JP2022525928A - 併用療法における移植に適したnk細胞画分の増殖及び増殖nk細胞画分の使用 - Google Patents
併用療法における移植に適したnk細胞画分の増殖及び増殖nk細胞画分の使用 Download PDFInfo
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Abstract
Description
本願は、2019年3月21日に出願した米国仮出願第62/821,535号の優先権を主張するものであり、当該仮出願の内容の全てが本参照をもって本願に組み込まれるものとする。
(a)オビヌツズマブを対象に投与する工程と、
(b)少なくとも1種の免疫抑制剤を対象に投与する工程と、
(c)栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドを用いたエクスビボ培養によって増殖させた、増殖CD3枯渇HLA半合致又はHLA不適合NK細胞画分をそれを必要とする対象に移植する工程と、
(d)IL-2を対象に投与して、対象の血液疾患を治療する工程と
を含む方法を提供する。
(a)最初の自家幹細胞移植の2~18ヶ月後に再発した疾患、
(b)同種幹細胞移植の少なくとも4ヶ月後に再発し、活動性移植片対宿主病(GVHD)の証拠がない疾患、
(c)プロテアソーム阻害剤と免疫調節薬(IMiD)を含む少なくとも2種類の治療後の再発性/難治性疾患、
(d)血清IgG、IgA、IgM又はIgD骨髄腫タンパク質(Mタンパク質)が0.5g/dL以上、及び
(e)尿中Mタンパク質が200mg/24回採取以上。
(a)従来の治療に失敗した再発性/難治性疾患、
(b)自家幹細胞移植の少なくとも60日後に再発した疾患、
(c)同種幹細胞移植の少なくとも4ヶ月後に再発し、活動性移植片対宿主病の証拠がない疾患、及び
(d)直径1.5cm以上の測定可能な疾患。
(a)NK細胞画分の第1の用量と第2の用量は、各々、1×107個/kgの増殖CD3枯渇HLA半合致又は不適合NK細胞を含み、増殖CD3枯渇HLA半合致又は不適合NK細胞の総用量は2×107個/kgである、又は
(b)NK細胞画分の第1の用量と第2の用量は、各々、5×107個/kgの増殖CD3枯渇HLA半合致又は不適合NK細胞を含み、増殖CD3枯渇HLA半合致又は不適合NK細胞の総用量は1×108個/kgである、又は
(c)NK細胞画分の第1の用量と第2の用量は、各々、1×108個/kgの増殖CD3枯渇HLA半合致又は不適合NK細胞を含み、増殖CD3枯渇HLA半合致又は不適合NK細胞の総用量は2×108個/kgである。
(i)少なくとも1種の免疫抑制剤は、シクロホスファミド(40mg/kg)とフルダラビン(25mg/m2)の両方を含み、
(ii)シクロホスファミドは、増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の5日前に投与し、フルダラビンは、増殖CD3枯渇HLA半合致又はHLA不適合NK細胞の輸注の5日前、4日前及び3日前の各々で投与する。
(i)増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注当日、及び
(ii)増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の2日後、及び
(iii)増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の4日後に行う。
(a)対象用のHLA半合致(ハプロタイプ一致)又はHLA不適合のCD3枯渇(除去)NK細胞画分を取得する工程と、
(b)細胞増殖を可能にする条件下でCD3枯渇NK細胞画分をエクスビボ培養する工程であって、上記の条件が、栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドを供給することを含む工程と、
