JP7479635B2 - γδT細胞の製造方法 - Google Patents
γδT細胞の製造方法 Download PDFInfo
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Description
近年、がんに対する治療法として免疫細胞治療が注目されている。免疫細胞治療とは、患者の体外で増殖および活性化させた免疫細胞を患者に投与し、その免疫細胞にがん細胞を攻撃させる治療法である。免疫細胞治療は、従来の外科治療、放射線治療、化学治療の三大療法に比べて副作用がほとんどないという利点を有している。免疫細胞治療には様々な種類の治療法があるが、その中でも、自然免疫を担い、がん細胞に対して細胞傷害活性を有するγδT細胞を用いた治療が注目されている。
[1]人工多能性幹細胞からγδT細胞を製造する方法であって、前記人工多能性幹細胞が、αβT細胞以外の細胞由来である、方法。
[2]以下の工程を含む、[1]に記載の方法。
(1)αβT細胞以外の細胞から人工多能性幹細胞を樹立する工程
(2)工程(1)で樹立された人工多能性幹細胞をT細胞に分化させる工程
[3]前記αβT細胞以外の細胞が、αβT細胞以外の単核細胞である、[1]または[2]に記載の方法。
[4]前記αβT細胞以外の細胞が単球である、[1]~[3]のいずれか一つに記載の方法。
[5]前記(1)および(2)のいずれかの工程中に得られる細胞に、腫瘍特異的抗原若しくは腫瘍関連抗原を認識し結合する
(i)αTCRをコードする核酸およびβTCRをコードする核酸、
(ii)γTCRをコードする核酸およびδTCRをコードする核酸、並びに/または
(iii)CARをコードする核酸を導入する工程を含む、[2]~[4]のいずれか一つに記載の方法。
[6]前記γTCRがVγ9TCRであり、且つ前記δTCRがVδ2TCRである、[5]に記載の方法。
[7]前記(1)および(2)のいずれかの工程中に得られる細胞に、IL-15およびIL-15Rαを含む融合タンパク質をコードする核酸を導入する工程を含む、[1]~[6]のいずれか一つに記載の方法。
[8]人工多能性幹細胞由来のγδT細胞であって、前記人工多能性幹細胞が、αβT細胞以外の細胞由来である、細胞。
[9][1]~[7]のいずれか一つに記載の方法により製造されるγδT細胞。
[10]前記αβT細胞以外の細胞が、αβT細胞以外の単核細胞である、[8]または[9]に記載の細胞。
[11]前記αβT細胞以外の細胞が単球である、[8]~[10]のいずれか一つに記載の細胞。
[12]前記γδT細胞が、Vγ9TCRおよびVδ2TCRを発現している、[8]~[11]のいずれか一つに記載の細胞。
[13]前記γδT細胞が、CARを発現している、[8]~[12]のいずれか一つに記載の細胞。
[14]前記γδT細胞が、IL-15およびIL-15Rαを含む融合タンパク質を発現している、[8]~[13]のいずれか一つに記載の細胞。
[15]少なくとも全細胞の90%以上がγδT細胞である細胞集団であって、前記γδT細胞が、αβT細胞以外の細胞由来の人工多能性幹細胞から分化した細胞である、細胞集団。
[16][8]~[14]のいずれか一つに記載の細胞または[15]に記載の細胞集団を含む医薬。
[17]腫瘍の予防又は治療に使用するための、[16]に記載の医薬。
[18][8]~[14]のいずれか一つに記載の細胞または[15]に記載の細胞集団を含む、細胞の殺傷剤。
[19]腫瘍の予防又は治療に使用するための、[8]~[14]のいずれか一つに記載の細胞または[15]に記載の細胞集団。
[20]腫瘍の予防剤又は治療剤の製造における、[8]~[14]のいずれか一つに記載の細胞または[15]に記載の細胞集団の使用。
[21][8]~[14]のいずれか一つに記載の細胞または[15]に記載の細胞集団を投与することを含む、腫瘍の予防又は治療方法。
本明細書において、「遺伝子の発現」には、該遺伝子の特定のヌクレオチド配列からmRNAが合成されること(転写又はmRNAの発現ともいう)及び該mRNAの情報に基づきタンパク質が合成されること(翻訳又はタンパク質の発現ともいう)の両方が包含されるものであるが、特に断らない限り、「遺伝子の発現」又は単なる「発現」はタンパク質の発現を意味するものとする。
本発明は、人工多能性幹細胞からγδT細胞、および該γδT細胞を含む細胞集団を製造する方法(以下「本発明の製法」と略記する)を提供する。本発明の製法は、人工多能性幹細胞をT細胞に分化させる工程を含む。本発明の製法に用いる人工多能性幹細胞は、既に樹立され、ストックされた細胞であってもよく、αβT細胞以外の細胞から樹立された人工多能性幹細胞であってもよい。従って、本発明の一実施態様において、本発明の製法は、(1)αβT細胞以外の細胞から人工多能性幹細胞を樹立する工程、および(2)工程(1)で樹立された人工多能性幹細胞をT細胞に分化させる工程を含む。
本発明において「人工多能性幹細胞」(以下「iPS細胞」と称する場合がある)とは、体細胞に初期化因子を導入することにより樹立される、生体に存在する多くの細胞に分化可能である多能性を有し、かつ、増殖能をも併せもつ幹細胞を意味し、少なくとも本発明で使用される造血前駆細胞に誘導される任意の細胞が包含される。人工多能性幹細胞は哺乳動物(例:マウス、ラット、ハムスター、モルモット、イヌ、サル、オランウータン、チンパンジー、ヒト)由来であることが好ましく、ヒト由来であることがより好ましい。
人工多能性幹細胞からT細胞への分化方法としては、人工多能性幹細胞をγδT細胞へ分化できる限り特に制限されないが、本発明の一実施態様において、人工多能性幹細胞をT細胞に分化させる工程は、(2-1)人工多能性幹細胞を造血前駆細胞に分化させる工程、および(2-2)該造血前駆細胞をCD3陽性T細胞に分化させる工程を含み得る。
