JP2013505296A - 多発性骨髄腫細胞からの抗原ペプチドの同定 - Google Patents
多発性骨髄腫細胞からの抗原ペプチドの同定 Download PDFInfo
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Abstract
Description
本発明は、少なくとも1つの抗原ペプチドを含む組成物に関し、この抗原ペプチドは、SLVLNLLEL(配列番号:3)、KNPVLLKIL(配列番号:7)、NLLPKLHVV(配列番号:9)、FLLPHPGLQV(配列番号:10)、LLNMPPAHLK(配列番号:11)、TLVDLPGMTKV(配列番号:13)、TLIDLPGITRV(配列番号:14)、LSLDSSLSSLL(配列番号:17)、LLLDVAYGAVQA(配列番号:22)、FLASESLLKGAL(配列番号:23)、LVLNLLE(配列番号:32)、TLVDLPGM(配列番号:40)、IDLPGITR(配列番号:61)、WLTVLFIFRI(配列番号:66)、LVYLGHVIYL(配列番号:67)、FVPEVSFEL(配列番号:70)、FQMEQIVYC(配列番号:72)からなる群から選択されるアミノ酸配列を含み、この抗原ペプチドはTリンパ球を活性化でき、その活性化Tリンパ球は多発性骨髄腫癌細胞に対して細胞傷害性である。
本発明の抗原ペプチドは、ナイーブT細胞を活性化し、選択したペプチドに特異的な活性化T細胞(例えば、活性化した表面抗原分類(CD)CD4+ T細胞、又は活性化したCD8+ T細胞のいずれかであり、それぞれ活性化ヘルパーT細胞、又はCTLである)になり得る、1つ以上の抗原ペプチドを負荷した人工抗原提示細胞(aAPC)の生成に有用である。aAPCは、ペプチド負荷aAPCを接触させることにより生成される活性化T細胞を含む、治療用組成物及び細胞療法生成物の調製に有用である。抗原提示系の調製及び利用に関する一般的指針については、例えば、米国特許第6,225,042号、同第6,355,479号、同第6,362,001号、及び同第6,790,662号、米国特許公開第2009/0017000号、及び同第2009/0004142号、並びに国際公開第2007/103009号を参照されたい。
本発明は更に、患者への投与用の治療用組成物及び細胞療法生成物として用いられる、活性化Tリンパ球をエクスビボで産生する方法に関する。活性化Tリンパ球をエクスビボで産生するために、被験者から採取されたフェレーシスサンプルからナイーブT細胞を得て、それを選択された1つ以上の本発明の抗原ペプチドを負荷したaAPCと接触させる。その結果、接触されたナイーブT細胞は活性化され、その場合、ナイーブT細胞を活性化するのに使用した、選択された1つ以上の抗原ペプチドに対応する少なくとも1つのエピトープを発現する「標的細胞」に対して感作される。活性化T細胞に遭遇すると、このような標的細胞は、特異的な標的細胞傷害性を示す活性化T細胞の能力に基づく活性化T細胞によって死滅され得る(すなわち、特異的殺細胞)。したがって、その活性化T細胞は細胞傷害性Tリンパ球(CTL)となる。活性化Tリンパ球のCTL活性を測定するのに使用し得る評価法に関しては当該技術分野において多くの例があり、例えば、CTL活性は標準的なクロム(51Cr)遊離アッセイを用いて測定できる(Brunnerら、Immunology.1968 Feb;14(2):181〜96)。
抗原同定に用いた細胞株であるU266(ATCC番号TIB−196)を、10%ウシ胎児血清(FCS)(Invitrogen)を補完したRPMI培地(Invitrogen)中で、細胞培養用フラスコ及び攪拌ボトル内で増幅した。1日目に、通常は0.5×106個細胞/mLで細胞を播種し、細胞密度が2×106個細胞/mLになったとき、典型的には3日目又は4日目に細胞を分割した。
細胞懸濁液を4000rpmで20分間遠心分離して培養した細胞を集め、50mLのコニカルチューブ内で氷冷1×リン酸緩衝生理食塩液(PBS)(Invitrogen)を用いて3回洗浄し、その後カウントした。約1×109個の細胞に相当する細胞ペレットのアリコートを液体窒素で急速に凍らせ、使用まで−80℃で保存した。