(c)工程(b)の8~10日後にCD3枯渇NK細胞画分に新しい栄養素、血清、IL-15及びニコチンアミドを補充して、増殖CD3枯渇NK細胞画分を得る工程と、
(d)工程(b)の14~16日後に増殖CD3枯渇NK細胞画分を回収する工程と、
(e)工程(d)の増殖CD3枯渇NK細胞画分を洗浄及び濃縮する工程と
を含み、対象への移植のための、移植可能NK細胞画分を得る、方法を提供する。
(a)A及びB遺伝子座の中間解像度DNAベースのクラス1タイピングにおいて4種のクラス1対立遺伝子の内の少なくとも2種がHLA適合しており、且つ
(b)(MFI≦1000)のレシピエントのドナー特異的抗HLA抗体が存在しない。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。
(a)対象用のHLA半合致又はHLA不適合のCD3枯渇NK細胞画分を取得する工程と、
(b)細胞増殖を可能にする条件(前記条件は、栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドを供給することを含む)の下で前記CD3枯渇NK細胞画分をエクスビボ培養する工程と、
(c)工程(b)の8~10日後に前記CD3枯渇NK細胞画分に新しい栄養素、血清、IL-15及びニコチンアミドを補充して、増殖CD3枯渇NK細胞画分を得る工程と、
(d)工程(b)の14~16日後に、前記増殖CD3枯渇NK細胞画分を回収する工程と、
(e)工程(d)の前記増殖CD3枯渇NK細胞画分を洗浄及び濃縮する工程と
を含み、前記対象への移植のための、移植可能NK細胞画分を得る方法が提供される。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。
(a)抗癌モノクローナル抗体を対象に投与する工程と、
(b)少なくとも1種の免疫抑制剤を対象に投与する工程と、
(c)栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドを用いたエクスビボ培養によって増殖させた、増殖CD3枯渇HLA半合致又はHLA不適合NK細胞画分をそれを必要とする対象に移植する工程と、
(d)IL-2を前記対象に投与して、対象の血液疾患を治療する工程と
を含む方法が提供される。
1.高力価のドナー特異的抗HLA抗体(MFI>1000)。
2.活動性で未治療のCNSの関与。
3.慢性リンパ性白血病(CLL)/小リンパ球性リンパ腫(SLL)、又は高悪性度リンパ腫(バーキットリンパ腫/リンパ芽球性リンパ腫)。
4.妊娠中又は授乳中。
5.多発性骨髄腫の対象の場合:妊娠の可能性がある女性は、治療開始から14日以内(抗癌抗体投与開始の24時間前)に血清又は尿妊娠検査が陰性(最低感度25IU/L又は同等単位のHCG)でなければならない。
6.QT/QTc間隔の印付きベースライン延長(例えば、500ミリ秒を超えるQTc間隔の表示)。
7.ニューヨーク心臓協会の機能分類基準(付録III)がクラスII以上、又はサイトカイン療法の心合併症のリスクを増加させる可能性が高い重篤な心不整脈(例えば、心室頻拍、頻繁な異所性心室興奮、又は慢性治療を必要とする上室性頻脈性不整脈)。
8.免疫抑制療法を必要とする活動性自己免疫疾患。
9.現在慢性薬物療法を受けている重度の喘息の病歴(吸入ステロイドのみを必要とする軽度の喘息の病歴は適格である)。
10.胸部X線又は胸部CTスキャンのスクリーニングにおける新規又は進行性肺浸潤物[肺専門医による研究が許可されている場合を除く。感染に起因する浸潤物は、1週間の適切な治療後(真菌感染症が推定又は実証された場合は4週間後)に安定/改善(関連する臨床的改善を伴う)していなければならない]。
11.活動性で非制御の細菌性、真菌性又はウイルス性感染症-全ての事前の感染症は最適な治療によって回復していなければならない。
12.本発明の方法で使用される任意の治療剤に対する既知の過敏症。
