JP6952029B2 - T細胞療法用のt細胞を調製する方法 - Google Patents
T細胞療法用のt細胞を調製する方法 Download PDFInfo
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- JP6952029B2 JP6952029B2 JP2018520185A JP2018520185A JP6952029B2 JP 6952029 B2 JP6952029 B2 JP 6952029B2 JP 2018520185 A JP2018520185 A JP 2018520185A JP 2018520185 A JP2018520185 A JP 2018520185A JP 6952029 B2 JP6952029 B2 JP 6952029B2
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Description
本発明は、米国保健社会福祉省の機関である、米国立がん研究所(NCI)との共同研究開発契約の履行においてなされた。米国政府は本発明において一定の権利を有する。
本発明は、T細胞療法用の1つまたは複数のT細胞を調製する方法に関する。特に、本発明は、1つまたは複数のT細胞をAKTインヒビター(「AKTi」)ならびに外因性インターロイキン-7(IL-7)および外因性インターロイキン-15(IL-15)のうちの少なくとも1つと接触させることによってT細胞療法の効能を改善する方法に関する。
ヒトのがんは、本質的に、遺伝的または後成的変換を受けて異常ながん細胞となった正常細胞から構成される。そうする際に、がん細胞は、正常細胞によって発現されるものとは異なるタンパク質および他の抗原を発現し始める。これらの異常な腫瘍抗原は、がん細胞を特異的にターゲティングおよび死滅させるために身体の自然免疫系によって使用され得る。しかしながら、がん細胞は、様々な機構を用いて、TおよびBリンパ球のような免疫細胞が首尾よくがん細胞をターゲティングすることを妨げる。
本発明は、T細胞療法において使用するためのT細胞を調製するための方法に関する。特に、本発明は、1つまたは複数のT細胞を、AKTiと、外因性IL-7および外因性IL-15のうちの少なくとも1つとに接触させることによって、インビトロでT細胞の成熟または分化を調節する、例えば、遅らせるまたは阻害する、方法に関する。T細胞の成熟または分化を遅らせるまたは阻害することによって、ドナーT細胞の集団は、あまり分化していない未熟なT細胞(例えば、ナイーブT細胞またはセントラルメモリーTcm細胞)について富化され得、対象、例えば患者へ投与された後の1つまたは複数のT細胞の持続可能性が増加され得る。結果として、富化された未熟T細胞の集団は、分化段階が混合しているT細胞の集団よりも持続した抗腫瘍効果を生じさせる可能性が高い。
本開示がより容易に理解され得るように、一定の用語を先ず定義する。本出願において使用される場合、本明細書において特に明示的に提供される場合を除き、以下の用語の各々は下記に記載される意味を有するものとする。追加の定義は本出願の全体にわたって記載される。
本開示は、細胞療法において使用するための免疫細胞(例えば、リンパ球または樹状細胞)を調製するための方法に関する。あるインビトロ操作された細胞(例えば、CAR T細胞、TCR細胞、または樹状細胞)は、インビトロ操作後に患者へ投与される際に同じほどには有効でないことが分かる。いかなる理論によっても拘束されないが、一つの理由は、リンパ球が、患者へ投与される前にインビトロで時期尚早に分化され得ることであり得ることが、注意される。本開示は、ある態様において、AKTiと、外因性IL-7および外因性IL-15のうちの少なくとも1つとを添加することによって、インビトロで細胞の時期尚早な分化を遅らせる、妨げるまたは阻害するための方法を記載する。
