)を受けた。A群は、免疫メモリーテスト群として指定され、該群中のマウスは、3種類の異なる用量の再刺激細胞のうちの1種(A1群、5×104細胞;A2群、1.5×105細胞;及びA3群、5×105細胞)(n=5/群)を受けた。PA1、2、及び3群は、それぞれ各群Aの対照群(n=3/群)として用いられた。これらの群は表2に記載されている。図6Aには、腫瘍細胞、CAR-T細胞、及び再刺激細胞の使用の時間ラインが示されている。
患者に腫瘍生細胞を注射することは実現できない。したがって、次に、照射されて死亡した腫瘍細胞が生細胞と類似した方式でCAR-T-19細胞の効能を高めるか否かを研究する。この実験には、生細胞実験と同じマウス群が使用された。投与された細胞の群及び数量を表3中に示した。時間ラインを図7Aに示した。前記のとおり、PIの異なる時間に生物発光イメージングを行った。照射された死亡Raji-Fluc細胞を用いてCAR-T-19細胞を再刺激することは、全生存率及び無再発生存率を増加できなかったことを見出した(図7B及びC)。
Raji-Fluc細胞は高増殖能力を有する腫瘍細胞である。したがって、患者が刺激用量のRaji細胞を受ければ、これらの細胞が腫瘍を形成するリスクが存在する。明らかなように、これは受け入れられない。したがって、Raji-Fluc細胞の代わりにヒトCD19遺伝子を持ったT細胞(aT19細胞)を用いてCAR-T-19細胞を再刺激した。注射時間及び使用された細胞数を表4に示した。陽性/NC群(P及びN群)中のマウスは、それぞれ腫瘍細胞を受けた、又はPBSだけを受けた。NT群中のマウスは、単回用量のCAR-T-19細胞を受け、次の用量の刺激細胞がなかった。A1群は、Raji-Fluc細胞(n=4)で再刺激され、一方、aT19群はaT19細胞(n=6)で再刺激された(図8A)。また、D10、D20、及びD30に内眼角から採血した(図8D)。結果により示すように、aT19群のマウスの生存時間は、NT群のマウスよりも有意に長く、aT19群中の3匹のマウスはD160まで生存した(図8C)。
過去10年間、CAR-T細胞療法は発展を遂げており、しかしながら、多くの障害はまだ克服しなければならない。これらのうち、CAR-T細胞の生体内の効能の延長及びCAR-T治療の副作用の減少は最も重要である。CAR-T細胞の効能は、細胞外認識19,20、CAR媒介細胞内シグナル伝達21の最適化(CAR+細胞の割合及びタイプを調整することにより実現)22及び標的薬23の併用などの戦略により、延長させることができる。CAR-T細胞の用量を調整し、且つ免疫抑制薬を併用することにより、CAR-T治療に関連する毒性及び副作用を低減できる24。ワクチンに対しては類似した方法が取られており、これらの方法は最適化し続けており、それにより、より長い時間内で有効な保護を提供し、それと同時に有害反応を減らす25。最もよく見られたワクチン接種プロトコルは、複数回の免疫、又はひいては免疫応答を強化するために異なる免疫原を使用することに関する。HIVワクチン戦略を例として、一次免疫及びブースター免疫は、それぞれウイルス抗原及び核酸を含み、それぞれ抗体保護の継続時間を増加し、免疫活性化を向上させる26。しかしながら、CAR-T細胞療法に対しては、複数回の接種は、コストや毒性を増加するものの、効能を低減させる。
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Claims (25)
- 対象においてCD19を発現する癌を治療するための医薬品の製造における組成物の使用であって、
前記組成物は、CD19を特異的に標的化する治療用T細胞と、CD19を発現させた細胞と、を含み、
前記治療用T細胞は、キメラ抗原受容体(CAR)を含むT細胞(CAR-T細胞)であり、前記CD19を発現させた細胞は、照射されたことのない生T細胞であり、
前記治療は、
(a)前記対象にCD19を特異的に標的化するCAR-T細胞を治療有効量である10 4 ~10 9 細胞/kg体重で投与するステップと、
(b)ステップ(a)の後、前記対象に前記CD19を発現させた細胞を刺激有効量である10 3 ~10 6 細胞/kg体重で投与するステップと、
を含む、使用。 - 前記CAR-T細胞は1回又は複数回投与される請求項1に記載の使用。
- 前記CD19を発現させた細胞は1回又は複数回投与される請求項1又は2に記載の使用。
- 前記CAR-T細胞を投与してから1日、2日、3日、4日、5日、6日、7日、8日、9日、10日、11日、12日、13日、14日、15日、16日、17日、18日、19日又は20日後、前記CD19を発現させた細胞を投与する請求項3に記載の使用。
- 前記CAR-T細胞を投与することで癌細胞負荷を低減させた後、前記CD19を発現させた細胞を投与する;又は