13.MM患者のみ:本発明のNK細胞画分の投与前2週間以内の事前の放射線療法、4週間以内の手術又は3週間以内の化学療法(メルファラン又はモノクローナル抗体の場合は6週間以内)。
14.NK細胞画分による治療開始前14日以内の治験薬の投与。
1.A及びB遺伝子座の中間解像度DNAベースのクラスIタイピングが最小値(4種のクラスI対立遺伝子の内の少なくとも2種)であり、且つ選択ドナーに対する(MFI≦1000の)レシピエントの抗HLA抗体が不在であることに基づく、HLA半合致又はHLA不適合の血縁ドナー/レシピエントの組み合わせ。
2.12歳~70歳:年齢(<35歳)を優先し、その次にHLAマッチングを行う(HLA半合致とし、該当なしの場合には完全不適合のドナー)。
3.体重が少なくとも40キログラム。
4.医療提供者によって評価された一般的な健康状態。
5.次のように定義された適切な臓器機能:血液:ヘモグロビン、WBC、血小板が試験正常範囲の上限と下限の10%以内(ヘモグロビン値は性別による)、肝臓:ALTが正常上限値の2倍未満、及び腎臓:血清クレアチニンが1.8mg/dL未満。
6.ドナー感染症検査パネル(CMV抗体、B型肝炎表面抗原、B型肝炎コア抗体、C型肝炎抗体、HIV PCR、HIV1/2抗体、HTLVA1/2抗体、急速血漿(RPR)トレポネーマ、トリパノソーマ・クルージ(T.Cruzi)、NATによるHCV、NATによるHIV、及びNAT又は現在のパネルごとのWNV(ウエストナイルウイルス)を含む)の完了;HIVと活動性B型肝炎に対して陰性でなければならない。
7.妊娠していないこと:妊娠可能性がある女性は、アフェレーシスから7日以内に妊娠検査で陰性でなければならない。
8.アフェレーシスを受けることができ、進んで対応できる。
9.自発的な書面による同意(18歳未満のドナーの場合は同意書を使用)。
いくつかの実施形態において、必要とする対象には、本明細書に記載の増殖CD3枯渇NK細胞画分と、追加の癌療法との併用による処置を行う。いくつかの実施形態において、追加の癌療法は、細胞毒性薬及び/又は非細胞毒性薬を含む。「細胞毒性薬」とは、細胞機能の阻害又は防止及び/又は細胞の破壊をもたらす物質を意味する。この用語は、放射性同位体(例:131I、125I、90Y及び186Re)、化学療法薬、及び毒物(細菌、真菌、植物又は動物由来の酵素学的に活性な毒物又は合成した毒物、又はそれらの断片)を含むことを意図する。非細胞毒性薬は、細胞機能の阻害又は防止及び/又は細胞の破壊を生じない物質を意味する。「非細胞毒性薬」には、細胞毒性になるように活性化することができるものも含まれ得る。非細胞毒性薬には、ビーズ、リポソーム、マトリックス又は粒子も含まれ得る(例えば、本参照を持ってい本願に組み込まれる米国特許公開第2003/0028071号及び第2003/0032995号明細書を参照)。このような薬剤は、本明細書に記載の増殖CD3枯渇NK細胞画分組成物に結合、カップリング、連結又は付随(associated)していてもよい。
(i)前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注当日、及び
(ii)前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の2日後、及び
(iii)前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の4日後に行う。
(i)対象用のHLA半合致又はHLA不適合のCD3枯渇NK細胞画分を取得する工程と、
(ii)細胞増殖を可能にする条件(この条件は、栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドを供給することを含む)の下で、CD3枯渇NK細胞画分をエクスビボ培養する工程と、
(iii)工程(ii)の8~10日後にCD3枯渇NK細胞画分に新しい栄養素、血清、IL-15及びニコチンアミドを補充して、増殖CD3枯渇NK細胞画分を得る工程と、