AKTキナーゼファミリーは、各々が独特な機能および重複する機能を有する、3つの高度に相同なアイソフォーム:AKT1(PKBα)、AKT2(PKBβ)、およびAKT3(PKBγ)を有する。AKTは、PI3K-AKT-mTORシグナリング経路の一部として、mTORを活性化するためにPI3Kの下流で作用し、生存、成長、増殖、移動、および代謝を含む細胞中における様々な応答を誘発する。
式中:aは0または1であり;bは0または1であり;mは0、1または2であり;nは0、1または2であり;pは0、1、2または3であり;rは0または1であり;sは0または1であり;tは2、3、4、5または6であり;u、vおよびxはCHおよびNより独立して選択され;wは結合、CHおよびNより選択され;yおよびzはCHおよびNより独立して選択され、但し、yおよびzのうちの少なくとも1つはNであり;R1は:1) (C=O)aObC1-C10アルキル、2) (C=O)aObアリール、3) C2-C10アルケニル、4) C2-C10アルキニル、5) (C=O)aObヘテロシクリル、6) (C=O)aObC3-C8シクロアルキル、7) CO2H、8)ハロ、9) CN、10) OH、11) ObC1-C6ペルフルオロアルキル、12) Oa(C=O)bNR7R8、13) NRc(C=O)NR7R8、14) S(O)mRa、15) S(O)2NR7R8、16) NRcS(O)mRa、17)オキソ、18) CHO、19) NO2、20) NRc(C=O)ObRa、21) O(C=O)ObC1-C10アルキル、22) O(C=O)ObC3-C8シクロアルキル、23) O(C=O)Obアリール、および24) O(C=O)Ob-複素環より独立して選択され;前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル、およびシクロアルキルは、Rzより選択される1つまたは複数の置換基で置換されてもよく;R2は:1) (C=O)aObC1-C10アルキル、2) (C=O)aObアリール、3) C2-C10アルケニル、4) C2-C10アルキニル、5) (C=O)aObヘテロシクリル、6) (C=O)aObC3-C8シクロアルキル、7) CO2H、8)ハロ、9) CN、10) OH、11) ObC1-C6ペルフルオロアルキル、12) Oa(C=O)bNR7R8、13) NRc(C=O)NR7R8、14) S(O)mRa、15) S(O)2NR7R8、16) NRcS(O)mRa、17) CHO、18) NO2、19) NRc(C=O)ObRa、20) O(C=O)ObC1-C10アルキル、21) O(C=O)ObC3-C8シクロアルキル、22) O(C=O)Obアリール、および23) O(C=O)Ob-複素環より独立して選択され;前記アルキル、アリール、アルケニル、アルキニル、ヘテロシクリル、およびシクロアルキルは、Rzより選択される1、2または3個の置換基で置換されてもよく;R3およびR4は、H、C1-C6-アルキルおよびC1-C6-ペルフルオロアルキルより独立して選択されるか、またはR3およびR4は、組み合わされて-(CH2)t-を形成し、ここで、炭素原子のうちの1つは、O、S(O)m、-N(Rb)C(O)-、および-N(CORa)-より選択される部分によって置き換えられてもよく;R5およびR6は、1) H、2) (C=O)ObRa、3) C1-C10アルキル、4) アリール、5) C2-C10アルケニル、6) C2-C10アルキニル、7)ヘテロシクリル、8) C3-C8シクロアルキル、9) SO2Ra、および10) (C=O)NRb 