本発明において、「造血前駆細胞(Hematopoietic Progenitor Cell(s)(HPC))」とは、CD34陽性細胞を意味し、好ましくは、CD34/CD43両陽性(DP)細胞である。本発明において、造血前駆細胞と造血幹細胞は、区別されるものではなく、特に断りがなければ同一の細胞を示す。
造血前駆細胞からCD3陽性T細胞への分化方法としては、造血前駆細胞をCD3陽性T細胞へ分化できる限り特に制限されないが、例えば、国際公開第2016/076415号または国際公開第2017/221975号などに記載されているような、造血前駆細胞からT細胞を誘導する方法と同様の培養条件で、造血前駆細胞を培養する方法が挙げられる。
接着培養の場合であって、培養容器をコーティングする場合のコーティング剤としては、例えば、マトリゲル(Niwa A, et al. PLos One, 6(7):e22261, 2011))、コラーゲン、ゼラチン、ラミニン、ヘパラン硫酸プロテオグリカン、レトロネクチン(登録商標)、DLL4若しくはDLL1、あるいはDLL4若しくはDLL1と抗体のFc領域(以下、Fcと称することがある)等との融合タンパク質(例:DLL4/Fc chimera)、エンタクチン、および/またはこれらの組み合わせが挙げられ、レトロネクチンおよびDLL4とFc等との融合タンパク質の組み合わせが好ましい。
CD3陽性T細胞を濃縮させる方法としては、γδT細胞が濃縮される限り特に制限されないが、例えば、国際公開第2016/076415号および国際公開第2017/221975号などに記載されているような、CD4CD8両陽性T細胞からCD8陽性T細胞を誘導する工程と同様の培養条件で、CD3陽性T細胞を培養する方法が挙げられる。
γδT細胞を含むCD3陽性T細胞を拡大培養する方法としては、γδT細胞が増殖する限り特に制限されないが、例えば、国際公開第2016/076415号および国際公開第2018/135646号などに記載されているような、CD8α+β+細胞傷害性T細胞を拡大培養する工程と同様の培養条件で、γδT細胞を含むCD3陽性T細胞を培養する方法が挙げられる。
またそのまま用いる場合、当業者に周知の方法を用いて、γδT細胞が細胞集団に占める割合を増やしても良い。細胞集団に占めるγδT細胞の割合を増やす方法としては、Front. Immunol., 5:636 (2014)、特表2017-537625、特表2003-529363などの方法が挙げられるがこれに限定されない。
本発明はまた、γδT細胞、または該γδT細胞を含む細胞集団であって、該γδT細胞が、αβT細胞以外の細胞由来の人工多能性幹細胞から分化した細胞である、細胞または細胞集団を提供する。上記細胞集団中に含まれるγδT細胞の割合(該細胞集団に含まれるγδT細胞数/該細胞集団に含まれる全細胞数)は、90%以上(例:90%以上、95%以上、96%以上、97%以上、98%以上、99%以上または100%)であることが好ましい。このような細胞集団は、例えば、本発明の製法により得ることができる。該割合は、γTCR、δTCRおよびCD3を発現する細胞の割合を、フローサイトメトリーにより測定することで算定することができる。従って、一実施態様において、本発明は、本発明の製法により製造されるγδT細胞および/または該γδT細胞を含む細胞集団を提供する。前記γδT細胞は、上記1.で記載した外因性のTCRをコードする核酸、CARをコードする核酸ならびに/またはIL-15およびIL-15Rαを含む融合タンパク質をコードする核酸を含んでいてもよい。ここで言及したγδT細胞、または該γδT細胞を含む細胞集団を、以下「本発明の細胞等」と略記する場合がある。
本発明は、本発明の細胞等を有効成分として含む医薬(以下、「本発明の医薬」と称する場合がある)を提供する。本発明の細胞等は、例えば、がん細胞、がん幹細胞、腫瘍細胞等に対して細胞傷害活性を示し得るため、本発明の細胞等を含む医薬は、がんなどの腫瘍の予防または治療のために用いることができ、例えば哺乳動物(例:マウス、ラット、ハムスター、ウサギ、ネコ、イヌ、ウシ、ヒツジ、サル、ヒト)、好ましくはヒトに投与することができる。従って、本発明の一態様において、腫瘍の予防又は治療に使用するための、本発明の細胞等が提供される。また、本発明の細胞等を、好ましくは該細胞等を含む医薬の形態で、投与することを含む、腫瘍の予防又は治療方法が提供される。
造血前駆細胞を含む細胞集団として、京都大学iPS細胞研究所から供与されたiPS細胞(Ff-I01s04株:健常人末梢血単核球由来)を公知の方法(例えば、Cell Reports 2(2012)1722-1735や国際公開第2017/221975号に記載された方法)に準じて分化させた浮遊細胞集団を用いた。具体的には、超低接着処理された6 well plateにFf-I01s04株を3 x 105 cells/wellで播種し(Day0)、EB培地(StemPro34に10 μg/mlヒトインスリン、5.5 μg/mlヒトトランスフェリン、5 ng/ml 亜セレン酸ナトリウム、2 mM L-グルタミン、45 mM α-モノチオグリセロール、および50 μg/ml Ascorbic acid 2-phosphate を添加)に10 ng/ml BMP4、50 ng/ml bFGF、15 ng/ml VEGF、2 μM SB431542、を加えて、低酸素条件下(5% O2) にて5日間 培養を行った(Day5)。続いて、50 ng/ml SCF、30 ng/ml TPO、10 ng/ml FLT-3Lを添加し、さらに5~9日間培養を行い(~Day14)、浮遊細胞集団を得た。なお、培養期間中は2日または3日ごとに培地交換を行った。HPCを含む上記浮遊細胞集団を、以下の抗体セットを用いて染色した。