(iv)工程(ii)の14~16日後に増殖CD3枯渇NK細胞画分を回収する工程と、
(v)工程(iv)の増殖CD3枯渇NK細胞画分を洗浄及び濃縮して、対象への移植用の移植可能NK細胞画分を得る工程と、
(vi)抗癌モノクローナル抗体を対象に投与する工程と、
(vii)少なくとも1種の免疫抑制剤を対象に投与する工程と、
(viii)(v)の増殖CD3枯渇HLA半合致又は不適合NK細胞画分をそれを必要とする対象に移植する工程と、
(ix)IL-2を対象に投与して、対象の血液疾患を治療する工程と
を含む方法が提供される。
厳密な完全寛解(sCR):
sCRにはCR(下で定義)に加え、次の全てが必要である。
・フローサイトメトリーで確認したとき、骨髄中に悪性形質細胞がない
・フローサイトメトリーで確認したとき、末梢血中に悪性形質細胞がない
・正常な遊離軽鎖比(FLC)
CRには次の全てが必要である。
・骨髄穿刺液中の形質細胞が5%未満
・末梢血中に形質細胞がない
・通常の電気泳動及び免疫固定法で確認したとき、血清及び尿中に元のモノクローナルパラプロテインがない
・髄外疾患がない
VGPRには次の全てが必要である。
・骨髄穿刺液中の形質細胞が5%未満
・末梢血中に形質細胞がない
・血清中モノクローナルパラプロテインの抑制が90%以上、且つパラプロテインが100mg/24時間2未満
・髄外疾患がない
部分寛解には次の全てが必要である。
・骨髄穿刺液中の形質細胞が5%~25%
・末梢血中の形質細胞が1%~5%
・血清中モノクローナルパラプロテインの抑制が50%以上、24時間尿中モノクローナルパラプロテインの抑制が90%以上で200mg/24時間3未満
・髄外疾患のサイズの減少が50%以上
sCR、CR、VGPR、PR又は進行性疾患(下で定義)の基準を満たさない患者は安定状態(SD)であると見なされる。
・血清中及び尿中Mタンパク質が測定できない場合、正常な血清κ/λFLC比も必要である。
・血清中及び尿中Mタンパク質が測定できない場合、Mタンパク質の代わりに、関与するFLCレベルと関与しないFLCレベルの差を90%以上減少させる必要がある。
・血清中及び尿中Mタンパク質が測定できない場合、Mタンパク質の代わりに、関与するFLCレベルと関与しないFLCレベルの差を50%以上減少させる必要がある。
CR又はsCRからの進行には次の1種以上が必要である。
・骨髄穿刺液中の形質細胞の増加が25%超、又は絶対増加が10%以上
・末梢血中の形質細胞の絶対増加が5%超
・血清中モノクローナルパラプロテインのレベルの増加が25%超で、絶対増加が5g/L以上
・24時間尿中タンパク質電気泳動の増加が25%超で、絶対増加が少なくとも200mg/24時間
・高カルシウム血症
・溶解性骨病変の明確な増大
・髄外疾患のサイズ又は数の明確な増加
血液細胞試料及びT細胞の枯渇
0日に、健康なドナーからアフェレーシスにより血液細胞を回収した。赤血球(RBC)をACK緩衝液(アイルランド国、ダブリン、Gibco社)で洗浄することにより溶解した。CD3+細胞は、CliniMACS及びCD3試薬(Miltenyi 273-01)(ドイツ国、グラドバッハ、Miltenyi Biotec社)を使用し、製造者の推奨する方法により枯渇させた。
CD3+枯渇NK細胞を、ゲンタマイシン(スイス国、ラーヘン、Octapharma社)、2mMのL-グルタミン(Biologica industries社)、10%のABヒト血清(カリフォルニア州、ウエストサクラメント、Gemini Bio Products社)、5mMのニコチンアミド及び20ng/mLのIL-15(ドイツ国、グラドバッハ、Miltenyi社)を含むMEMa w/ヌクレオシド(ユタ州、サウスローガン、HyClone社)に播種した。280×106細胞を800mLの培地を含むG-REX100MCS細胞培養フラスコ(ミネソタ州、セントポール、Wilson Wolf社)に播種し、加湿インキュベーターにおいて、5%のCO2及び37℃でインキュベートした。