JP2018530333A - Pscaを標的とするキメラ抗原レセプター - Google Patents
Pscaを標的とするキメラ抗原レセプター Download PDFInfo
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Abstract
Description
DIQLTQSPSTLSASVGDRVTITCSASSSVRFIHWYQQKPGKAPKRLIYDTSKLASGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQWGSSPFTFGQGTKVEIKGSTSGGGSGGGSGGGGSSEVQLVEYGGGLVQPGGSLRLSCAASGFNIKDYYIHWVRQAPGKGLEWVAWIDPENGDTEFVPKFQGRATMSADTSKNTAYLQMNSLRAEDTAVYYCKTGGFWGQGTLVTVSS(配列ID番号:38)又は最大で5個のアミノ酸置換(substitutions)を有するそのバリアント(variant)。
表1:スペーサーの例
表2:膜貫通ドメインの例
表3:CD3ζシグナリングドメイン及び共刺激ドメインの例
表4:PSCAを標的とするCARの例
図1は、様々なCAR発現するために使用される、発現ベクターの翻訳領域内の要素(上方のパネル)及び結果として生じるCAR(下方のパネル)を模式に描写する。CARは、PSCAを標的とするMB1 scFvを使用した。A11 scFvは使用されなかったが、適切な代替物である。3つの異なるスペーサーが使用された:IgG4(EQ)、これは、CH3、CH4及びヒンジ領域を含むIgG4 Fc領域を含み、ネイティブなFcレセプターへの結合を低下させる二つのアミノ酸置換を有する;IgG4(HL‐CH3)、これは
IgG4(EQ)に類似するが、CH2ドメインを欠き、ヒンジ領域とCH3領域との間に位置する短いリンカー配列を有する;並びに、短いリンカー配列であるL。全3つのスペーサーは、表1に詳細に記載されている。二つの代替的な膜貫通ドメインが使用された:CD4及びCD28、両方が表2に詳細に記載されている。二つの代替的な共刺激ドメインが使用された:CD28共刺激ドメインのバリアントであるCD28gg、及び4−IBB。両方が表3に詳細に記載されている。CARの全ては、表3にも記載されている、CD3ζ細胞質シグナリングドメインを含んでいた。CARコード配列には、T2Aリボソームスキップ配列、及び表面の、シグナル伝達において機能しない、マーカーとしての切断型CD19の同時発現を可能にする切断型CD17配列が続いた。
二つの異なる前立腺癌腫瘍細胞株、PC‐3及びDU145は、PSCAを発現するように操作された。図3Aは、元の細胞及び操作された細胞並びにLCL細胞についてのPSCA発現データを提供する
図3B‐Eは、フローサイトメトリーによって測定された、腫瘍標的(DU145細胞、PC3細胞、PSCA発現ベクターを用いてトランスフェクトされたDU145細胞、又はPSCA発現ベクターを用いてトランスフェクトされたPC3細胞)との5時間の共培養に続いての、二つの異なるCARについてのIFNγ産生データ及びCD107a脱顆粒データを提供する。図4D‐Eは、ELISAによって測定された、組み換えPSCA又は腫瘍標的を用いた24時間の培養に続いてのCAR T細胞によるIFNγ産生についてのデータを提供する。ここでも、4‐IBB共刺激ドメインを有するCARは、CD28共刺激ドメインを有するCARよりも少ないIFNγ及びより低いレベルの脱顆粒マーカーを産生することをみることができる。