2より独立して選択され、前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル、およびアルキニルは、Rzより選択される1つまたは複数の置換基で置換されてもよく、またはR5およびR6は、それらが結合されている窒素と一緒になって、各環中に5〜7員を有し、さらに任意で、窒素に加えて、N、OおよびSより選択される1つまたは2つの追加のヘテロ原子を含有してもよい、単環式または二環式複素環を形成し得、この単環式または二環式複素環は、Qで置換されてもよく、さらにRzより選択される1つまたは複数の置換基で置換されてもよく;Qは、-NR7R8、アリールおよびヘテロシクリルより選択され、前記アリールおよびヘテロシクリルは、Rzより選択される1〜3個の置換基で置換されてもよく;R7およびR8は、1) H、2) (C=O)ObC1-C10アルキル、3) (C=O)ObC3-C8シクロアルキル、4) (C=O)Obアリール、5) (C=O)Obヘテロシクリル、6) C1-C10アルキル、7)アリール、8) C2-C10アルケニル、9) C2-C10アルキニル、10)ヘテロシクリル、11) C3-C8シクロアルキル、12) SO2Ra、および13) (C=O)NRb 2より独立して選択され;前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル、およびアルキニルは、Rzより選択される1つまたは複数の置換基で置換されてもよく、またはR7およびR8は、それらが結合されている窒素と一緒になって、各環中に5〜7員を有し、さらに任意で、窒素に加えて、N、OおよびSより選択される1つまたは2つの追加のヘテロ原子を含有してもよい、単環式または二環式複素環を形成し得、この単環式または二環式複素環は、Rzより選択される1つまたは複数の置換基で置換されてもよく;Rzは、1) (C=O)rOs(C1-C10)アルキル、2) Or(C1-C3)ペルフルオロアルキル、3) (C0-C6)アルキレン-S(O)mRa、4)オキソ、5) OH、6)ハロ、7) CN、8) (C=O)rOs(C2-C10)アルケニル、9) (C=O)rOs(C2-C10)アルキニル、10) (C=O)rOs(C3-C6)シクロアルキル、11) (C=O)rOs(C0-C6)アルキレン-アリール、12) (C=O)rOs(C0-C6)アルキレン-ヘテロシクリル、13) (C=O)rOs(C0-C6)アルキレン-N(Rb)2、14) C(O)Ra、15) (C0-C6)アルキレン-CO2Ra、16) C(O)H、17) (C0-C6)アルキレン-CO2H、18) C(O)N(Rb)2、19) S(O)mRa、20) S(O)2N(Rb)2、21) NRc(C=O)ObRa、22) O(C=O)ObC1-C10アルキル、23) O(C=O)ObC3-C8シクロアルキル、24) O(C=O)Obアリール、および25) O(C=O)Ob-複素環より選択され;前記アルキル、アルケニル、アルキニル、シクロアルキル、アリール、およびヘテロシクリルは、Rb、OH、(C1-C6)アルコキシ、ハロゲン、CO2H、CN、O(C=O)C1-C6アルキル、オキソ、およびN(Rb)2より選択される3個までの置換基で置換されてもよく;Raは、置換または非置換(C1-C6)アルキル、置換または非置換(C2-C6)アルケニル、置換または非置換(C2-C6)アルキニル、置換または非置換(C3-C6)シクロアルキル、置換または非置換アリール、(C1-C6)ペルフルオロアルキル、2,2,2-トリフルオロエチル、または置換または非置換ヘテロシクリルであり;かつ、Rbは、H、(C1-C6)アルキル、置換または非置換アリール、置換または非置換ベンジル、置換または非置換ヘテロシクリル、(C3-C6)シクロアルキル、(C=O)OC1-C6アルキル、(C=O)C1-C6アルキルまたはS(O)2Raであり;Rcは、1) H、2) C1-C10アルキル、3)アリール、4) C2-C10アルケニル、5) C2-C10アルキニル、6)ヘテロシクリル、7) C3-C8シクロアルキル、8) C1-C6ペルフルオロアルキルより選択され、前記アルキル、シクロアルキル、アリール、ヘテロシクリル、アルケニル、およびアルキニルは、Rzより選択される1つまたは複数の置換基で置換されてもよい。