8日目にフラスコを振盪させ、体積の半分を新鮮なG-REX100MCS細胞培養フラスコ(Wilson Wolf社)に移すことで、細胞集団を分割した。400mLの作製したばかりの新鮮培地を各G-REX100MCS培養フラスコに加えた。14日目に細胞を回収し、リン酸生理食塩水(PBS)(イスラエル国、Biological Industries社)中の0.5%のHAS(ヒト血清アルブミン)(Octapharma社)で洗浄した。回収時の細胞懸濁液は、FCS Canto II(カリフォルニア州、サンホセ、BD社)で求めたところ、その90%超がCD56+(クローンB159、カリフォルニア州、サンホセ、BD社)細胞であった。
BL2細胞系は、7歳の男性バーキットリンパ腫患者由来であり、CD20+である。BL2細胞系のさらなる詳細についてはexpasy(dot)orgウェブサイトのcellosaurus(slash)CVCL 1966を参照。
回収した増殖NK細胞(エフェクター細胞)を、事前に製造社の推奨する方法により、バイオレットCFSE(マサチューセッツ州、ウォルサム、Invitrogen、Thermo Fisher)で標識したBL2細胞(標的細胞)と1:1の比でインキュベートした。抗CD20抗体の存在又は不在時のNK細胞及びBL2細胞の共インキュベーションは5%CO2、37℃のインキュベーターで3時間継続させた。ヨウ化プロピジウム(PI)(Sigma社)の染色による標的細胞の殺滅の評価は、FCS Canto II(BD Biosciences社)による検証の直前に実施した。FACSデータ解析はFACS DIVAソフトウエア(BD Biosciences社)で実施した。NK細胞によって溶解されたBL2細胞は、総BL2 CFSE+細胞数に対する二重陽性(PI+/CFSE+)BL2細胞のパーセンテージとして表した。
実施例I:ニコチンアミドはNK細胞によるFc受容体(CD16)発現を増強する
CD16としても知られるNK細胞表面Fc受容体(FCgammaRIII)による抗体被覆細胞の認識は、末梢血NK細胞による直接細胞殺滅及びサイトカイン産生をもたらす。添加外因性ニコチンアミド(5mM)と共に培養したNK細胞による表面CD16発現のFACS解析は、CD3-/CD56+NK細胞集団における豊富なCD16発現を示した(図1のCD56+/CD16+画分≧75%を参照)。
CD20は、血液系癌(例:リンパ腫及び白血病)及びB細胞自己免疫性疾患の免疫療法において臨床的意義が増しているB細胞表面腫瘍マーカーである。複数のCD20標的化モノクローナル抗体の臨床使用が認可されている。
Claims (37)
- 血液疾患の治療を必要とする対象において血液疾患を治療する方法であって、
(a)オビヌツズマブを前記対象に投与する工程と、
(b)少なくとも1種の免疫抑制剤を前記対象に投与する工程と、
(c)栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドを用いたエクスビボ培養によって増殖させた、HLA半合致又はHLA不適合の増殖CD3枯渇NK細胞画分をそれを必要とする前記対象に移植する工程と、
(d)IL-2を前記対象に投与して、前記対象の前記血液疾患を治療する工程と
を含む方法。 - 前記対象はヒト対象であり、前記NK細胞画分はヒトNK細胞画分である、請求項1に記載の方法。
- 前記免疫抑制剤は、化学療法免疫抑制剤及び/又は放射線である、請求項1に記載の方法。
- 前記血液疾患は、血液系腫瘍である、請求項1に記載の方法。
- 前記血液疾患は、CD20陽性リンパ系腫瘍である、請求項1に記載の方法。
- 前記血液疾患は、多発性骨髄腫である、請求項1に記載の方法。
- 前記多発性骨髄腫は、下記の少なくとも1種によって特徴付けられる、請求項6に記載の方法。