[実施例1]で得られたiPS細胞(Ff-I01s04株)由来γδT細胞の細胞傷害活性を評価した。中皮腫細胞株NCI-H226を標的細胞として、DELFIA BATDA Reagent (Perkin Elmer) を37℃、30分反応させた。反応液を洗浄後に、Vδ1陽性γδT細胞、およびVδ2陽性γδT細胞を含むiPS細胞(Ff-I01s04株)由来γδT細胞の細胞集団を、標的細胞に対して0.5, 1, 2, 4, 8, 16倍の割合で混和して、2時間後における標的細胞死をもとに、iPS細胞(Ff-I01s04株)由来γδT細胞の細胞傷害活性を評価した。
[実施例3] iγδT細胞の製造
抗CD3抗体として、UCHT1(GeneTex社製)を用いたことを除き、実施例1と同様の方法により、iPS細胞(Ff-I01s04株)由来γδT細胞(iγδT細胞)を製造した。
[実施例3]で得たiγδT細胞を、15% FBSを含むα-MEM培地に表3のサイトカインを含む添加剤を加えた培地で2,000,000 cells/mLで懸濁し、抗CD3抗体(UCHT1)とレトロネクチンが固相化されたプレートに播種して、5% CO2/37℃下で3日間培養した。培養3日目にプレートから細胞を回収し、NucleoCounter(登録商標) NC-200(ChemoMetec)を用いて細胞数を計測すると共に、15% FBSを含むα-MEM培地に表4のサイトカインを含む添加剤を加えた培地で適量に懸濁し、固相化されていないG-Rex (登録商標) 6 穴プレート(WILSONWOLF)に添加し、5% CO2/37℃下で培養した。その後培養5、6、7、8、9、10、11、14、17日目のいずれか4-6回、一部の細胞をプレートから回収して細胞数を血球計数板を用いて計測した。
抗CD3抗体およびレトロネクチンの培養プレートへの固相化は、以下の方法で行った。必要な濃度でPBSに溶解した抗CD3抗体(UCHT1、最終濃度3000 ng/mL)およびレトロネクチン(最終濃度150 μg/mL)をプレートに添加した後、4℃下一晩静置した。PBSで洗浄した後に試験に供した。
1.iPS細胞の準備
iPS細胞には、[実施例1]と同様に、京都大学iPS細胞研究所(CiRA)から供与されたFf-I01s04株を使用した。iPS細胞培養は、CiRAが配布するプロトコール「フィーダーフリーでのヒトiPS 細胞の培養」に準じて行った。
iPS細胞の造血前駆細胞(HPC)への分化は、[実施例1]と同様に公知の方法(WO2017/221975)に準じて行った。
G115γδT細胞クローン由来のVγ9Vδ2 T細胞受容体(Vγ9Vδ2TCR G115)を用いた。Vγ9Vδ2TCR G115をコードする遺伝子を含む核酸として、N末から表5の順番で並ぶように設計したポリペプチド(配列番号7)をコードするオリゴDNAを人工合成した。
レンチウイルスベクターには、pLVSIN-CMV Neo(クロンテック社)からネオマイシン耐性遺伝子をコードする配列を除去し、CMVプロモーターをヒトユビキチンプロモーターに置換したpLVSIN-Ubを用いた。[実施例5]3.で合成した人工オリゴDNAをpLVSIN-Ubレトロウイルスベクターのマルチクローニングサイトに組込んだ。このプラスミドとクロンテック社のLenti-XTM 293T細胞株およびLenti-XTMPackaging Single Shots (VSV-G)を用いてレンチウイルスベクターを作製した。
[実施例5]4.で作製したVγ9Vδ2遺伝子を搭載したレトロウイルスベクターを、[実施例5]1.で準備したiPS細胞および実施例[実施例5]2.で作製したiPS細胞由来造血前駆細胞(HPC)に感染させた。これらの細胞を、[実施例1]と同様に公知の方法(WO2017/221975)に準じてT細胞へ分化させ、iPS細胞由来Vγ9Vδ2T細胞を作製した。分化の工程において使用する抗CD3抗体としては、500 ng/mL UCHT1(GeneTex社製)を用いた。(以下、iPS細胞から作製したiPS細胞由来Vγ9Vδ2T細胞を「iγ9δ2T細胞」と称し、iPS細胞由来HPCから作製したiPS細胞由来Vγ9Vδ2T細胞を「iHγ9δ2T細胞」と称することがある。)得られたiγ9δ2T細胞およびiHγ9δ2T細胞について、細胞膜表面上のCD3、γδTCR、Vγ9およびVδ2の発現をフローサイトメーター(BD FACSAriaTM Fusion、BD Biosciences社製)で測定した(図5および6)。
1.抗CD19-CAR遺伝子
抗CD19-CAR遺伝子を含む核酸として、N末から表6の順番で並ぶように設計したポリペプチド(配列番号2)をコードするオリゴDNAを人工合成した。
[実施例6]1.で合成した人工オリゴDNAをpMYレトロウイルスベクターのマルチクローニングサイトに組込んだ。レトロウイルスベクター産生用のFRY-RD18細胞を用いてウイルスベクターを作製した。
IL-15Rα/IL-15遺伝子を含む核酸として、N末から表7の順番で並ぶように設計したポリペプチド(配列番号6)をコードするオリゴDNAを人工合成した。
[実施例6]3.で合成した人工オリゴDNAをpMYレトロウイルスベクターのマルチクローニングサイトに組込んだ。レトロウイルスベクター産生用のFRY-RD18細胞を用いてウイルスベクターを作製した。
[実施例6]2.で作製した抗CD19-CAR遺伝子を搭載したレトロウイルスベクターおよび[実施例6]4.で作製したIL-15Rα/IL-15遺伝子を搭載したレトロウイルスベクターを、[実施例4]で得たiγδT細胞および[実施例5]5.で作製したiHγ9δ2T細胞に感染させて、iPS細胞由来抗CD19-CAR/IL-15γδT細胞を作製した。(以下、iγδT細胞から作製したiPS細胞由来抗CD19-CAR/IL-15γδT細胞を「iCD19CAR/IL-15γδT細胞」と称し、iHγ9δ2T細胞から作製したiPS細胞由来抗CD19-CAR/IL-15γδT細胞を「iHCD19CAR/IL-15γ9δ2T細胞」と称することがある。)
