JP2018516548A - 生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット - Google Patents
生体内での存続性及び治療活性及びその増殖のためのnkt細胞サブセット Download PDFInfo
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Abstract
Description
本発明は国立衛生研究所によって授与されたRO1CA116548及びP50CA126752のもとで政府の支援によって行われた。政府は本発明に特定の権利を有する。
本開示の実施形態は、細胞生物学、分子生物学、免疫学、及び少なくとも癌医学を含む医学の少なくとも分野を包含する。
本開示は、NKT細胞が十分なレベルまで増殖し、生体内にて十分なレベルで持続して治療効果を達成することができるので免疫療法での使用に好適なNKT細胞を提供する。本開示のNKT細胞は、少なくともある程度それらが高い治療適用性を有するようにするCD62Lを発現し、その発現を維持するように操作される。NKT細胞におけるCD62Lの発現のそのような維持は、1以上の共刺激作用因子への曝露の際を含む同時刺激の際に少なくともある程度生じる。
特定の実施形態では、NKT細胞は、細胞がCD62Lの発現を維持できるようにする1以上の共刺激作用因子への曝露に続いて向上した試験官内の増殖及び生体内での存続性を有するので、NKT細胞は治療応用で有用である。1以上の共刺激作用因子は任意の種類のものでもよいが、具体的な実施形態では、それらは、1以上のサイトカイン;(b)共刺激受容体を標的とする1以上のアゴニスト抗体を含む基材(たとえば、ビーズ、プレート等);及び/または(c)CD1dの発現を含み、且つ1以上の共刺激受容体の1以上のリガンドの発現を含む抗原提示細胞のような細胞を含む。NKT細胞がサイトカインに曝露される場合では、サイトカインは好適な種類のものであってもよいが、具体的な場合では、サイトカインはIL−21、IL−2、IL−7、IL−15、IL−12、IL−18、TNFアルファまたはそれらの組み合わせである。具体的な実施形態では、CD62L+NKT細胞はIL−2の存在下での培養の際、IL−21を発現し、IL−21はCD62Lの発現を保持する。
特定の実施形態では、それを必要とする個体への送達に先立ってNKT細胞は遺伝子操作される。NKT細胞は普通、TCR刺激及び同時刺激の後に操作され;特定の実施形態では、遺伝子操作は刺激後1、2、3、4、5日以上以内に発生する(且つこれは、使用される形質導入の種類に左右されてもよく;たとえば、レトロウイルスベクターではそれは2日以内である)。
本開示の細胞は、1以上の共刺激作用因子によって同時刺激されているCD62L陽性NKT細胞と同様にそれ自体抗原提示細胞である特定の共刺激作用因子(抗原提示細胞活性を有する非天然の細胞と呼ばれてもよい)の双方を含む。一部の実施形態では、CD1dを発現している非天然の細胞であり、且つ1以上の共刺激受容体の1以上のリガンドを発現している人工的な抗原提示細胞である、物質の組成物がある。
本開示はまた、本明細書で定義されているような抗原特異的なCARをコードする核酸配列を含む組成物及び該核酸配列を抱えている細胞も包含する。核酸配列は特定の態様では組換え核酸配列であり、合成であってもよい。それはPNA(ペプチド核酸)と同様にDNA、RNAを含んでもよく、それはそれらのハイブリッドであってもよい。
本開示によれば、用語「医薬組成物」は個体に投与するための組成物を指す。本開示の特定の態様では、医薬組成物は複数のNKT細胞を含む。好まれる実施形態では、医薬組成物は、非経口、経皮、腔内、動脈内、クモ膜下もしくは静脈内の投与、または癌への直接注入のための組成物を含む。前記医薬組成物は点滴または注射を介して個体に投与されることが特に想定される。好適な組成物の投与は、様々な方法によって、たとえば、静脈内、皮下、腹腔内、筋肉内、局所または皮内の投与によって達成されてもよい。
実例として、癌患者または癌に感受性の患者または癌を有することが疑われる患者は本明細書に記載されているように治療されてもよい。本明細書に記載されているように操作されたNKT細胞を個体に投与し、長期間保持してもよい。個体は1回以上の細胞の投与を受けてもよい。一部の実施形態では、遺伝子操作された細胞を被包して免疫認識を阻害し、腫瘍の部位に配置する。