CD28共刺激ドメインを有するCARと4‐IBB共刺激ドメインを有するCARの比較(図3Aに記載)は、4‐1BB共刺激ドメインを含むPSCA‐CARsは優れた特異性、増殖及び腫瘍細胞死滅能力を示すことを実証した。この分析の結果は、図4A‐Eに示されている。PSCA発現コンストラクトを用いてトランスフェクトされていない細胞のより少ない死滅によって示されるように(図4A)、腫瘍死滅は、CD28共刺激ドメインを有するCARよりも、4‐IBB共刺激ドメインを有するCARに関して、より特異的であった。4‐IBBを有するCARはまた、より低いレベルのPD‐1誘導を提示した(図4B)。死滅及びPD‐1誘導は、腫瘍標的(DU145、PC‐3、DU145‐PSCA及びPC‐3‐PSCA)との72時間の共培養に続いて測定された。図4Cは、0.25:1から4:1のエフェクター:腫瘍(E:T)比を用いた腫瘍死滅の分析の結果を示す。図4Dは、腫瘍標的との72時間の共培養に続いての、CAR T細胞の増殖の分析の結果を描写し、図4Eは、腫瘍標的(DU145、左;DU145‐PSCA、右)との1、2又は3日間の共培養に続いてのCAR T細胞における腫瘍死滅及びPD‐1誘導の動態を示す。
図5A‐Bに描写される研究は、スペーサー領域がCD107a発現(脱顆粒)及びIFN−γ産生に影響を与え得ることを示す。ここでのCARは全て、CD4膜貫通ドメイン及び4‐IBB共刺激ドメインを含む。
上述の二つのPSCA‐CAR Tは、前立腺癌異種移植及び同所性モデルにおいて効能のある抗腫瘍効果を示す。PC‐3‐PSCA(2×106)細胞は、NSG雄マウスに皮下注射され、腫瘍が約30‐50mm3に達したときに、CAR Tcm(5×106)は腫瘍内に注射され、腫瘍成長がキャリパー測定によって監視された(図6A)。DU145‐PSCA(2×106)細胞は、NSG雄に皮下注射され、CAR PBMC細胞(5×106)細胞は静脈内に送り込まれた(図6B)。同所性(orthotopic)モデルを作り出すために、PC‐3‐PSCA(2×105)細胞は、NSG雄に脛骨内に注射され、CAR PBMC細胞(2×106又は5×106)は、静脈内に送り込まれた(図6C)。パネルBからの各群における腫瘍注射後58日目における、血液中のCAR T細胞持続性が評価された(図6D)。
1G8(A11クローン)に由来するヒト化PSCAscFv、ΔCH2細胞外スペーサー、CD3ζ細胞溶解性ドメイン、及びCD19t細胞トラッカーを含み、それらの共刺激ドメインのみが異なる(4‐1BB対CD28が比較された(図7A)、二つのPSCA‐CARコンストラクト[Lepinら 2010 Eur J Nucl Med Mol Imaging 37:529)。本実施例及び実施例8‐11は、特に示されない限り、PBMC由来T細胞において操作されたPSCA‐CARsを使用した研究を記述する。例えば、異なる開始細胞表面T細胞表現型を有するセントラルメモリーT細胞(TCM)が、いくつかの研究において使用された(図12)。
CD28含有PSCA‐CARsと4‐1BB含有PSCA‐CARsとの間の差異を更に調べるために、それらのそれぞれのT細胞活性化及びサイトカイン産生を比較するための研究が行われた。これらの研究は、DU145‐PSCA腫瘍細胞との一晩の共培養に続いての、PSCA(ΔCH2)28ζ CAR T細胞と比較したPSCA(ΔCH2)BBζ CAR T細胞によるIFNγ産生の有意な減衰を明らかにした(図9A)。サイトカイン産生の同様の減衰は、PC‐3‐PSCAに対する4‐1BB含有CARsについても観察された。CD28含有PSCA‐CAR T細胞は、低PSCA発現腫瘍細胞及び高PSCA発現腫瘍細胞に対して同等のIFNγレベルを産生したが、4‐1BB含有CAR T細胞は、低PSCA発現腫瘍細胞に対してより低いIFNγを産生した(図9B)。腫瘍細胞によるサイトカイン産生に対する潜在的な非CAR媒介効果を除外するために、プレート結合組換えヒトPSCAタンパク質に対するPSCA(ΔCH2)BBζ CAR T細胞による同様のIFNγ測定が実行された。CD28含有CAR T細胞は、低レベル又は高レベルのPSCAに対して飽和応答を示したが、4‐1BB含有PSCA‐CAR T細胞によるIFNγ産生は、抗原密度に左右された(図9C)。同様のサイトカイン応答は、PSCA‐CAR T細胞を生成するために使用されるT細胞サブセットから独立して観察された(図15)。