1.iCD19CAR/IL-15γδT細胞の拡大培養
[実施例6]で得たiCD19CAR/IL-15γδT細胞を[実施例4]と同様の方法で拡大培養した。ただし、表3のサイトカインを含む添加剤の代わりに表8のサイトカインを含む添加剤を、表4のサイトカインを含む添加剤の代わりに表9のサイトカインを含む添加剤をそれぞれ加えた培地を使用した。
[実施例6]で得たiHCD19CAR/IL-15γ9δ2T細胞を[実施例7]1.と同様の方法で拡大培養した。ただし、抗ヒトCD30抗体(human CD30 Antibody)は添加していない。
抗CD3抗体(UCHT1)の刺激により、iHCD19CAR/IL-15γ9δ2T細胞の増殖が認められた(図8)。
[実施例7]で得られたiCD19CAR/IL-15γδT細胞およびiHCD19CAR/IL-15γ9δ2T細胞の細胞傷害活性を評価した。CD19陽性Raji細胞およびCD19陰性CCRF-CEN細胞を標的細胞として、iCD19CAR/IL-15γδT細胞またはiHCD19CAR/IL-15γ9δ2T細胞を、標的細胞に対して0.5, 1, 2, 4, 8, 16倍の割合で混和して、2時間後における標的細胞死の割合をもとに、iCD19CAR/IL-15γδT細胞およびiHCD19CAR/IL-15γ9δ2T細胞の細胞傷害活性を評価した。
NOD/Shi-scid,IL-2RγKO (NOG) マウス(実験動物中央研究所、雌性、7-8週齢)に5x105 個(cells)のNalm6細胞(ATCC)を尾静脈移植してNalm6ゼノグラフトマウスを作製した。移植後4日目に、[実施例6]で製造したiCD19CAR/IL-15γδT細胞(5x106個(cells))を0.1 mLのHBSS-緩衝液に懸濁した懸濁液または等量のHBSS-緩衝液(コントロール)を尾静脈投与した後、生存日数を確認した。
CD19陽性Nalm6がん細胞を経尾静脈移植したマウスは、コントロール投与群では3週間以内に全例死亡したのに対して、iCD19CAR/IL-15γδT細胞投与群では、少なくとも6週間後まで全例において生存していた。(図11)。
NOD/Shi-scid,IL-2RγKO (NOG) マウス(実験動物中央研究所、雌性、7-8週齢)に5x105 個(cells)のルシフェラーゼ発現Nalm6細胞(ATCC)を尾静脈移植してルシフェラーゼ発現Nalm6ゼノグラフトマウスを作製した。移植後4日目に、[実施例6]で製造したiHCD19CAR/IL-15γ9δ2T細胞(5x106 個(cells))を0.1 mLのHBSS-緩衝液に懸濁した懸濁液または等量のHBSS-緩衝液(コントロール)を尾静脈投与した。投与2週間後にルシフェリンを尾静脈投与して、Nalm6細胞が発現するルシフェラーゼの活性をIVIS Imaging System(IVIS LUMINA II、CaliperLS社製)を用いて測定した。
コントロール投与群では、全身にNalm6細胞由来の発光が確認されたのに対して、iHCD19CAR/IL-15γ9δ2T細胞投与群では、ほとんど発光は検出されなかった(図12)。
Claims (13)
- 人工多能性幹細胞からγδT細胞を製造する方法であって、前記人工多能性幹細胞が、αβT細胞以外の細胞由来であり、
以下の工程を含む、方法:
(1)αβT細胞以外の細胞から人工多能性幹細胞を樹立する工程
(2-1)工程(1)で樹立された人工多能性幹細胞を造血前駆細胞に分化させる工程、及び
(2-2)工程(2-1)で得られた造血前駆細胞を、フィーダー細胞を用いずに培養してCD3陽性T細胞に分化させ、γδT細胞またはγδT細胞を含む細胞集団を得る工程、
ここで、αβT細胞以外の細胞は単球である。 - 前記(1)、(2-1)および(2-2)のいずれかの工程中に得られる細胞に、腫瘍特異的抗原若しくは腫瘍関連抗原を認識し結合する
(ii)γTCRをコードする核酸およびδTCRをコードする核酸、並びに/または
(iii)CARをコードする核酸
を導入する工程を含む、請求項1に記載の方法。 - 前記γTCRがVγ9TCRであり、且つ前記δTCRがVδ2TCRである、請求項2に記載の方法。
- 前記(1)、(2-1)および(2-2)のいずれかの工程中に得られる細胞に、IL-15およびIL-15Rαを含む融合タンパク質をコードする核酸を導入する工程を含む、請求項1~3のいずれか一項に記載の方法。
- 請求項1~4のいずれか一項に記載の方法により製造されたγδT細胞。
- 前記γδT細胞が、CARを発現している、請求項5に記載の細胞。
- 前記γδT細胞が、IL-15およびIL-15Rαを含む融合タンパク質を発現している、請求項5または6に記載の細胞。
- 少なくとも全細胞の90%以上がγδT細胞である細胞集団であって、前記γδT細胞が、αβT細胞以外の細胞由来の人工多能性幹細胞から分化した細胞であり、αβT細胞以外の細胞は単球であり、請求項1~4のいずれか一項に記載の方法により製造された、細胞集団。
- 請求項5若しくは6に記載の細胞または請求項8に記載の細胞集団を含む医薬。
- 腫瘍の予防又は治療に使用するための、請求項9に記載の医薬。
- 請求項5若しくは6に記載の細胞または請求項8に記載の細胞集団を含む、細胞の殺傷剤。
- 腫瘍の予防又は治療に使用するための、請求項5若しくは6に記載の細胞または請求項8に記載の細胞集団。
- 腫瘍の予防剤又は治療剤の製造における、請求項5若しくは6に記載の細胞または請求項8に記載の細胞集団の使用。
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Families Citing this family (10)
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---|---|---|---|---|