ATCC(登録商標)番号:HB−82(商標)(Parham及びBrodsky、Hum Immunol.3(4):277〜99(1981))であるハイブリドーマ細胞株の細胞培養上清から、BB7.2 HLA−A2抗体を精製した。BB7.2抗体は、Santa Cruz Biotechnology,Inc.(Product# sc−32236)及びAbcam(Product# ab74674)から入手することもできる。BB7.2抗体はマウスモノクローナル抗HLA−A2抗体であり、IgG2bアイソタイプである。この抗体は、ヒトHLA−A2組織適合抗原内の、α−2ヘリックスのC末端にあるエピトープ、及び下部βストランドの1つ上のターンを認識する。BB7.2は全てのHLA−A2サブタイプを認識するであろう。HLA−A2.1は、90%がA2サブタイプを示し、残りの10%には主にA2.2、A2.3、A2.5及びA2.7が含まれることを意味する。BB7.2 HLA−A2抗体の結合前に、0.5mLのDynabeads(登録商標)MyOne(商標)トシル活性化(Tosylactivated)ビーズ(Dynal(登録商標)Biotech、カタログ番号655.01)を集め、pH9.5の0.1Mホウ酸ナトリウム緩衝液を含むコーティング緩衝液を用いて4回洗浄した。次いで、0.42mLの4.8mg/mL BB7.2 HLA−A2抗体、コーティング緩衝液3.26mL中、2.08mLの3M(NH4)2SO4を用いて、室温(RT)で72時間ビーズをインキュベートした。Dynal(登録商標)MPC(商標)−1磁気粒子濃縮器(Dynal Biotech ASA,OSLO,Norway)で上清を除去した。続いて、0.5%ウシ血清アルブミン(BSA)及び0.05% Tween 20を含む総容積が同じPBSをビーズに添加し、このビーズをRTで更に48時間インキュベートした。次いで、0.1% BSA及び0.05% Tween 20を含むPBSでビーズを3回洗浄し、0.02%アジ化ナトリウムを含むPBS 2mLに再懸濁した。
U266細胞ペレットのアリコート(1×109個細胞より)を、2.5×107個細胞/mL(50mM Tris(pH8.0)、150mM NaCl、1% CHAPS(Aldrich、カタログ番号226947)、5μM EDTA、0.2%アジ化ナトリウム、17.4μg/mL PMSF(Calbiochem−Novabiochem)、及び2錠のComplete Proteases Inhibitor Cocktail Tablets(Roche、カタログ番号1697498)の濃度で含有する溶解用緩衝液40mL中、回転装置を用いて1時間4℃にて再懸濁した。可溶化液を100,000×gで1時間遠心分離した。沈殿物を捨て、上清を0.22μmのフィルターに通した。続いて、上清をBB7.2 HLA−A2抗体を結合したDynabeads(登録商標)(1mg BB7.2 HLA−A2抗体/25mg Dynabeads(登録商標)、4℃で24時間、回転装置使用)と共にインキュベートした。ビーズペレットをDynal(登録商標)MPC(商標)−1を用いて回収し、以下の4種類の洗浄緩衝液を用いて、一連の50mL洗浄液で洗浄した。
洗浄緩衝液1:50mM Tris(pH8.0)、150mM NaCl、0.05% CHAPS、5μM EDTA、0.2%アジ化ナトリウム、17.4μg/mL PMSF
洗浄緩衝液2:50mM Tris(pH8.0)、150mM NaCl
洗浄緩衝液3:50mM Tris(pH8.0)、450mM NaCl
洗浄緩衝液4:50mM Tris(pH8.0)
ペプチド溶液(HLA−A2関連ペプチドを単離したろ液)を、1%トリフルオロ酢酸(TFA)を添加することにより酸性化した。各サンプルについて脱塩/トラップを目的に10μLをEksigent nanoLC(Eksigent Technologies,Inc.)に次の設定で注入した:トラップカラム=LC PackingsのC18 Pepmap 100、粒径5μm、ポア径100Å、カラム内径300μm×5mm;トラップ用移動相=水、2%メタノール、0.05% TFA;トラップ用流速=5μL/分;分析カラム=Vydac Everest C18、粒径5μm、ポア径300Å、カラム内径75μm×150mm;分析移動相:A=水、2%メタノール、0.1%ギ酸;B=10%水、90%アセトニトリル、0.1%ギ酸;流速=0.2μL/分;分析勾配=0〜80分10〜30% B、80〜120分30〜60% B。Masslynx 4.0を備えるMicromass qTOF Ultima及びESI+モードのnanoSourceにおいて、データ依存MS/MS取り込みを実施した。デノボペプチドシーケンス解析にはProteinLynx 2.0を使用した。