この研究において、皮下PC‐3‐PSCA腫瘍を有するマウスは、5×106のPSCA(ΔCH2)BBζ CAR T細胞の単一の腫瘍内注射を用いて処置された。腫瘍内T細胞注射に続いて、2週間以内に完全な腫瘍退縮(regression)が観察された。腫瘍退縮は30日以上にわたって明白であったが、原発腫瘍と同様の動態を有する動物の大部分において腫瘍がやがて再発した(図17A)、我々は以下でこれに取り組むであろう。CAR T細胞の全身療法がこの固形腫瘍モデルにおいて達成可能であったかどうかを確立するために、様々な投与量のPSCA(ΔCH2)BBζ CAR T細胞が静脈内に送り込まれた。5×106のPSCA‐CAR T細胞が腫瘍の完全な退縮を示したが、0.25x106の小さなCAR投与量においては、同様であるが遅延した治療効果が観察された(図10A)。この発見を大きな腫瘍の負担(large tumor burden)にまで広げるために、大きなPC‐3‐PSCA腫瘍(約500mm3)は、5×106のPSCA(ΔCH2)BBζ CAR T細胞の単一の静脈内注射を用いて処置された。ここで、急速な腫瘍退縮が観察された(図10B)。ヒトT細胞の有意な腫瘍浸潤はCAR T細胞注入に続いて11日目に観察され(図10C、上方のパネル)、それはまた、T細胞活性のマーカーであるグランザイムBも発現した(図10D、下方のパネル)。モック処理されたマウスからの腫瘍は、同じ時点でヒトT細胞又はグランザイムB発現をほとんど示さなかった。
細胞免疫療法にとっての主要な障害の一つは、固形腫瘍におけるT細胞の有効な輸送及び生存を妨げる免疫抑制的な微小環境である。骨転移性前立腺腫瘍における輸送及び抗原依存性CAR T細胞増殖を直接的に評価するために、ホタルルシフェラーゼ標識されたPSCA(ΔCH2)BBζ CAR T細胞は、脛骨内野生型PC‐3(解剖学的右脛骨)腫瘍及びPC‐3‐PSCA(解剖学的左脛骨)腫瘍を有するマウスに静脈内注射された。興味深いことに、モック及びPSCA‐CAR T細胞は両方の腫瘍に対して等しい初期の輸送を示したが(T細胞注入の4時間後)、PSCA‐CAR T細胞は、T細胞注射に続いて第1日目にPSCA発現腫瘍において優勢に見出され、それは4日間の動的画像化にわたって増大し(図10D)、PSCA陽性腫瘍における抗原依存性の輸送及び/又はCAR T細胞増殖を示している。次に、PC‐3‐PSCA腫瘍細胞が脛骨内空間の中に注入された研究が行われた。腫瘍移植後14日目に、これらの癌を有するマウスは、段階的に減少する投与量(dose de-escalation)のPSCA(ΔCH2)BBζ CAR T細胞(0.5×106から5×106)を用いて静脈内処置された(図10E)。5×106又は2.5×106のCAR T細胞を用いて処置された大多数のマウスは完全な腫瘍退縮を示したが、1×106又は0.5×106のCAR T細胞のいずれかを用いて処置されたマウスは、より不均一な治療応答を有した(図10F)。同所性研究からの有効な投与量が、0.25×106の小さなCAR T細胞投与量を用いて完全な退縮が観察された皮下モデルにおいて使用される投与量と比較された場合に、このモデルの臨床的関連性(clinical relevance)は明らかである。これらのモデルにおいて観察される全体的な治療における食い違い(discrepancy)は、これらの腫瘍微小環境におけるCAR T細胞の浸潤及び生存の差によるものである可能性が高い。
上記の研究は、内因性PSCA発現骨転移性前立腺癌患者由来の腫瘍異種移植片、LAPC‐9を使用して拡張された。腫瘍移植後14日目に、5×106のPSCA(ΔCH2)BBζ CAR T細胞の単一の静脈内注射によって処置されたマウスは、脛骨内の腫瘍部位において腫瘍のほぼ完全な退縮を示した(図11A)。脛骨内の腫瘍は効果的に標的化されていたが、LAPC‐9腫瘍は体内の他の部位に播種され、それは、免疫組織化学によって確認されたときに様々なリンパ節(腋窩部及び鼠径部)並びに胸腺において特に明白であることが見出された(データは示されていない)。これらは、骨における初期の腫瘍退縮後数週間にわたって見かけ上成長したが、それらは、最終的にPSCA(ΔCH2)BBζ CAR T細胞によって根絶された。