CN109337870B (zh) * | 2018-12-24 | 2020-07-03 | 广东暨德康民生物科技有限责任公司 | 人Vγ9Vδ2T细胞扩增方法与培养基 |
BR112022011072A2 (pt) * | 2019-12-06 | 2022-08-23 | Fate Therapeutics Inc | Intensificação de célula imune efetora derivada de ipsc usando compostos pequenos |
WO2021256522A1 (ja) | 2020-06-17 | 2021-12-23 | 国立大学法人京都大学 | キメラ抗原受容体発現免疫担当細胞 |
CA3206400A1 (en) * | 2021-02-05 | 2022-08-11 | Takashi Aoi | .gamma..delta. t cells derived from induced pluripotent stem cells, and production method therefor |
BR112023018844A2 (pt) * | 2021-04-07 | 2023-10-10 | Century Therapeutics Inc | Composições e métodos para geração de células t gama-delta de células-tronco pluripotentes induzidas |
CN113583955A (zh) * | 2021-08-24 | 2021-11-02 | 羽铂精制生物技术(成都)有限公司 | 一种因子法扩增t细胞的培养基及培养方法 |
AU2022388808A1 (en) * | 2021-11-12 | 2024-06-27 | Janssen Biotech, Inc. | Materials and methods for improved expansion and uses of immune cells |
WO2023149555A1 (ja) | 2022-02-04 | 2023-08-10 | 国立大学法人京都大学 | T細胞の製造方法 |
WO2023194915A1 (en) * | 2022-04-04 | 2023-10-12 | Gammadelta Therapeutics Ltd | Novel gene armoring |
WO2023194911A1 (en) * | 2022-04-04 | 2023-10-12 | Gammadelta Therapeutics Ltd | Cells expressing an anti-mesothelin car |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010017134A (ja) | 2008-07-10 | 2010-01-28 | Hyogo College Of Medicine | Vγ9Vδ2T細胞の増殖剤、活性化Vγ9Vδ2T細胞の製造方法およびこれらの利用 |
JP2012528599A (ja) | 2009-06-05 | 2012-11-15 | セルラー ダイナミクス インターナショナル, インコーポレイテッド | リプログラミングt細胞および造血細胞 |
WO2014165707A2 (en) | 2013-04-03 | 2014-10-09 | Memorial Sloan-Kettering Cancer Center | Effective generation of tumor-targeted t-cells derived from pluripotent stem cells |
WO2016010155A1 (ja) | 2014-07-18 | 2016-01-21 | 宏 河本 | 抗原特異的t細胞受容体遺伝子を有する多能性幹細胞の製造方法 |
WO2016076415A1 (ja) | 2014-11-13 | 2016-05-19 | 国立大学法人京都大学 | 多能性幹細胞からt細胞への誘導方法 |
WO2017075389A1 (en) | 2015-10-30 | 2017-05-04 | The Regents Of The Universtiy Of California | Methods of generating t-cells from stem cells and immunotherapeutic methods using the t-cells |
JP2017535284A (ja) | 2014-11-05 | 2017-11-30 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 免疫エフェクター細胞の拡大のための遺伝子改変免疫エフェクター細胞及び遺伝子操作細胞 |
WO2018143243A1 (ja) | 2017-02-03 | 2018-08-09 | 国立大学法人神戸大学 | 人工多能性幹細胞の作製方法 |
JP2020506713A (ja) | 2017-02-07 | 2020-03-05 | エージェンシー フォー サイエンス,テクノロジー アンド リサーチ | 多能性幹細胞から模倣自然免疫細胞を生成する方法及びキット |
Family Cites Families (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4937190A (en) | 1987-10-15 | 1990-06-26 | Wisconsin Alumni Research Foundation | Translation enhancer |
