JP6207783B2 - 抗原特異的t細胞の増殖のための方法 - Google Patents
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Description
本発明は、腫瘍を有する患者への投与に好適な遺伝子改変型の抗原特異的CD4+および/またはCD8+T細胞のプライミングのためのin vitro法に関する。この方法は、治療される患者に由来する抗原受容体発現標的T細胞、樹状細胞、抗CD3抗体、ならびに抗原提示細胞(APC)上のMHCクラスIおよび/またはMHCクラスII抗原に感作したリンパ球を共培養することを含む。
本発明を記載する前に、本発明の範囲は添付の特許請求の範囲およびその等価物によってのみ限定されるので、本明細書で使用する用語は単に特定の実施形態を記載する目的で用いられ、限定を意図するものではないと理解されるべきである。
本発明は、抗CD3抗体と組み合わせた、樹状細胞(DC)を含む抗原提示細胞による活性化の際に抗原特異的T細胞の増殖および生存の増大を促進するための、同種感作した同種異系リンパ球(ASAL)の生産に関する。
a)患者または健常ドナー由来の非増殖抗原提示細胞を、前記抗原提示細胞に対して同種異系である末梢血単核細胞とともに培養する工程、
b)患者または健常ドナー由来の単球を、その単球を成熟DCへ成熟させる組成物中で培養する工程(この組成物はさらに下記に記載される)、および
c)工程a)から得られた、限定されるものではないがCD4+T細胞、CD8+T細胞および/またはナチュラルキラー(NK)細胞を含む、同種感作したリンパ球を、工程b)から得られた成熟DCとともに、CD4+T細胞およびCD8+T細胞を含むTCRまたはCARで形質転換された標的細胞を伴って、抗CD3抗体を含有する培養培地中で共培養する工程
を含む。
・増殖能
・低レベルのアポトーシスマーカーアネキシン−Vの発現(すなわち、FACS測定により、アネキシン−V陽性染色を示す細胞が40%以下、好ましくは20%以下であるべきである)
・細胞表面におけるCD27および/またはCD28の発現
材料および方法: 同種感作した同種異系リンパ球(ASAL)は、組織培養フラスコ内の血清不含X−VIVO 15培地中で5〜7日間、健常血液ドナー由来のγ線照射PBMCと同種異系ドナー(前記健常血液ドナーに対して)由来の非照射PBMCを1:1の比で共培養することによる標準的な一方向性混合白血球反応(MLR)において生成した。未熟DCの増殖のため、健常血液ドナーから得た末梢血単核細胞(PBMC)を密度勾配(ノルウェー、オスロ、Nycomed社、Lymphoprep)で単離した。単離されたPBMCをAIM−V培地(UK、ペイズリー、Invitrogen社)に再懸濁させ、24ウェルプラスチック培養プレートに2.5×106細胞/ウェルで播種し、2時間接着させた。非接着細胞を除去し、残った接着単球を組換えヒトGM−CSFおよびIL−4(UK、アビンドン、R&D Systems社;共に1,000U/mL)を添加したAIM−V培地で4〜6日間培養した。未熟DCの成熟は、インキュベーションの最後の24時間に培養培地にIFN−α(3,000U/mL)、IFN−γ(1,000U/mL)、TNF−α(50ng/mL)、IL−1β(25ng/mL)(全てR&D Systems社製)およびp−I:C(Sigma−Aldrich;20μg/mL)を添加することにより誘導した。
材料および方法: ASALは、刺激因子として照射同種異系PBMCを用い、7日間の従来のMLRで生成した(実施例1参照)。採取および照射の後に、ASALのバルク集団(「MLR」)またはCD4+、CD8+またはCD56+(NK/NKT)細胞を除去したASALを、成熟同種異系単球由来DC(ASALのプライミングに用いたPBMCに対して自己)とともに共培養した。24時間後に共培養上清を採取し、その後、IL−2、IL−12およびIFN−γ生産に関してアッセイした。
材料および方法: 未熟DCは、単球のプラスチック接着により生成した。単球は、IL−4およびGM−CFSを両方とも1000U/mLで添加したCellGro(登録商標)DC中で7日間培養した。DCの成熟は、インキュベーションの最後の2日間に50ng/mL TNF−α、25ng/mL IL−1β、50ng/mL IFN−γ、3000U/mL IFN−αおよび20μg/mLポリI:Cを加えることによって誘導した。