インターロイキン-7(IL-7)は、リンパ球恒常性を促進し、T細胞発達に必要な、サイトカインである。内因性IL-7は、胸腺および骨髄中の上皮細胞によって産生され、その受容体であるIL-7受容体-α(IL-7R-α)は、ナイーブT細胞およびTCM細胞を含むT細胞のサブセットによって発現される。IL-7シグナリングは、Janusキナーゼ/シグナル伝達性転写因子(Jak/STAT)経路、PI3K、およびSrcファミリーチロシンキナーゼを含む様々なチロシンキナーゼを生じさせる。
本明細書に記載される1つまたは複数のT細胞は、例えばヒトドナーを含む、任意の供給源から得ることができる。ドナーは、抗がん治療(例えば、本明細書に記載される方法によって作製される1つまたは複数のT細胞での治療)の必要がある対象であり得(即ち、自己ドナー)、または、本明細書に記載される方法によって作製される細胞の集団が作製された後に、異なる個体またはがん患者を治療するために使用されるリンパ球サンプルを供与する個体であり得る(即ち、同種異系ドナー)。リンパ球の集団は、当技術分野において使用される任意の好適な方法によってドナーから得ることができる。例えば、リンパ球の集団は、任意の好適な体外的方法、静脈穿刺、または血液および/もしくはリンパ球のサンプルが得られる他の血液採取方法によって、得ることができる。一態様において、リンパ球の集団をアフェレーシスによって得る。1つまたは複数のT細胞は、腫瘍を含むがこれに限定されない、1つまたは複数のT細胞を含む任意の組織から採取することができる。いくつかの態様において、腫瘍またはその一部分を対象から採取し、腫瘍組織から1つまたは複数のT細胞を単離する。T細胞療法に適した任意のT細胞を含んで、任意のT細胞が本明細書に開示される方法において使用され得る。例えば、本発明に有用な1つまたは複数の細胞は、腫瘍浸潤リンパ球(TIL)、細胞傷害性T細胞、CAR T細胞、改変TCR T細胞、ナチュラルキラーT細胞、樹状細胞、および末梢血リンパ球からなる群より選択され得る。一つの特定の態様において、T細胞は腫瘍浸潤白血球である。ある態様において、1つまたは複数のT細胞は、CD8を発現し、例えば、CD8+ T細胞である。他の態様において、1つまたは複数のT細胞は、CD4を発現し、例えば、CD4+ T細胞である。
本発明は、T細胞療法のためにインビトロでT細胞の成熟または分化を調節する、例えば、遅らせるまたは阻害する方法であって、T細胞療法の必要がある対象由来の1つまたは複数のT細胞を、(i)AKTインヒビターと、外因性インターロイキン-7(IL-7)および外因性インターロイキン-15(IL-15)のうちの少なくとも1つとに接触させる工程を含み、ここで、結果として生じるT細胞が遅延した成熟または分化を示す、方法を提供する。いくつかの態様において、方法は、1つまたは複数のT細胞をその必要がある対象へ投与する工程をさらに含む。当業者は、本明細書に記載される方法によって生成される1つまたは複数のT細胞が、1つまたは複数のT細胞を患者へ投与する工程を含む、患者を治療する任意の方法において使用され得ることを理解するだろう。
本発明の方法は、対象中のがんを治療し、腫瘍のサイズを低減させ、腫瘍細胞を死滅させ、腫瘍細胞増殖を予防し、腫瘍の成長を予防し、患者から腫瘍を排除し、腫瘍の再発を予防し、腫瘍転移を予防し、患者において寛解を誘発し、またはそれらの任意の組み合わせを行うために使用することができる。ある態様において、方法は完全奏効を誘発する。他の態様において、方法は部分奏効を誘発する。