pHIV7プラスミドは、様々なCAR発現ベクターがシティ・オブ・ホープ(COH)のT細胞治療研究所(TCTRL)において導き出された、元のプラスミドである。CARの発現に使用されたepHIV7ベクターは、pHIV7ベクターから産生された。重要なことに、このベクターは、CARの発現を駆動するためにヒトEF1プロモーターを使用する。ベクターの5’配列及び3’配列の両方は、以前にHXBc2プロウイルスから導き出されたように、pv653RSNから導き出された。ポリプリントラクトDNAフラップ配列(cPPT)は、NIH AIDS Reagent RepositoryからのHIV‐1系統pNL4‐3から導き出された。ウッドチャック転写後調節エレメント(WPRE)配列は以前に記述されている。
CARを発現する各プラスミドについて、十分な量のプラスミドDNAを産生するために発酵槽に接種する(inoculate)ために使用される、シードバンクが生成された。プラスミドDNAは、レンチウイルスベクターの産生におけるその使用に先立って、同一性、無菌性及びエンドトキシンについて試験された。
Tリンパ球は、白血球フェレーシスによって患者から得られ、適切な同種又は自己のT細胞サブセット、例えばセントラルメモリーT細胞(TCM)がCARを発現するように遺伝的に変更され、次いで抗癌治療を達成するために、任意の臨床的に許容される手段によって患者に投与して戻された。
細胞株:ヒト転移性前立腺癌細胞株DU145(ATCC HTB‐81)及びPC‐3(ATCC CRL‐1435)は、10%ウシ胎児血清(FBS、Hyclone)を含むRPMI‐1640(Lonza)、並びに100U/mLペニシリン、100μg/mLストレプトマイシン、及び0.25μg/mLのファンギゾンを含む1X抗生物質‐抗真菌剤(Gibco)(完全RPMI)中で培養された。ヒト線維肉腫細胞株、HT1080(ATCC CCL‐121)、及びヒト胎性腎臓細胞、293T(ATCC CRL−3216)は、10%FBS、1X抗生物質‐抗真菌剤、25mM HEPES(Irvine Scientific)、及び2mM L‐グルタミン(Fisher Scientific)を含むダルベッコ改変イーグル培地(DMEM、Life Technologies))(完全DMEM)中で培養された。ヒト前立腺癌異種移植片LAPC‐9(Robert Reiter博士、UCLAからの親切な贈り物)は、20%FBS及び1X抗生物質‐抗真菌剤を含有するイスコフ改変ダルベッコ培地(IMDM、Irvine Scientific)(完全IMDM)中で培養された。LAPC‐9細胞は雄のNOD.Cg‐Prkdcscid IL2rgtm1Wj1/SzJ(NSG)マウス内で継代培養され、単一細胞懸濁液は、以前に記載されたように調製された(Craftら、1999 Cancer Res 59:5030)。簡潔には、腫瘍組織が採取され、ペトリ皿で細かく刻まれ、1%プロナーゼE(Roche)を用いて消化された。完全IMDMによる洗浄に続き、単一細胞懸濁液は、40μm細胞ストレーナ(Falcon)を通して濾過され、再度洗浄され、直ちに凍結された。EBCL転換リンパ芽球様細胞株(LCL)、並びに膜係留CD3イプシロン特異的scFvアゴニストOKT3(LCL‐OKT3(Wangら、2011 Blood 117:1888)を含むLCL細胞は、完全RPMI中で培養された。全ての細胞は37℃、5%CO2で培養された。DU145及びPC‐3細胞は、STRプロファイリングによって認証され、マイコプラズマ陰性を確認された(DDC Medical、オハイオ)。
標的遺伝子の発現は、GAPDHに対して正規化された。
Claims (28)