LC/MS/MSを用いたデノボシーケンス解析で得られるペプチド配列は、不完全なペプチド断片化により通常は曖昧である。ペプチドがアルゴンガスと衝突するとき、全ての可能性があるフラグメントが必ず発生するわけではない。実際に、ペプチド結合の一部は、変わらずに無傷である場合がある。加えて、様々な理由(例えば、共溶出、イオン抑制、又はフラグメントが正電荷を持たない場合)により、質量分析計で全てのペプチドフラグメントを検出できるわけではない。したがって、特定のペプチドのLC/MS/MSスペクトルは、完全ではない場合があり、すなわち、ラダー中に欠落段階があり得る。本発明では、ProteinLynx 2.0シーケンス解析ツールを用い、続いて5回の反復評価のうち少なくとも3回から得られた類似する大きさのLC/MS/MSピーク配列を比較することにより、及び、ペプチド配列をヒトタンパク質配列データベースと比較することにより、ペプチド配列の曖昧さを低減した。この方法で、21個のLC/MS/MSピークについて、9〜12個のアミノ酸長を有する24種類のペプチド配列を選択した。24種類のペプチド配列のうち19種を既知のヒト完全長タンパク質にマッピングした(表1)。その後、完全長タンパク質中のHLA結合モチーフの探索により、コンピュータ予測された更なるペプチドを得た(Parkerら、J Immunol.1992 Dec 1;149(11):3580〜7)。24種類の実験的に同定されたペプチド、ペプチドの一部の切断部、及びコンピュータ予測されたペプチドを合成し(ProImmune Inc.,Bradenton,FL)、HLA−A2安定化評価法で試験し、CTLを生成してそれらの活性を標準的な51Cr遊離アッセイで試験した。ペプチド同定方法の略図は図1に示される。表1は、更なる特性評価のために合成された24種類の選択したペプチドのリスト、及び同定された場合はその各ペプチドの関連タンパク質を示す。
配列決定され、HLA−A2安定化及びCTL活性に対する更なる特性評価のために合成するよう選択された24種類のペプチド。完全長タンパク質が同定されなかったペプチド配列は、遺伝子記号、タンパク質受入番号、及び完全長タンパク質のアミノ酸残基の数について空欄である。
クラスI主要組織適合遺伝子複合体(MHC/HLA−A2)分子へのペプチド結合の評価は、抗原プロセシング関連トランスポーター(TAP)欠失細胞株、T2(ATCC(登録商標)番号:CRL−1992)内で合成されるMHCクラスI、HLA−A2分子に対するペプチドの安定化能力に基づく。MHCクラスI分子の安定化の程度は、添加されたペプチドの結合親和性に直接関連する(Townsendら、Cell.1990 Jul 27;62(2):285〜95;Andersenら、Tissue Antigens.1999 Aug;54(2):185〜90)。
24種類の選択したペプチドの相対結合親和性。
ショウジョウバエaAPCをSchneider S2細胞(S2細胞)から生成した。この細胞は数百のOregon−R(野生型)キイロショウジョウバエ(Oregon−R)の胚(American Type Culture Collection(ATCC)CRL−1963)から、発表された手順(Schneider,J.Embryol.Exp.Morph.1972 Vol 27,pp.353〜365)に従って、元々は1969年に確立され、ATCCに寄託されたものである(CRL10974)。S2細胞を10%加熱不活化ウシ胎児血清を補充した市販のSchneiderショウジョウバエ用培地で増殖した。aAPCを生成させるため、HLA−A2.1、B7.1、LFA−3、ICAM−1、及びCD70に対するヒト相補的DNA(cDNA)をpRmHa−3ベクターに別々に挿入し、HLA−A2.1、B7.1、LFA−3、ICAM−1、及びCD70のプラスミドDNAの混合物(aAPCクローン1120について)及びphshneoプラスミドを用いて、リン酸カルシウム沈降法によりS2細胞を形質転換した(pRMHaプラスミドベクターの構築及び使用法については米国特許第6,225,042号を参照されたい)。