本明細書に記載されている組成物のいずれかがキットに含まれてもよい。非限定例では、細胞または細胞を操作する試薬がキットに含まれてもよい。特定の実施形態では、NKT細胞またはNKT細胞を含む細胞の集団がキットに含まれてもよい。そのようなキットは細胞の操作用の1以上の試薬を有してもよいし、または有さなくてもよい。そのような試薬には、たとえば、小分子、タンパク質、核酸、抗体、緩衝液、プライマー、ヌクレオチド、塩及び/またはそれらの組み合わせが挙げられる。1以上のサイトカインをコードするヌクレオチドまたはサイトカイン自体がキットに含まれてもよい。サイトカインまたはアゴニストモノクローナル抗体を含む抗体のようなタンパク質がキットに含まれてもよい。抗体を含む基材または裸の基材自体がキットに含まれてもよく、一部の実施形態では、抗体保有の基材を生成する試薬がキットに含まれる。基材はビーズまたはプレートを含む任意の種類のものであってもよい。抗原提示細胞活性を含む細胞またはそれを生成する試薬がキットに含まれてもよい。それを生成する試薬を含む、キメラ抗原受容体またはT細胞受容体をコードするヌクレオチドがキットに含まれてもよい。
実施例1
生体内の存続性に関与するNKT細胞サブセットの特定及び治療活性及び培養でのこのサブセットの増殖に必要とされる条件を定義すること
実施例2
CD62L+NKT細胞は優れた生体内での存続性及び抗腫瘍活性を有する
実施例3
方法及び材料の実施例
Daudi、Raji、DAOY、Ramos及び293Tの細胞はATCCから購入した。Daudi、Raji、及びRamosの細胞はRPMIで培養したのに対してDAOY及び293Tの細胞はIMDM(Invitrogen)で維持した。双方の種類の培地は10%FBS(Hyclone)、2mMのGlutaMAX−1(Gibco−BRL)によって補完した。
臍帯血のNKT細胞を分析するために、MD Anderson癌センター及びBaylor College of Medicineの施設内倫理委員会によって認可されたプロトコールに従って、MD Anderson癌センター臍帯血バンクから得た廃棄される臍帯血単位を使用した。健常ドナー(少なくとも18歳)のPBMCは、Gulf Coast地域血液センターから購入したバフィーコートから勾配遠心分離によって単離した。NKTは抗iNKTマイクロビーズ(Miltenyi Biotec)によって精製した。陰性PBMC分画を放射線照射(40Gy)して、等分した。100ng/mLのαGalCer(Kyowa Hakko Kirin)でパルスした自己PBMCのアリコートによってNKTを刺激した。組換えIL−2(200U/ml,National Cancer Institute Frederick)を隔日で完全RPMI(HyClone RPMI1640,10%の熱非働化ウシ胎児血清及び2mMのGlutamax)に添加した。NKTを10日間増殖させ、次いで自己PBMC(40Gyで照射した)または指示した場合APCとしてのRamos細胞(100Gyで照射した)によって再刺激した。再刺激の3日後、24穴の非組織培養プレートをレトロネクチン(Takara Bio)で被覆し、洗浄後、CAR.CD19を含有する1mlのレトロウイルス上清によって植菌し、4600Gで60分間遠心した。次いで、ウイルス上清を取り除き、刺激したNKTを完全培地及び200U/mlのrhIL−2でのウェルに加えた。48時間後、細胞をプレートから取り出し、洗浄し、106個/mlの濃度で200U/mlのIL−2を伴った完全RPMIに再浮遊させ、連続した増殖のためにプレートに播いた。トリパンブルー(Life technologies)計数によってNKT細胞の数を決定した。指示された場合、NKTまたはCAR−NKTをCD62L−PEmAb(GREG−56,BD Biosciences)と抗PEマイクロビーズ(Miltenyi)によって標識し、その後、製造元の指示書に従ってCD62L+及びCD62L−のサブセットに磁気で選別した。選別した細胞の表現型をFACSによって決定した。
CAR.CD19及びCAR.GD2の構築物は、以前記載された(Heczeyら,2014;Puleら,2005)ように作製され、それらは、IgG1のヒンジ領域に由来する短いスペーサーを介してCD8αに由来する膜貫通ドメインに接続されたCD19に特異的な抗体FMC−63またはGD2に特異的な抗体14G2aに由来するscFvとその後のζ鎖に融合された4−1BBのシグナル伝達細胞内ドメイン配列を含有した。レトロウイルス上清は、キメラ抗原を含有するプラスミドの組み合わせによる293T細胞の形質移入によって産生されたが、以前記載された(Veraら,2006)ようにRDFプラスミドはRD114のエンベロープをコードし、PegPam3プラスミドはMoMLVのgag−polをコードした。
NKTをCFSE(Invitrogen)で標識し、αGalCerでパルスしたPBMCによって、または20ng/mlの抗CD3(OKT3)を単独で、もしくは0.5μg/mlの抗CD28(CD28.2)及び/または1.5μg/mlの抗4−1BB(h41BB−M127)(BD Biosciences)との組み合わせで被覆したプレートによって刺激した。フローサイトメトリーを用いてCFSEの希釈を測定することによって3日目及び6日目に細胞増殖を調べた。加えて、アネキシン−V及び7−AAD(BD Biosciences)による染色とその後のフローサイトメトリーによって3日目に早期及び後期段階のアポトーシスを測定した。