インビトロで1つまたは複数のT細胞と接触させるためのAKTインヒビターと外因性IL-7および外因性IL-15のうちの1つまたは複数とを含むキット、例えば、薬学的キットが、本発明の範囲内にさらに含まれる。キットは、典型的に、キットの内容物の意図される使用を表示するラベルおよび使用説明書を含む。用語「ラベル」は、キット上にもしくはキットと共に提供されるか、または他の方法でキットに付随する、任意の記述または記録された材料を含む。
(i)AKTインヒビター、
(ii)外因性IL-7、および
(iii)T細胞療法における使用に意図される1つまたは複数のT細胞をAKTインヒビターおよび外因性IL-7と接触させるための説明書。
(i)AKTインヒビター、
(ii)外因性IL-15、および
(iii)T細胞療法における使用に意図される1つまたは複数のT細胞をAKTインヒビターおよび外因性IL-15と接触させるための説明書。
(i)AKTインヒビター、
(ii)外因性IL-7、
(iii)外因性IL-15、および
(iii)T細胞療法における使用に意図される1つまたは複数のT細胞をAKTインヒビター、外因性IL-7、および/または外因性IL-15と接触させるための説明書。
E1.T細胞療法のためにインビトロでT細胞の成熟または分化を遅らせるまたは阻害するための方法であって、T細胞療法の必要がある対象由来の1つまたは複数のT細胞を、AKTインヒビターと、外因性インターロイキン-7(IL-7)および外因性インターロイキン-15(IL-15)のうちの少なくとも1つとに接触させる工程を含み、ここで、結果として生じるT細胞が遅延した成熟または分化を示し、かつ/または、ここで、結果として生じるT細胞が、AKTインヒビターの非存在下で培養されたT細胞のT細胞機能と比べて改善されたT細胞機能を示す、方法。
(i)増加したT細胞増殖;
(ii)増加したサイトカイン産生;
(iii)増加した細胞溶解活性;および
(iv)(i)〜(iii)の任意の組み合わせ
からなる群より選択される、E1またはE2の方法。
ドナーT細胞を、等しい平板培養濃度で10日間、IL-2、IL-7、IL-15、および/またはAKTインヒビターの存在下で培養した。培養されたT細胞のT細胞表現型を、(i)IL-7およびIL-15と比較してのIL-2単独中において7および14日間培養された、ならびに(ii)IL-7、IL-15、およびAKTインヒビターと比較してのIL-7およびIL-15中において培養された、CD4+ T細胞およびCD8+ T細胞について決定した(図1A〜図1F)。細胞をIL-7およびIL-15の存在下で増殖させた場合に、より幼若なT細胞への傾向が観察された。特に、有意により高い(p = 0.03, n = 6)パーセントのナイーブおよびTcm細胞 CD4+が、IL-2処理細胞と比較してIL-7/IL-15処理細胞において観察されたが(図1A)、より成熟したエフェクターT細胞のパーセントにおいて差は観察されなかった(図1B)。この効果は、CD4+コンパートメント中において長期培養後に維持されなかった(データを示す(data now shown))。同様の効果がCD8+コンパートメント中において観察され、IL-2処理細胞培養と比較してIL-7/IL-15処理細胞培養において、有意により高い(p = 0.03, n = 6)パーセントのナイーブおよびTcm細胞(図1C)ならびに有意により低い(p = 0.03, n = 6)パーセントのエフェクターT細胞(図1D)を伴った。しかしながら、CD4+コンパートメント中とは異なり、この効果はCD8+コンパートメント中において長期培養後に観察された(図1E, p = 0.03, n = 6;および図1F, p = 0.03, n = 6)。