K562細胞からのHLA−A2.1、K562細胞からのB7.1、HL60細胞からのLFA−3、K562細胞からのICAM−1、及びHLA−A2.1+LCL細胞からのCD70について既報の配列から誘導されたプライマーを使用する、逆転写PCRによる標準的な手法を用いてヒトcDNAを調製した。K562細胞はヒト赤白血病細胞株であり、HL60細胞は前骨髄球性白血病ヒト細胞株であり、かつHLA−A2.1+LCL細胞はエプスタイン・バールウィルス(EBV)形質転換リンパ芽球様細胞株(LCL)である。ジェネテシンを含むSchneider培地で培養し、安定的に形質転換された細胞を選択した。細胞のスケールアップ前に、CuSO4を添加して形質転換遺伝子の発現を誘導する。抗HLA−A2.1、抗B7.1、抗LFA−3、抗ICAM−1、及びCD70抗体を用いるフローサイトメトリーにより発現レベルを評価する。CD8+リンパ球の効率的なインビトロ活性化には、30%超のショウジョウバエ細胞がHLA−A2.1分子を発現しなくてはならない。ショウジョウバエ細胞は、70〜90%のレベルで各分子を恒常的に発現している。ショウジョウバエaAPCを洗浄し、続いて10μMの異なる組み合わせの混合ペプチド、又は個々のペプチドと共にRTで4時間インキュベートした(例えば、米国特許第6,225,042号、同第6,355,479号、同第6,362,001号、及び同第6,790,662号、米国特許公開第2009/0017000号、及び同第2009/0004142号、並びに国際公開第WO2007/103009号、を参照されたい)。続いて、HLA−A2陽性ドナー由来の精製されたヒトCD8+ T細胞を、ペプチド負荷ショウジョウバエAPCと共に、37℃、5%CO2で5日間インキュベートした。5日目にヒトIL−2(20U/mL、R&D Systems)及びIL−7(30U/mL、R&D Systems)を添加し、ペプチド存在下における同一ドナー由来の総末梢血単核球細胞(PBMC)調製物中の非CD8接着細胞を用いて、7日目及び15日目に活性化CD8+ T細胞(CTL)を2回再刺激した。
11種の異なるCTLバッチ(ドナー1:PM1、PM2、PM3、PM4、及びP14、ドナー2:PM1、PM2、PM3、PM4、P5、及びP14)の産生に用いた混合ペプチドの組み合わせを含む組成物、及びペプチド1種のみを含む組成物。
多くの更なるHLA−A2陽性ドナー由来のCTL産生に用いた混合ペプチドの組み合わせを含む組成物、及びペプチド1種のみを含む組成物。
CTL(エフェクター)活性を、個々のペプチドを負荷したT2細胞(標的)、及び標的細胞として多くの腫瘍細胞株も用いた標準的なクロム(51Cr)遊離アッセイにより測定した(Brunnerら、Immunology.1968 Feb;14(2):181〜96)。用量反応を起こすために、1:5で連続希釈したCTL(エフェクター)を用いると、エフェクター(E)標的(T)比(E/T)の最高値は50:1であった。評価の前に、標的細胞(3×106個細胞/4% FCSを含む1×PBS 100μLにおけるT2細胞)を、100μLの51Cr(Perkin Elmer)を添加し、37℃で1時間インキュベートすることにより、標識した。インキュベート後、2.5%ウマ血清(Invitrogen)を含む1×Hank’s Balanced Salt Solution(Invitrogen)で標識標的細胞を4回洗浄し、4℃において1200〜1500rpmで8分間回転し、15mLの新しいMLR培地(10%FCS、1%グルタミン(Glutamin)、1%ペニシリン−ストレプトマイシン、1% HEPES、及び1% MEM非必須アミノ酸溶液を含むRPMI−1640)に再懸濁した。標識T2細胞の最終濃度は0.2×106個細胞/mLであった。評価前に、10μMの個々のペプチドを用いて室温(R.T.)で30分間標識T2細胞を負荷した。評価を開始するため、100μLのCTL(開始時濃度5×106個細胞/mL)を、丸底96ウェルプレート内でMLR培地を用いて1:5に段階的に希釈し、各エフェクター細胞濃度について2回反復とした。100μLの異なる希釈段階のCTLを含む各ウェルに、50μLのK−562細胞(4×106個細胞/mL)(ATCC(登録商標)番号:CCL−243(商標))及び50μLのペプチド負荷51Cr標識T2標的細胞(0.2×106個細胞/mL)を加えた。プレートを37℃、5% CO2で4時間インキュベートし、次いで900rpmで5分間回転し、各ウェルの上清100μLを51Cr計数用チューブに移し、カウントした。