APCまたはアゴニスト抗体被覆のプレート(クローン6B11、BD Biosciences)によってNKTを24時間刺激した。上清を回収し、製造元の指示書に従ってLuminex(登録商標)アッセイを用いてヒトサイトカイン/ケモカインアッセイキット(Millipore)によって解析した。
以下に対する以下のmAb:HLA−C EMR8−5、CD1d CD1d42、CD86 2331、4−1BBL C65−485、OX40L ik−1、CD3 OKT、Vα24−Jα18 6B11、CD4 SK3、CD62L DREG−56、CD134 ACT35、CD137 4B4−1、PD−1 EH12.1、GATA3 L50−823(BD Biosciences)、LAG−3ポリクローナル、TIM−3 344823(R&D System)、及びウサギ抗LEF1 EP2030YmAb(ABCAM)を用いて免疫表現型検査を行った。BDまたはR&Dが提案した蛍光色素及びアイソタイプが一致したAbを陰性対照として用いた。NKT上でのCAR.CD19の発現は、抗Id(クローン136.20.1)CD19−CAR特異的なmAb(Torikaiら、2013)及びヤギ抗マウスIgG(BD Biosciences)を用いて測定した。BD FACSDivaソフトウエアv.6.0及びFlowJo7.2.5(Tree Star)を用いたLSR−II5レーザーフローサイトメトリー(BD Biosciences)で解析を行った。
以前記載された(Liuら、2013)ように4時間のルシフェラーゼアッセイを用いて親NKT及びCAR.CD19 NKTのDAOYまたはRaji細胞に対する細胞傷害性を評価した。
TRIzol試薬(Qiagen)を用いて全RNAを回収した。nCounter解析システムを用いたBCMゲノム及びRNAプロファイリングコアにて免疫学パネルv.2(NanoString)を用いて遺伝子発現の解析を行った。nSolver2.0ソフトウエア(NanoString)を用いてデータを解析した。
NSGマウスのコロニーは元々Jackson Laboratoryから入手し、BCM動物管理施設で維持されていた。ルシフェラーゼを形質導入したRajiリンパ腫細胞を2×105個i.v.注射することによって腫瘍の増殖を開始させた。3日目に4〜8×106個のCAR−NKTで処理し、その後、3日ごとにIL−2(1000U/マウス)のi.p.注射を行った。生物発光画像法(Small Animal Imaging Core facility,Texas Children’s Hospital)によって週に2回腫瘍増殖を評価した。生体内での存続性の実験については、レトロウイルス構築物を用いてCAR.CD19とルシフェラーゼをNKTに同時形質導入し、それを腫瘍のないマウスまたは担腫瘍マウスにi.v.注射し、生物発光画像法を用いて週2回モニターした。動物実験はIACUCが認可したプロトコールに従って実施した。
試験管内及び生体内の実験については、本発明者らは、対応のある両側t検定を用いて2群の連続変数を評価し、Bonferroniの事後検定と共に一元配置ANOVAを用いて2を超える群の連続変数を評価した。Kaplan/Meier法及びログランク(Mantel−Cox)検定によって生存を解析して群の対を比較した。GraphPad(商標)Prism5.0(GraphPadソフトウエア)を用いて統計データを計算した。p値が0.05未満であれば、差異を有意と見なした。
MD Anderson癌センター(H−16320)及びBaylor College of Medicine(H−20911)における施設内倫理委員会によって認可されたプロトコールに従ってMD Anderson癌センター臍帯血バンクから臍帯血単位を得た。プロトコールH−16320に加わるのに先立って参加女性すべてから文書でのインフォームドコンセントを受け取った。臨床使用に好適ではない(普通少ない細胞数のために)臍帯血単位は廃棄したか、またはBaylor College of MedicineにおけるプロトコールH−20911のもとでの研究目的に使用した。動物実験は、Baylor College of Medicineの施設内動物管理委員会によって認可されたプロトコールAN−5194に従って実施した。
実施例4
NKT細胞に対するIL−21の効果
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Claims (29)
- 免疫療法で使用するためのナチュラルキラーT(NKT)細胞を調製する方法であって、CD62L陽性NKT細胞についてNKT細胞の集団を濃縮する工程を含む、前記方法。
- 前記CD62L陽性NKT細胞が、T細胞受容体の刺激と共刺激受容体及び/またはサイトカインの同時刺激とによって活性化される請求項1に記載の方法。