(a)最初の自家幹細胞移植の2~18ヶ月後に再発した疾患、
(b)同種幹細胞移植の少なくとも4ヶ月後に再発し、活動性移植片対宿主病(GVHD)の証拠のない疾患、
(c)プロテアソーム阻害剤と免疫調節薬(IMiD)を含む少なくとも2種類の治療後の再発性/難治性疾患、
(d)血清IgG、IgA、IgM又はIgD骨髄腫タンパク質(Mタンパク質)が0.5g/dL以上、及び
(e)尿中Mタンパク質が200mg/24回採取以上。 - 前記血液疾患は、非ホジキンリンパ腫(NHL)である、請求項1に記載の方法。
- 前記NHLは、CD20陽性B細胞NHLである、請求項8に記載の方法。
- 前記NHLは下記の少なくとも1種によって特徴付けられる、請求項8に記載の方法。
(a)従来の治療に失敗した再発性/難治性疾患、
(b)自家幹細胞移植の少なくとも60日後に再発した疾患、
(c)同種幹細胞移植の少なくとも4ヶ月後に再発し、活動性移植片対宿主病の証拠がない疾患、及び
(d)直径1.5cm以上の測定可能な疾患。 - 工程(a)を3回行う、請求項1に記載の方法。
- 工程(c)は、前記増殖CD3枯渇HLA半合致又は不適合NK細胞画分の第1の用量を投与し、その2日後に前記増殖CD3枯渇HLA半合致又は不適合NK細胞画分の第2の用量を投与することを含む、請求項1に記載の方法。
- 工程(a)を前記増殖CD3枯渇HLA半合致又は不適合NK細胞画分の前記第1の用量の投与の9~11日前、3日前、及び11日後の計3回行う、請求項12に記載の方法。
- 前記NK細胞画分は、1×107個/kg~5×108個/kgの増殖CD3枯渇HLA半合致又はHLA不適合NK細胞を含む、請求項1に記載の方法。
- 前記第1の用量と前記第2の用量の合計は、2×107個/kg~2×108個/kgの増殖CD3枯渇HLA半合致又はHLA不適合NK細胞を含む、請求項13に記載の方法。
- (a)前記NK細胞画分の前記第1の用量と前記第2の用量は、各々、1×107個/kgの増殖CD3枯渇HLA半合致又は不適合NK細胞を含み、増殖CD3枯渇HLA半合致又は不適合NK細胞の総用量は、2×107個/kgである、又は
(b)前記NK細胞画分の前記第1の用量と前記第2の用量は、各々、5×107個/kgの増殖CD3枯渇HLA半合致又は不適合NK細胞を含み、増殖CD3枯渇HLA半合致又は不適合NK細胞の総用量は、1×108個/kgである、又は
(c)前記NK細胞画分の前記第1の用量と前記第2の用量は、各々、1×108個/kgの増殖CD3枯渇HLA半合致又は不適合NK細胞を含み、増殖CD3枯渇HLA半合致又は不適合NK細胞の総用量は、2×108個/kgである、請求項12に記載の方法。 - 前記増殖CD3枯渇HLA半合致又はHLA不適合NK細胞画分の前記対象への投与は、前記移植用画分の供給後1時間以内、及び前記画分の最終生成物放出後10時間以内に行う、請求項1に記載の方法。
- 前記増殖CD3枯渇HLA半合致又は不適合NK細胞画分の前記対象への投与は、フィルター又はポンプを使用せずに、注入によって15分以上60分以内で行う、請求項1に記載の方法。
- 前記少なくとも1種の免疫抑制剤は、シクロホスファミド及び/又はフルダラビンを含む、請求項1に記載の方法。
- (i)前記少なくとも1種の免疫抑制剤は、シクロホスファミド(40mg/kg)とフルダラビン(25mg/m2)との両方を含み、
(ii)前記シクロホスファミドは、前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の5日前に投与し、前記フルダラビンは、前記増殖CD3枯渇HLA半合致又はHLA不適合NK細胞の輸注の5日前、4日前及び3日前の各々で投与する、請求項19に記載の方法。 - 前記工程(d)は、前記増殖CD3枯渇NK細胞の輸注後に6×106単位のIL-2を投与することを含み、前記投与を
(i)前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注当日、及び