細胞増殖に対するAKTiインヒビターの効果を様々な条件下で調べた。先ず、ドナー細胞の様々な供給源に対するAKTi培養条件の効果を以下のように評価した。4名の健康なドナーからのアフェレーシスプロダクトを、高密度遠心分離を使用して処理し、末梢血単核細胞(PBMC)を得た(図4A〜4D)。4名のドナーからの細胞をカウントし、OKT3(CD3に対するモノクローナル抗体)を使用して刺激し、そして7〜10日間、IL-2(円);IL-2およびAKTi(正方形);IL-7およびIL-15(三角形);またはIL-7、IL-15、およびAKTi(逆三角形)の存在下で培養した(図4A〜4D)。細胞増殖を各培養条件下での各ドナー細胞株について観察したところ、AKTiは細胞増殖に対してマイナスの影響を有さなかった(図4A〜4D)。
AKTiの存在下での培養に続いてのT細胞の形質導入効率に対する効果を調べた。以前に凍結されたドナーT細胞を刺激し、次いで、IL-2、IL-2およびAKTi;IL-7およびIL-15;またはIL-7、IL-15、およびAKTiの存在下で10日間培養した。細胞に、T-75組織培養フラスコ中においてクラスI TCR(HPV-E6)を(図10)、またはOriGen PERMALIFE(商標)バッグ中においてクラスII TCR(MAGE-A3)を(図11A〜11F)、刺激後2日目に形質導入した。T細胞形質導入効率を10日目に抗mTCRb抗体染色によって測定した(図10および11A〜11F)。抗mTCRb染色MFIは、IL-7およびIL-15のみと比べて、IL-7、IL-15、およびAKTiの存在下で培養された細胞について僅かにより大きな全体的な強度を示すが(図11Cおよび11F)、AKTiは形質導入効率に対してマイナスの影響を有さなかった(図10、11A、11B、11D、および11E)。
分化状態に対する様々な培養条件の効果を決定するために、3名のドナーからのCD4+/CD8+ T細胞にクラスII TCR (MAGE-A3)を形質導入し、IL-2;IL-2およびAKTi;IL-7およびIL-15;ならびにIL-7、IL-15、およびAKTiの存在下で培養した。次いで、細胞を、分化の初期段階のマーカーであるCD62Lへ向けられた抗体で染色した。CD62L発現に陽性に染まる細胞のパーセントを、ドナー1、2、および3の各々についての各培養条件からの細胞について決定した(それぞれ、図13A、13B、および13C)。平均蛍光強度(MFI)は、AKTiの存在下で培養された細胞が、AKTiの非存在下で培養された細胞と比較して、陽性細胞の表面上により大きなレベルのCD62Lを有したことを示した(図13D〜13E)。
T細胞機能に対するAKTiの効果を決定するために、サイトカイン産生およびT細胞増殖を、様々な条件下での培養に続いて評価した。4つの製造規模実行(21、22、および23)からのT細胞を、IL-2;IL-2およびAKTi;IL-7およびIL-15;ならびにIL-7、IL-15、およびAKTiの存在下で、OriGen PERMALIFE(商標)バッグ中において培養した。2日目に、T細胞にクラスII TCR(MAGE-A3)を形質導入し、次いで、IL-7およびIL-15、またはIL-7、IL-15およびAKTiの存在下で、XURI(商標)Bioreactor Cell Expansion System中において増殖させた。T細胞を、5.5時間、PMA+イオノマイシン+ブレファルジンA(BrefaldinA)+モネンシンで刺激した。細胞内フローサイトメトリーは、サイトカインIFNg(図14A)およびTNFa(図14B)の産生の産生増加によって証明されたように、AKTiの存在下で培養された細胞について増加したT細胞活性を示した。
T細胞の細胞溶解活性に対するAKTiの効果を決定するために、ルシフェラーゼを発現する標的細胞を、16〜96時間の範囲の期間にわたって、上述のように、様々な培養条件(IL-2単独;IL-2およびAKTi;IL-7およびIL-15;ならびにIL-7、IL-15、およびAKTi)下で増殖させたT細胞と共培養する。次いで、T細胞を、ルシフェラーゼを発現する標的細胞と共培養する。標的細胞生存能力をルシフェラーゼ強度によって測定し、ルシフェラーゼ強度の減少は、T細胞認識および標的特異的死滅を示す。従って、ルシフェラーゼレベルの低減はT細胞の細胞傷害性の直接的指標である。AKTインヒビターの存在下で培養された細胞は、AKTインヒビターの非存在下で培養された細胞よりも大きな細胞傷害性を有することが予想される。