CA2405050C (en) | 2000-04-03 | 2010-06-15 | Hemosol Inc. | Production of tcr gamma delta t cells |
US9453219B2 (en) | 2003-05-15 | 2016-09-27 | Mello Biotech Taiwan Co., Ltd. | Cosmetic designs and products using intronic RNA |
JPWO2006006720A1 (ja) | 2004-07-13 | 2008-05-01 | 株式会社メディネット | γδT細胞の培養方法、γδT細胞及び治療・予防剤 |
BRPI0619794B8 (pt) | 2005-12-13 | 2022-06-14 | Univ Kyoto | Uso de um fator de reprogramação, agente para a preparação de uma célula-tronco pluripotente induzida a partir de uma célula somática e métodos para preparar uma célula- tronco pluripotente induzida método e para preparar uma célula somática e uso de células-tronco pluripotentes induzidas |
SG193653A1 (en) | 2007-03-23 | 2013-10-30 | Wisconsin Alumni Res Found | Somatic cell reprogramming |
WO2008153029A1 (ja) | 2007-06-11 | 2008-12-18 | Takara Bio Inc. | 特異的遺伝子発現方法 |
JP2008307007A (ja) | 2007-06-15 | 2008-12-25 | Bayer Schering Pharma Ag | 出生後のヒト組織由来未分化幹細胞から誘導したヒト多能性幹細胞 |
ES2799897T3 (es) | 2007-08-31 | 2020-12-22 | Whitehead Inst Biomedical Res | Estimulación de la vía wnt en la reprogramación de células somáticas |
AU2008297024B2 (en) | 2007-10-31 | 2014-08-28 | Kyoto University | Nuclear reprogramming method |
KR101532442B1 (ko) | 2007-12-10 | 2015-06-29 | 고쿠리츠 다이가쿠 호진 교토 다이가쿠 | 효율적인 핵 초기화 방법 |
CA2709566A1 (en) | 2007-12-17 | 2009-06-25 | Gliamed, Inc. | Stem-like cells and method for reprogramming adult mammalian somatic cells |
WO2009091659A2 (en) | 2008-01-16 | 2009-07-23 | Shi-Lung Lin | Generation of tumor-free embryonic stem-like pluripotent cells using inducible recombinant rna agents |
US20100330677A1 (en) | 2008-02-11 | 2010-12-30 | Cambridge Enterprise Limited | Improved Reprogramming of Mammalian Cells, and Cells Obtained |
EP2090649A1 (en) | 2008-02-13 | 2009-08-19 | Fondazione Telethon | Method for reprogramming differentiated cells |
WO2009102983A2 (en) | 2008-02-15 | 2009-08-20 | President And Fellows Of Harvard College | Efficient induction of pluripotent stem cells using small molecule compounds |
EP2955222B1 (en) | 2008-03-17 | 2018-09-12 | The Scripps Research Institute | Combined chemical and genetic approaches for generation of induced pluripotent stem cells |
WO2009114949A1 (en) | 2008-03-20 | 2009-09-24 | UNIVERSITé LAVAL | Methods for deprogramming somatic cells and uses thereof |
AU2009234424A1 (en) | 2008-04-07 | 2009-10-15 | Nupotential, Inc. | Reprogramming a cell by inducing a pluripotent gene through use of an HDAC modulator |
SG10201402428WA (en) | 2008-06-27 | 2014-07-30 | Univ Kyoto | Method of efficiently establishing induced pluripotent stem cells |