- キメラ抗原レセプターをエンコードする核酸分子であって、
前記キメラ抗原レセプターは:
PSCA結合scFV又は1‐5個のアミノ酸改変を有するそのバリアント;
膜貫通ドメインであり:
CD4膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
CD8膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
CD28膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
から選択される、膜貫通ドメイン;
共刺激ドメインであり:
4‐IBB共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、及び
CD28共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
から選択される、共刺激ドメイン;
CD3ζシグナリングドメイン又は1‐5個のアミノ酸改変を有するそのバリアント;並びに
前記scFvと前記膜貫通ドメインとの間に位置する20‐150個のアミノ酸を有するスペーサー領域、
を含む、
核酸分子。 - 前記共刺激ドメインは:4‐IBB共刺激ドメイン及び1‐5個のアミノ酸改変を有するそのバリアントから成る群から選択される、請求項1に記載の核酸分子。
- 前記膜貫通ドメインは、CD4膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアントである、請求項1に記載の核酸分子。
- 前記膜貫通ドメインは、CD4膜貫通ドメインである、請求項1に記載の核酸分子。
- 前記キメラ抗原レセプターは、
二つの異なる共刺激ドメインであり:
CD28共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
4‐IBB共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、及び
OX40共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
から成る群から選択される、二つの異なる共刺激ドメイン、
を含む、
請求項1に記載の核酸分子。 - 前記キメラ抗原レセプターは、配列ID番号:38のアミノ酸配列を有するPSCA結合scFvを含む、請求項5に記載の核酸分子。
- 前記キメラ抗原レセプターは:
PSCA結合scFV又は1‐2個のアミノ酸改変を有するそのバリアント;
膜貫通ドメインであり:
CD4膜貫通ドメイン又は1‐2個のアミノ酸改変を有するそのバリアント、
CD8膜貫通ドメイン又は1‐2個のアミノ酸改変を有するそのバリアント、
CD28膜貫通ドメイン又は1‐2個のアミノ酸改変を有するそのバリアント、及び
CD3ζ膜貫通ドメイン又は1‐2個のアミノ酸改変を有するそのバリアント、
から選択される、膜貫通ドメイン;
4‐IBB共刺激ドメイン又は1‐2個のアミノ酸改変を有するそのバリアント;及び
CD3ζシグナリングドメイン又は1‐2個のアミノ酸改変を有するそのバリアント;並びに
前記scFvと前記膜貫通ドメインとの間に位置する20‐150個のアミノ酸を有するスペーサー領域、
を含む、
請求項1に記載の核酸分子。 - 前記スペーサー領域は、配列ID番号:2‐12又は1‐5個のアミノ酸改変を有するそれらのバリアントから成る群から選択されるアミノ酸配列を含む、請求項1又は請求項7記載の核酸分子。
- 前記スペーサーは、IgGヒンジ領域を含む、請求項1又は請求項7に記載の核酸分子。
- 前記スペーサーは、10‐50個のアミノ酸を含む、請求項1又は請求項7に記載の核酸分子。
- 前記4‐1BB共刺激ドメインは、配列ID番号:24又は1‐5個のアミノ酸改変を有するそれらのバリアントのアミノ酸配列を含む、請求項1又は請求項7に記載の核酸分子。
- 前記CD3ζシグナリングドメインは、配列ID番号:21のアミノ酸配列を含む、請求項1に記載の核酸分子。