Claims (10)
- ドナー由来の1種以上のT細胞を、AKTインヒビター、外因性インターロイキン−7(IL−7)および外因性インターロイキン−15(IL−15)に、インビトロで接触させる工程を含み、
前記1種以上のT細胞は外因性インターロイキン−2(IL−2)と接触されない、
T細胞を調製する方法。 - 前記T細胞は、ナイーブT細胞(T n )及び/又はセントラルメモリーT細胞(T cm )である、請求項1に記載の方法。
- 前記ドナーは、T細胞療法が必要な対象である、請求項1又は2に記載の方法。
- 前記1種以上のT細胞は、CD4+T細胞を含む、請求項1〜3のいずれかに記載の方法。
- 前記AKT阻害剤、外因性IL−7、及び外因性IL−15との接触後、前記T細胞は、
(i)CCR7およびCD45ROを発現する、
(ii)CCR7およびCD45RAを発現する、
(iii)AKTインヒビター、外因性IL−7および外因性IL−15と接触させられないT細胞によるCCR7、CD45ROおよびCD45RAの発現と比較して、CCR7、CD45RO、CD45RAまたはそれらの任意の組み合わせの増加した発現を示す、
(iv)CD62L、CD28または両方を発現する、
(v)AKTインヒビター、外因性IL−7および外因性IL−15と接触させられないT細胞によるCD62LおよびCD28の発現と比較して、CD62L、CD28または両方の増加した発現を示す、
(vi)AKTインヒビター及び外因性IL−7、外因性IL−15または両方との接触に続いて、AKTインヒビターならびに外因性IL−7および外因性IL−15と接触させられないT細胞によるCD95、IL−7受容体アルファ(IL−7Rα)、CXCR4、TCF7、FOXO1、ID3、BCL6、CD62LおよびCD45RAの発現と比較して、CD95、IL−7Rα、CXCR4、TCF7、FOXO1、ID3、BCL6、CD62L及びCD45RA又はこれらの任意の組み合わせの増加した発現を示す、或いは
(vii)(i)〜(vi)の任意の組み合わせである、
請求項1〜4のいずれかに記載の方法。 - 前記1種以上のT細胞が、腫瘍浸潤リンパ球、細胞傷害性T細胞、CAR T細胞、改変TCR T細胞、ナチュラルキラーT細胞、及び末梢血リンパ球からなる群より選択される、請求項1〜5のいずれかに記載の方法。
- 前記T細胞をレトロウイルスで形質導入することを更に含む、請求項1〜6のいずれかに記載の方法。
- 前記レトロウイルスが、T細胞受容体(TCR)またはキメラ抗原受容体(CAR)をコードする異種遺伝子を含む、請求項7に記載の方法。
- 前記TCRまたはCARが、707−AP(707アラニンプロリン)、AFP(アルファ(a)−フェトプロテイン)、ART−4(T4細胞により認識される腺癌抗原)、BAGE(B抗原; b−カテニン/m、b−カテニン/変異型)、BCMA(B細胞成熟抗原)、Bcr−abl(ブレイクポイントクラスター領域−Abelson)、CAIX(カルボニックアンヒドラーゼIX)、CD19(分化クラスター19)、CD20(分化クラスター20)、CD22(分化クラスター22)、CD30(分化クラスター30)、CD33(分化クラスター33)、CD44v7/8(分化クラスター44, エクソン7/8)、CAMEL(メラノーマ上のCTL認識抗原)、CAP−1(癌胎児抗原ペプチド−1)、CASP−8(カスパーゼ−8)、CDC27m(細胞分裂周期27変異型)、CDK4/m(サイクリン依存性キナーゼ4変異型)、CEA(癌胎児抗原)、CT(癌/精巣(抗原))、Cyp−B(サイクロフィリンB)、DAM(分化抗原メラノーマ)、EGFR(上皮成長因子受容体)、EGFRvIII(上皮成長因子受容体, バリアントIII)、EGP−2(上皮糖タンパク質2)、EGP−40(上皮糖タンパク質40)、Erbb2, 