前記CAR-T細胞を投与した後、前記CAR-T細胞の前記対象の生体内の量が低下したときに、前記CD19を発現させた細胞を投与する、
請求項1~4のいずれか1項に記載の使用。 - 癌細胞負荷を少なくとも5%、少なくとも10%、少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%低減させた後、前記CD19を発現させた細胞を投与する、請求項5に記載の使用。
- 癌が前記CAR-T細胞を投与することにより完全に寛解した後、前記CD19を発現させた細胞を投与する、請求項1~6のいずれか1項に記載の使用。
- 前記CARはCD19に特異的に結合する細胞外抗原結合ドメインを含む、請求項1に記載の使用。
- 前記CD19は前記生T細胞の表面で発現されている請求項1に記載の使用。
- 前記CD19を発現させた細胞は免疫細胞から誘導される請求項1~9のいずれか1項に記載の使用。
- 前記CAR-T細胞及び/又は前記CD19を発現させた細胞は対象の自家細胞から誘導される、請求項1~10のいずれか1項に記載の使用。
- 前記CAR-T細胞及び/又は前記CD19を発現させた細胞は同種細胞から誘導される、請求項1~10のいずれか1項に記載の使用。
- 対象においてCD19を発現する癌の進行又は再発を予防するための医薬品の製造における組成物の使用であって、
前記組成物は、CD19を特異的に標的化する治療用T細胞と、前記CD19を発現させた細胞と、を含み、
前記治療用T細胞は、キメラ抗原受容体(CAR)を含むT細胞(CAR-T細胞)であり、前記CD19を発現させた細胞は、照射されたことのない生T細胞であり、
前記予防は、
(a)前記対象にCD19を特異的に標的化するCAR-T細胞を治療有効量である10 4 ~10 9 細胞/kg体重で投与するステップと、
(b)ステップ(a)の後、前記対象に前記CD19を発現させた細胞を刺激有効量である10 3 ~10 6 細胞/kg体重で投与するステップと、
を含む、使用。 - 前記CD19を発現させた細胞は1回又は複数回投与される請求項13に記載の使用。
- 前記CAR-T細胞を用いて1日間、2日間、3日間、4日間、5日間、6日間、7日間、8日間、9日間、10日間、11日間、12日間、13日間、14日間、15日間、16日間、17日間、18日間、19日間又は20日間治療した後、前記CD19を発現させた細胞を投与する、請求項13又は14に記載の使用。
- 前記CAR-T細胞が癌細胞負荷を低減させた後、前記CD19を発現させた細胞を投与する、請求項13~15のいずれか1項記載の使用。
- 癌細胞負荷を少なくとも5%、少なくとも10%、少なくとも20%、少なくとも30%、少なくとも40%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%、少なくとも90%低減させた後、前記CD19を発現させた細胞を投与する、請求項16に記載の使用。
- 癌が前記CAR-T細胞を用いて治療することにより完全に寛解した後、前記CD19を発現させた細胞を投与する請求項13~17のいずれか1項に記載の使用。
- 前記CARは、CD19に特異的に結合される細胞外抗原結合ドメインを含む、請求項13又は18に記載の使用。
- 前記CD19は前記生T細胞の表面で発現されている請求項13に記載の使用。
- 前記CD19を発現させた細胞は免疫細胞から誘導される請求項13~20のいずれか1項に記載の使用。
- 前記CAR-T細胞及び/又は前記CD19を発現させた細胞は対象の自家細胞から誘導される請求項13~21のいずれか1項に記載の使用。
- 前記CAR-T細胞及び/又は前記CD19を発現させた細胞は同種細胞から誘導される供与体に由来する請求項13~21のいずれか1項に記載の使用。
- 対象においてCD19を発現する癌を治療する、又は対象においてCD19を発現する癌の進行若しくは再発を予防するための組み合わせ物であって、
CD19を特異的に標的化するCAR-T細胞と、前記CD19を発現させた細胞と、を含み、
前記CAR-T細胞は、キメラ抗原受容体(CAR)を含むT細胞(CAR-T細胞)であり、前記CD19を発現させた細胞は、照射されたことのない生T細胞であり、
前記CAR-T細胞は治療有効量である104~109 細胞/kg体重の前記CAR-T細胞を含み、
前記CD19を発現させた細胞は刺激有効量である103~106 細胞/kg体重の前記CD19を発現させた細胞を含む、組み合わせ物。 - キットであって、
請求項24に記載の組み合わせ物を含み、対象においてCD19を発現する癌を治療する、又は対象においてCD19を発現する癌の進行若しくは再発を予防するためのキット。
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