材料および方法: 実施例1の材料および方法を参照。
CD8+リンパ球はDC、照射ASAL(前記DCに対して同種異系)を6日間共培養した後に単離し(抗体コーティング磁性ビーズによる陰性選択を使用)、次に、B細胞(初回刺激の際に用いたDCに対して自己)で再刺激し、CD27およびアネキシン−Vの発現に関して染色を行った。続いての分析はFACSにより行った。
材料および方法: 実施例4の材料および方法を参照。
B細胞で再刺激する前に、プライミングおよび単離を行ったCD8+細胞を3H−チミジンでパルス処理した。
材料および方法: 実施例4の材料および方法を参照。
B細胞と予め活性化したCD8+細胞を2日間共培養した後、培養上清を採取し、従来のELISA(R&D Systems社製)によりIFN−γ生産に関して分析した。
材料および方法:
基本培養培地は、10%ヒト血清、1%ペニシリン(100U/ml)、1%HEPES、0.5%L−グルタミンおよび160μl βメルカプトエタノールを添加したRPMI培地1640からなった。
図12に示されるように、ASALのプライミングに用いた照射PBMCに対して自己である、照射した成熟単球由来DCに照射ASALを添加すると、CD64(Fc−γR)を発現するDCの数が増える。この受容体は可溶性抗CD3抗体のFc部分を捕捉すると予想される。このような抗CD3「アームを有する」DCは、次に、共培養された自己または同種異系CD3発現T細胞と直接相互作用してそれを活性化し得る。
Claims (14)
- 腫瘍を有する患者に投与するために好適な遺伝子改変型抗原特異的CD4+および/またはCD8+T細胞のプライミングのためのin vitro法であって、治療される患者に由来する腫瘍抗原受容体発現標的T細胞、成熟樹状細胞、ならびに抗原提示細胞(APC)上のMHCクラスIおよび/またはMHCクラスII抗原に感作したリンパ球を抗CD3抗体の存在下で共培養することを含み、そして前記感作リンパ球は、第2の健常ドナーからの抹消血単核細胞(PMBCs)と、第1の健常ドナーからの非増殖APCsを培養することによって得られる、方法。
- 前記腫瘍抗原受容体は、T細胞受容体(TCR)およびキメラ抗原受容体(CAR)から選択される、請求項1に記載の方法。
- 前記非増殖抗原提示細胞は、PBMCおよび単球由来樹状細胞からなる群から選択される、請求項1に記載の方法。
- 前記成熟樹状細胞は、まず、単球をGM−CSFおよびIL−4を含む組成物中で1〜7日間培養して未熟樹状細胞を得ること、次に、少なくとも12時間培養することで前記未熟樹状細胞を成熟樹状細胞とすることができる第2の組成物を加えることによって得られる、請求項1に記載の方法。
- 前記第2の組成物は、TNFα、IL−1β、インターフェロンγ、インターフェロンαまたはインターフェロンβ、およびTLR3リガンドを含む、請求項4に記載の方法。
- 前記第2の組成物は、TNFα、インターフェロンγ、TLR3リガンドおよび/またはTLR4リガンド、ならびにTLR7アゴニストおよび/またはTLR8アゴニストを含む、請求項4に記載の方法。
- 前記TLR3リガンドはポリ−I:Cであり、かつ、前記TLR8アゴニストはR848である、請求項6に記載の方法。
- 前記細胞は4〜20日間培養される、請求項1に記載の方法。
- 外因性IL−2、IL−7、IL−15、抗IL−4および/またはIL−21が細胞培養に加えられる、請求項1に記載の方法。
- 前記プライミングされた抗原特異的CD4+および/またはCD8+T細胞は、前記細胞を新たな樹状細胞、および新たな感作同種異系リンパ球とともに抗CD3抗体の存在下で培養することにより再刺激される、請求項1に記載の方法。
- 前記プライミングされた抗原特異的CD4+および/またはCD8+T細胞は、前記細胞を新たな樹状細胞、新たな感作同種異系リンパ球とともに抗CD3抗体の存在下で培養すること、および外因性IL−2、IL−7、IL−15、抗IL−4および/またはIL−21を前記細胞培養に添加することにより再刺激される、請求項1に記載の方法。
- 前記TLR3リガンドはポリ-I:Cを含む、請求項5に記載の方法。
- 前記非増殖APCsは前記成熟樹状細胞に対して自己である、請求項1に記載の方法。
- 前記非増殖APCsは照射された末梢血単核細胞(PMBCs)である、請求項1に記載の方法。
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