JP2011527905A (ja) | 2008-07-14 | 2011-11-10 | オクラホマ・メディカル・リサーチ・ファウンデーション | Bright/arid3a機能の阻害による多能性細胞の作製方法 |
WO2010147612A1 (en) | 2009-06-18 | 2010-12-23 | Lixte Biotechnology, Inc. | Methods of modulating cell regulation by inhibiting p53 |
WO2010033906A2 (en) | 2008-09-19 | 2010-03-25 | President And Fellows Of Harvard College | Efficient induction of pluripotent stem cells using small molecule compounds |
WO2010033920A2 (en) | 2008-09-19 | 2010-03-25 | Whitehead Institute For Biomedical Research | Compositions and methods for enhancing cell reprogramming |
WO2010042800A1 (en) | 2008-10-10 | 2010-04-15 | Nevada Cancer Institute | Methods of reprogramming somatic cells and methods of use for such cells |
EP2342333A4 (en) | 2008-10-30 | 2013-05-08 | Univ Kyoto | METHOD FOR THE PRODUCTION OF INDUCED PLURIPOTENTAL STEM CELLS |
WO2010056831A2 (en) | 2008-11-12 | 2010-05-20 | Nupotential, Inc. | Reprogramming a cell by inducing a pluripotent gene through use of an hdac modulator |
EP2376626A4 (en) | 2008-12-13 | 2012-10-17 | Dna Microarray | MICRO-ENVIRONMENTAL NICHE ASSAY FOR SCREENING OF INDUCED PLURIPOTENT STEM CELLS (CIPS) |
EP2607476B1 (en) | 2009-02-27 | 2015-04-08 | Kyoto University | Novel nuclear reprogramming substance |
WO2010102267A2 (en) | 2009-03-06 | 2010-09-10 | Ipierian, Inc. | Tgf-beta pathway inhibitors for enhancement of cellular reprogramming of human cells |
US20120076762A1 (en) | 2009-03-25 | 2012-03-29 | The Salk Institute For Biological Studies | Induced pluripotent stem cell generation using two factors and p53 inactivation |
WO2010111409A2 (en) | 2009-03-25 | 2010-09-30 | The Salk Institute For Biological Studies | Pluripotent stem cells |
WO2010115050A2 (en) | 2009-04-01 | 2010-10-07 | The Regents Of The University Of California | Embryonic stem cell specific micrornas promote induced pluripotency |
WO2010124290A2 (en) | 2009-04-24 | 2010-10-28 | Whitehead Institute For Biomedical Research | Compositions and methods for deriving or culturing pluripotent cells |
WO2010147395A2 (en) | 2009-06-16 | 2010-12-23 | Korea Research Institute Of Bioscience And Biotechnology | Medium composition comprising neuropeptide y for the generation, maintenance, prologned undifferentiated growth of pluripotent stem cells and method of culturing pluripotent stem cell using the same |
WO2013075222A1 (en) | 2011-11-21 | 2013-05-30 | University Health Network | Populations of hematopoietic progenitors and methods of enriching stem cells therefor |
GB201421716D0 (en) | 2014-12-05 | 2015-01-21 | King S College London | Cell expansion procedure |