- 3個から15個のアミノ酸のリンカーが、前記共刺激ドメインと前記CD3ζシグナリングドメイン又はそれらのバリアントとの間に位置する、請求項1又は請求項7に記載の核酸分子。
- 当該核酸分子は、配列ID番号:26‐37又は1‐5個のアミノ酸改変を有するそれらのバリアントから選択されるアミノ酸配列を含むポリペプチドを発現する、請求項1に記載の核酸分子。
- 前記1‐5個のアミノ酸改変は、置換である、請求項1に記載の核酸分子。
- 前記1‐2個のアミノ酸改変は、置換である、請求項7に記載の核酸分子。
- キメラ抗原レセプターをエンコードする発現カセットを含むベクターによって導入されたヒトT細胞の集団であって、
前記キメラ抗原レセプターは:
PSCA結合scFV又は1‐2個のアミノ酸改変を有するそのバリアント若しくは1‐5個のアミノ酸改変を有するそのバリアント;
膜貫通ドメインであり:
CD4膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
CD8膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
CD28膜貫通ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
から選択される、膜貫通ドメイン;
共刺激ドメインであり:
4IBB共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、及び
OX40共刺激ドメイン又は1‐5個のアミノ酸改変を有するそのバリアント、
から選択される、共刺激ドメイン;
CD3ζシグナリングドメイン又は1‐5個のアミノ酸改変を有するそのバリアント;並びに
前記scFvと前記膜貫通ドメインとの間に位置する20‐150個のアミノ酸を有するスペーサー領域、
を含む、
ヒトT細胞の集団。 - 配列ID番号:26‐37又は1‐5個のアミノ酸改変を有するそのバリアントから選択されるアミノ酸配列を含むキメラ抗原レセプターを発現するベクターを含む、ヒトT細胞の集団。
- 前記1‐5個のアミノ酸改変は、置換である、請求項18に記載のヒトT細胞の集団。
- 前記T細胞は、セントラルメモリーT細胞の集団で構成される、請求項7に記載のヒトT細胞の集団。
- 患者の癌を処置する方法であって、
キメラ抗原レセプターをエンコードする発現カセットを含むベクターによって導入された自己又は同種のヒトT細胞の集団を投与するステップであり、キメラ抗原レセプターは、配列ID番号:26‐37又は1‐5個のアミノ酸改変を有するそのバリアントから選択されるアミノ酸配列を含む、ステップ、
を含む、方法。 - 前記ヒトT細胞の集団は、セントラルメモリーT細胞を含む、請求項21に記載の方法。
- 前記癌は、前立腺癌である、請求項21に記載の方法。
- 前記癌は、前立腺癌の骨転位である、請求項21に記載の方法。
- 前記癌は、膵臓癌である、請求項21に記載の方法。
- 前記導入されたヒトT細胞は、
患者からT細胞を採取するステップ、
セントラルメモリーT細胞を単離するために前記T細胞を処理するステップ、及び
キメラ抗原レセプターをエンコードする発現カセットを含むウイルスベクターを用いて、前記セントラルメモリーT細胞の少なくとも一部分に導入するステップであり、キメラ抗原レセプターは、配列ID番号:26‐37又は1‐5個のアミノ酸改変を有するそのバリアントから選択されるアミノ酸配列を含む、ステップ、
を含む方法によって調製される、
請求項21に記載の方法。 - 配列ID番号:26‐37から選択されるアミノ酸配列と少なくとも95%一致するアミノ酸配列を含む、ポリペプチドをエンコードする、核酸分子。
- 配列ID番号:26‐37又は1‐5個のアミノ酸改変を有するそのバリアントから選択されるアミノ酸配列を含む、ポリペプチドを発現する、T細胞。
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