標的細胞として個々のペプチドを負荷したT2細胞を用いた51Cr遊離アッセイにおけるCTL活性CTL活性を強(S)、中(M)、弱(W)、なし(N)、又は未測定(n.d.)として特徴付け、各ペプチドのCTL生成に用いたドナーの総数に対する各レベルの活性を引き起こしたドナーの数の割合として、CTL活性を決定した。
ペプチドの切断バージョン、P3(A)、P13(B)、及びP14(C)で生成されたCTLに対する、標的細胞として個々のペプチドを負荷したT2細胞を用いる51Cr遊離アッセイにおけるHLA−A2結合親和性及びCTL活性。HLA−A2結合親和性及びCTL活性を強(S)、中(M)、弱(W)、なし(N)、又は未測定(n.d.)として特徴付けた。
標的細胞として、完全長タンパク質により同定される元のペプチド配列中のHLA結合モチーフの探索により得られたコンピュータ予測されたペプチドを負荷したT2細胞を用いる51Cr遊離アッセイにおけるHLA−A2結合親和性及びCTL活性。HLA−A2結合親和性及びCTL活性を強(S)、中(M)、弱(W)、なし(N)、又は未測定(n.d.)として特徴付けた。
ウェスタンブロッティングを用い、それぞれ2種の同定されたペプチドP14及びP13に対応する、2種のタンパク質、インターフェロン誘導型MXタンパク質(MX1)及びダイナミン1様タンパク質(DNM1L)の発現を定量した。ヤギ抗ヒトMX1ポリクローナル抗体(カタログ番号sc−34128)及びロバ抗ヤギAp結合抗体をSanta Cruz Biotechnologyから購入した。マウス抗ヒトDNM1Lポリクローナル抗体(カタログ番号NB110−55237)及び抗マウスAP結合抗体をNovus Biologicalから購入した。細胞可溶化物を新たに培養された細胞から作製した。簡潔に言うと、細胞を採取して1×PBSで3回洗浄し、細胞ペレットを溶解用緩衝液(CelLytic(商標)M細胞溶解試薬、Sigma、C2978−50、1×108個細胞/mL)に再懸濁し、4℃で1時間回転した。可溶化物を遠心分離により澄明にし、細胞可溶化物中のタンパク質濃度をBCA法で測定した。3μgの細胞可溶化物を10〜20% SDS−PAGEにかけ、ニトロセルロース膜に転写した。抗MX1及び抗DNM1L抗体を用いてブロットを精査し、WesternBreeze Kit(Invitrogen、WB7104)を用いて検出した。ウェスタンブロッティングの結果により、MX1はほとんどの腫瘍細胞で発現しており、細胞のIFNα処理後に発現が上昇することが示された。正常なヒトドナー由来のPBMCでは、MX1の発現は検出されなかった。ウェスタンブロッティングにより、DNM1Lが全ての細胞種で発現していることが示された。
Claims (9)
- Tリンパ球を活性化可能な合成ペプチドであって、該合成ペプチドが、SLVLNLLEL(配列番号:3)、KNPVLLKIL(配列番号:7)、NLLPKLHVV(配列番号:9)、FLLPHPGLQV(配列番号:10)、LLNMPPAHLK(配列番号:11)、TLVDLPGMTKV(配列番号:13)、TLIDLPGITRV(配列番号:14)、LSLDSSLSSLL(配列番号:17)、LLLDVAYGAVQA(配列番号:22)、FLASESLLKGAL(配列番号:23)、LVLNLLE(配列番号:32)、TLVDLPGM(配列番号:40)、IDLPGITR(配列番号:61)、WLTVLFIFRI(配列番号:66)、LVYLGHVIYL(配列番号:67)、FVPEVSFEL(配列番号:70)、及びFQMEQIVYC(配列番号:72)からなる群から選択されるアミノ酸配列を含み、該活性化Tリンパ球が多発性骨髄腫癌細胞に対して細胞傷害性である、合成ペプチド。