(ii)前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の2日後、及び
(iii)前記増殖CD3枯渇HLA半合致又は不適合NK細胞の輸注の4日後に行う、請求項1に記載の方法。 - 移植可能なNK細胞画分を調製するための下記工程をさらに含む、請求項1に記載の方法。
(a)前記対象用のHLA半合致又はHLA不適合のCD3枯渇NK細胞画分を取得する工程と、
(b)細胞増殖を可能にする条件の下で前記CD3枯渇NK細胞画分をエクスビボで培養する工程であって、前記条件が、栄養素、血清、IL-15及び1.0mM~10mMのニコチンアミドの供給を含む工程と、
(c)工程(b)の8~10日後に前記CD3枯渇NK細胞画分に新しい栄養素、血清、IL-15及びニコチンアミドを補充して、増殖CD3枯渇NK細胞画分を得る工程と、
(d)工程(b)の14~16日後に前記増殖CD3枯渇NK細胞画分を回収する工程と、
(e)工程(d)の前記増殖CD3枯渇NK細胞画分を洗浄及び濃縮する工程と
を含み、前記対象への移植のための、移植可能なNK細胞画分を得る、方法。 - 前記CD3枯渇NK細胞画分はアフェレーシスで入手したものである、請求項22に記載の方法。
- 前記エクスビボ培養では支持細胞層がない、請求項22に記載の方法。
- 前記血清はヒト血清である、請求項22に記載の方法。
- 細胞増殖を可能にする前記条件は、10%ヒト血清を供給することを含む、請求項25に記載の方法。
- 前記IL-15は、20ng/mLのIL-15を含む、請求項22に記載の方法。
- 前記ニコチンアミドは、5.0mMのニコチンアミドを含む、請求項22に記載の方法。
- 前記栄養素は、最小必須細胞培地を含む、請求項22に記載の方法。
- 前記NK細胞画分は、少なくとも下記の条件を満たすHLA半合致又はHLA不適合のドナー由来である、請求項22に記載の方法。
(a)A及びB遺伝子座の中間解像度DNAベースのクラス1タイピングにおいて4種のクラス1対立遺伝子の内の少なくとも2種がHLA適合しており、且つ
(b)(MFI≦1000)のレシピエントのドナー特異的抗HLA抗体が存在しない。 - 工程(a)の前記NK細胞は、CD56+/CD3-細胞を少なくとも40~90%含む、請求項22に記載の方法。
- 工程(d)の前記回収は、工程(b)の14日後に前記増殖CD3枯渇NK細胞画分の第1の部分を回収する工程と、工程(b)の16日後に前記増殖CD3枯渇NK細胞画分の第2の部分を回収することとを含む、請求項22に記載の方法。
- 前記第1の部分は前記増殖CD3枯渇NK細胞画分の約50%を含み、前記第2の部分は前記増殖CD3枯渇NK細胞画分の残りを含む、請求項32に記載の方法。
- 工程(e)において生成される前記洗浄及び濃縮した増殖NK細胞画分は、以下のパラメータによって特徴付けられる、請求項22に記載の方法。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。 - 工程(b)の前記培養をフラスコ内にて行い、前記フラスコ1個当たり200~300×106個の細胞とする、請求項22に記載の方法。
- 前記増殖CD3枯渇HLA半合致又はHLA不適合のNK細胞画分は、以下のパラメータによって特徴付けられる、請求項1に記載の方法。
(a)CD56+/CD3-細胞が少なくとも70%、
(b)生存率が少なくとも70%、
(c)注入の際の、患者当たりのCD3+細胞数が5.0×105個/体重1Kg未満、
(d)注入の際の、患者当たりの内毒素が5EU/体重1Kg以下、及び
(e)グラム陽性微生物なし。 - 前記増殖CD3枯渇HLA半合致又はHLA不適合のNK細胞画分は、フッ素化エチレンプロピレン(FEP)培養バッグで提供される、請求項1に記載の方法。
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