3, 4(赤芽球性白血病ウイルスがん遺伝子ホモログ−2, −3, 4)、ELF2M(伸長因子2変異型)、ETV6−AML1(Etsバリアント遺伝子6/急性骨髄性白血病1遺伝子ETS)、FBP(葉酸結合タンパク質)、fAchR(胎児アセチルコリン受容体)、G250(糖タンパク質250)、GAGE(G抗原)、GD2(ジシアロガングリオシド2)、GD3(ジシアロガングリオシド3)、GnT−V(N−アセチルグルコサミニルトランスフェラーゼV)、Gp100(糖タンパク質100kD)、HAGE(ヘリコーゼ(helicose)抗原)、HER−2/neu(ヒト表皮受容体−2/神経学的;EGFR2としても公知)、HLA−A(ヒト白血球抗原−A) HPV(ヒト乳頭腫ウイルス)、HSP70−2M(熱ショックタンパク質70 − 2変異型)、HST−2(ヒト印環腫瘍−2)、hTERTまたはhTRT(ヒトテロメラーゼ逆転写酵素)、iCE(腸カルボキシルエステラーゼ)、IL−13R−a2(インターロイキン−13受容体サブユニットアルファ−2)、KIAA0205、KDR(キナーゼ挿入ドメイン受容体)、κ−軽鎖、LAGE(L抗原)、LDLR/FUT(低密度脂質受容体/GDP−L−フコース:b−D−ガラクトシダーゼ2−a−Lフコシルトランスフェラーゼ)、LeY(ルイスY抗体)、L1CAM(L1細胞接着分子)、MAGE(メラノーマ抗原)、MAGE−A1(メラノーマ関連抗原1)、MAGE−A3、MAGE−A6、メソテリン、マウスCMV感染細胞、MART−1/Melan−A(T細胞により認識されるメラノーマ抗原−1/メラノーマ抗原A)、MC1R(メラノコルチン1受容体)、Myosin/m(ミオシン変異型)、MUC1(ムチン1)、MUM−1, −2, −3(メラノーマユビキタス変異型1, 2, 3)、NA88−A(患者M88のNA cDNAクローン)、NKG2D(ナチュラルキラーグループ2, メンバーD)リガンド、NY−BR−1(ニューヨーク乳房分化抗原1)、NY−ESO−1(ニューヨーク食道扁平上皮癌−1)、腫瘍胎児抗原(h5T4)、P15(タンパク質15)、p190 minor bcr−abl(190KD bcr−ablのタンパク質)、Pml/RARa(前骨髄球性白血病/レチノイン酸受容体a)、PRAME(メラノーマの優先的に発現される抗原)、PSA(前立腺特異抗原)、PSCA(前立腺幹細胞抗原)、PSMA(前立腺特異的膜抗原)、RAGE(腎臓抗原)、RU1またはRU2(腎臓ユビキタス1または2)、SAGE(肉腫抗原)、SART−1またはSART−3(腫瘍拒絶扁平上皮抗原1または3)、SSX1, −2, −3, 4(滑膜肉腫X1, −2, −3, −4)、TAA(腫瘍関連抗原)、TAG−72(腫瘍関連糖タンパク質72)、TEL/AML1(転座Etsファミリー白血病/急性骨髄性白血病1)、TPI/m(トリオースホスフェートイソメラーゼ変異型)、TRP−1(チロシナーゼ関連タンパク質1、またはgp75)、TRP−2(チロシナーゼ関連タンパク質2)、TRP−2/INT2(TRP−2/イントロン2)、VEGF−R2(血管内皮成長因子受容体2)、WT1(ウィルムス腫瘍遺伝子)、およびそれらの任意の組み合わせからなる群より選択される抗原に結合することができる、請求項8に記載の方法。
- 前記TCRまたはCARは、CD19(分化クラスター19)、HPV(ヒト乳頭腫ウイルス)、及びMAGE(メラノーマ抗原)から選択される抗原に結合することができる、請求項9に記載の方法。
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