- Tリンパ球を活性化可能な少なくとも1つの抗原ペプチドを含む組成物であって、該抗原ペプチドが、SLVLNLLEL(配列番号:3)、KNPVLLKIL(配列番号:7)、NLLPKLHVV(配列番号:9)、FLLPHPGLQV(配列番号:10)、LLNMPPAHLK(配列番号:11)、TLVDLPGMTKV(配列番号:13)、TLIDLPGITRV(配列番号:14)、LSLDSSLSSLL(配列番号:17)、LLLDVAYGAVQA(配列番号:22)、FLASESLLKGAL(配列番号:23)、LVLNLLE(配列番号:32)、TLVDLPGM(配列番号:40)、IDLPGITR(配列番号:61)、WLTVLFIFRI(配列番号:66)、LVYLGHVIYL(配列番号:67)、FVPEVSFEL(配列番号:70)、及びFQMEQIVYC(配列番号:72)からなる群から選択されるアミノ酸配列を含み、該活性化Tリンパ球が多発性骨髄腫癌細胞に対して細胞傷害性である、組成物。
- 多発性骨髄腫と診断された患者に投与するための活性化Tリンパ球を作製する方法であって、該方法が、
(a)抗原ペプチド負荷ショウジョウバエ人工抗原提示細胞(aAPC)を、少なくとも1つの抗原ペプチドをショウジョウバエaAPCに負荷することにより調製する工程であって、該抗原ペプチドが、SLVLNLLEL(配列番号:3)、KNPVLLKIL(配列番号:7)、NLLPKLHVV(配列番号:9)、FLLPHPGLQV(配列番号:10)、LLNMPPAHLK(配列番号:11)、TLVDLPGMTKV(配列番号:13)、TLIDLPGITRV(配列番号:14)、LSLDSSLSSLL(配列番号:17)、LLLDVAYGAVQA(配列番号:22)、FLASESLLKGAL(配列番号:23)、LVLNLLE(配列番号:32)、TLVDLPGM(配列番号:40)、IDLPGITR(配列番号:61)、WLTVLFIFRI(配列番号:66)、LVYLGHVIYL(配列番号:67)、FVPEVSFEL(配列番号:70)、及びFQMEQIVYC(配列番号:72)からなる群から選択されるアミノ酸配列を含む工程と、
(b)前記患者からTリンパ球を単離する工程と、
(c)該Tリンパ球を該抗原ペプチド負荷ショウジョウバエaAPCと接触させる工程と、
(d)活性化Tリンパ球を生成する工程であって、該活性化Tリンパ球が多発性骨髄腫癌細胞に対して細胞傷害性である工程と、
(e)前記患者に戻し投与するために該活性化Tリンパ球を回収する工程とを含む、方法。 - 前記回収工程で回収された有効量の活性化Tリンパ球を前記患者に投与する工程を更に含む、請求項3に記載の方法。
- 前記少なくとも1つの抗原ペプチドが2つ以上の抗原ペプチドの混合物である、請求項3に記載の方法。
- 前記2つ以上の抗原ペプチドの混合物が、配列番号:3、配列番号:13、及び配列番号:14を含有する組成物を含む、請求項5に記載の方法。
- 前記活性化Tリンパ球を再刺激する工程を更に含み、前記再刺激手順が、
(a)前記活性化Tリンパ球を、IL−2、IL−4、IL−7、IL−12、IL−15、IL−17、IL−21、IFN−g、及びTNF−αからなる群から選択される少なくとも1つのサイトカインと接触させ、これにより活性化T細胞の成長、増殖、及び/又は分化を促進する工程と、
(b)前記活性化T細胞を、照射した自己非CD8+細胞、接着性非CD8+細胞、又は抗原ペプチド負荷ショウジョウバエaAPCとインキュベートし、これにより再刺激された活性化Tリンパ球を生成する工程とを含む、請求項3に記載の方法。 - 前記再刺激手順が、
(a)前記活性化Tリンパ球を、IL−2と、IL−7、IL−15又はIL−21からなる群から選択される少なくとも1つの別のサイトカインとの組み合わせと接触させ、これにより活性化T細胞の成長、増殖、及び/又は分化を促進する工程と、
(b)前記活性化T細胞を、照射した自己非CD8+細胞、接着性非CD8+細胞、又は抗原ペプチド負荷ショウジョウバエaAPCとインキュベートし、これにより再刺激された活性化Tリンパ球を生成する工程とを含む、請求項7に記載の方法。 - 前記再刺激手順が、濃度1〜100U/mLのIL−2;濃度1〜100U/mLのIL−7、濃度1〜100ng/mLのIL−15及び濃度1〜100ng/mLのIL−21の存在下で、前記活性化Tリンパ球を抗原ペプチド負荷ショウジョウバエaAPCと接触させる工程を含む、請求項8に記載の方法。
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