CN109415699B (zh) | 2016-06-23 | 2024-08-27 | 国立大学法人京都大学 | Cd4cd8双阳性t细胞的制备方法 |
WO2018135646A1 (ja) | 2017-01-20 | 2018-07-26 | 国立大学法人京都大学 | CD8α+β+細胞傷害性T細胞の製造方法 |
JP2018133727A (ja) | 2017-02-16 | 2018-08-23 | 富士通株式会社 | 無線通信システム、無線通信装置、及びビームパターン決定方法 |
JP7109916B2 (ja) | 2017-12-27 | 2022-08-01 | 株式会社ディスコ | 分割装置 |
-
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- 2024-04-16 JP JP2024065962A patent/JP2024096899A/ja active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010017134A (ja) | 2008-07-10 | 2010-01-28 | Hyogo College Of Medicine | Vγ9Vδ2T細胞の増殖剤、活性化Vγ9Vδ2T細胞の製造方法およびこれらの利用 |
JP2012528599A (ja) | 2009-06-05 | 2012-11-15 | セルラー ダイナミクス インターナショナル, インコーポレイテッド | リプログラミングt細胞および造血細胞 |
WO2014165707A2 (en) | 2013-04-03 | 2014-10-09 | Memorial Sloan-Kettering Cancer Center | Effective generation of tumor-targeted t-cells derived from pluripotent stem cells |
WO2016010155A1 (ja) | 2014-07-18 | 2016-01-21 | 宏 河本 | 抗原特異的t細胞受容体遺伝子を有する多能性幹細胞の製造方法 |
JP2017535284A (ja) | 2014-11-05 | 2017-11-30 | ボード・オブ・リージエンツ,ザ・ユニバーシテイ・オブ・テキサス・システム | 免疫エフェクター細胞の拡大のための遺伝子改変免疫エフェクター細胞及び遺伝子操作細胞 |
WO2016076415A1 (ja) | 2014-11-13 | 2016-05-19 | 国立大学法人京都大学 | 多能性幹細胞からt細胞への誘導方法 |
WO2017075389A1 (en) | 2015-10-30 | 2017-05-04 | The Regents Of The Universtiy Of California | Methods of generating t-cells from stem cells and immunotherapeutic methods using the t-cells |
WO2018143243A1 (ja) | 2017-02-03 | 2018-08-09 | 国立大学法人神戸大学 | 人工多能性幹細胞の作製方法 |
JP2020506713A (ja) | 2017-02-07 | 2020-03-05 | エージェンシー フォー サイエンス,テクノロジー アンド リサーチ | 多能性幹細胞から模倣自然免疫細胞を生成する方法及びキット |
Non-Patent Citations (12)
Title |
---|
Cell Stem Cell,2018年12月,Vol.23,pp.850-858 |
Journal of Leukocyte Biology,Vol.96,2014年,pp.1165-1175 |
Nature Biotechnology,2013年,Vol.31, No.10,pp.928-933, ONLINE METHODS |
PLOS ONE, 2014, Vol.9, No.5, e97335 |
Stem Cell Reports,2023年04月,Vol.18,pp.853-868 |
Stem Cells Translational Medicine,2017年11月,Vol.7,pp.34-44 |
Stem Cells,2015年,Vol.33,pp.3174-3180 |
WATANABE, D. et al.,Development of ipsc-based γδT-cell immunotherapy for digestive cancer,Gastroenterology,2017年04月,Vol.152, No.5, Supplement 1,p.S641,ISSN: 0016-5085, 全文 |
渡邉大輔 他,iPS細胞由来Vγ9Vδ2T細胞を用いる新規消化器がん治療法の開発,第24回日本消化器関連学会週間,2016年,消P-413 |
渡邉大輔 他,iPS細胞由来Vγ9Vδ2T細胞を用いる新規消化器がん治療法の開発,第24回日本消化器関連学会週間,2016年,消P-413,全文 |
青井貴之,同種iPS細胞由来γδT細胞を用いたがん免疫療法の可能性,医学のあゆみ,2017年12月,Vol.263, Nos.11,12,pp.915-919 |
青井貴之,同種iPS細胞由来γδT細胞を用いたがん免疫療法の可能性,医学のあゆみ,2017年12月,Vol.263, Nos.11,12,pp.915-919,ISSN: 0039-2359, 特にp.916左欄第2段落, p.917右欄第4段落, p.918右欄第2段落, 図1 |
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