- 治療を必要とする個体に治療上有効な量の前記細胞を送達する工程をさらに含む請求項1または2に記載の方法。
- 前記細胞が、1以上のキメラ抗原受容体、T細胞受容体、1以上のサイトカイン、1以上のサイトカイン受容体、1以上のキメラサイトカイン受容体、またはそれらの組み合わせを発現するように操作される請求項1、2または3に記載の方法。
- 免疫療法を用いて病状について個体を治療する方法であって、
(a)CD62L陽性NKT細胞についてNKT細胞の集団を濃縮するまたはCD62L陽性NKT細胞について濃縮されているNKT細胞の集団を得る工程と、
(b)治療上有効な量の前記CD62L陽性NKT細胞を前記個体に提供する工程とを含む、前記方法。 - 免疫療法を用いて病状について個体を治療する方法であって、
CD62L+NKT細胞とCD62L−NKT細胞の集団混合物を1以上の共刺激作用因子に曝露して同時刺激されたCD62L+NKT細胞について濃縮し、CD62L+NKT細胞を作出することによって前記集団混合物からCD62L+NKT細胞を増殖させる工程と、
前記個体に治療上有効な量の前記同時刺激されたCD62L+NKT細胞を提供する工程とを含む、前記方法。 - 刺激作用因子及び共刺激作用因子が
(a)1以上のサイトカイン、
(b)T細胞受容体に対するアゴニスト抗体またはリガンド(たとえば、OKT3mAb、6B11mAb、または結合したアルファ−ガラクトシルセラミドのようなアゴニスト糖脂質を伴った組換えヒトCD1d)及び共刺激受容体を標的とする1以上のアゴニスト抗体を含む基材、または
(c)CD1dの発現を含み、且つ1以上の共刺激受容体の1以上のリガンドの発現を含む抗原提示細胞を含む請求項6に記載の方法。 - 前記CD1dの発現が結合したアゴニスト糖脂質を伴う請求項7に記載の方法。
- 前記糖脂質がアルファ−ガラクトシルセラミドである請求項8に記載の方法。
- 前記サイトカインが、IL−21、IL−2、IL−7、IL−15、IL−12、TNFアルファ及びそれらの組み合わせから成る群から選択される請求項7、8または9に記載の方法。
- 前記基材がビーズ、プレートまたはゲルである請求項7〜10のいずれか1項に記載の方法。
- 前記抗原提示細胞に1以上のポリヌクレオチドが形質導入され、1以上の共刺激受容体の1以上のリガンドを発現する請求項7〜11のいずれか1項に記載の方法。
- 前記共刺激受容体がCD28、OX40、4−1BB、ICOS、CD40、CD30、CD27、またはそれらの組み合わせである請求項7〜12のいずれか1項に記載の方法。
- 前記共刺激受容体の前記リガンドが、CD80、CD86、OX40L、4−1BBL、ICOSリガンド、CD154、CD30L、またはそれらの組み合わせである請求項7〜13のいずれか1項に記載の方法。
- 前記NKT細胞が遺伝子操作を含む請求項7〜14のいずれか1項に記載の方法。
- 前記遺伝子操作が前記細胞に癌細胞ターゲティング活性を提供する請求項15に記載の方法。
- 前記癌細胞ターゲティング活性が癌細胞上の抗原のターゲティングを含む請求項16に記載の方法。
- 前記遺伝子操作がT細胞受容体を含む請求項15〜17のいずれか1項に記載の方法。
- 前記遺伝子操作がキメラ抗原受容体を含む請求項15〜17のいずれか1項に記載の方法。
- 1以上の共刺激作用因子に前記集団を曝露した後、前記NKT細胞が遺伝子操作される請求項15〜19のいずれか1項に記載の方法。
- 1以上の共刺激作用因子に前記集団を曝露した後1、2、3、4、5、6日以上以内に、前記NKT細胞が遺伝子操作される請求項20に記載の方法。
- 免疫療法のためのNKT細胞を作出する方法であって、NKT細胞の集団を同時刺激して前記NKT細胞の少なくとも一部でCD62Lの発現を維持する工程を含む、前記方法。
- さらに、それを必要とする個体に有効な量の前記NKT細胞を提供する工程を含む請求項22に記載の方法。
- 免疫療法のためのNKT細胞を作出する方法であって、CD62L+NKT細胞の集団を目的があって濃縮するまたは保持するように設計された1以上の共刺激作用因子にCD62L+NKT細胞の事前に選別された集団またはCD62L+NKT細胞とCD62L−NKT細胞との混合集団を曝露する工程を含む、前記方法。
- さらに、前記混合集団を得る工程を含む請求項24に記載の方法。
- 前記混合集団が、前記濃縮された集団が送達されるであろう個体に由来する請求項24または25に記載の方法。
- 前記混合集団が、前記濃縮された集団が送達されるであろう前記個体とは異なる個体に由来する請求項24または25に記載の方法。
- 前記混合集団が寄託物に由来する請求項24または25に記載の方法。
- 前記混合集団が商業的に得られる請求項24または25に記載の方法。
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