JP2019522054A - Nk細胞ベースの療法で使用するためのhdac阻害剤 - Google Patents
Nk細胞ベースの療法で使用するためのhdac阻害剤 Download PDFInfo
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Abstract
Description
本出願は、2016年7月15日に出願された米国仮特許出願第62/362,959号に対する優先権および利益を主張するものであり、当該文献はその全体として本明細書に組み込まれる。
本明細書で言及されるすべての公報、特許、および特許出願は、個々の公報、特許、または特許出願が、それぞれ、明確かつ個々に示されて、引用によって組み込まれているかのような程度まで、引用によって本明細書に組み込まれる。
ヘルペスウイルスはヒトの疾患の原因となるDNAウイルスの大きな科である。この科のメンバーも、ヘルペスウイルスとして知られている。この科のウイルスとしては、単純ヘルペスウイルス(HSV)1および2;サイトメガロウイルス(CMV);エプスタイン−バーウイルス(EBV);ならびにヒトヘルペスウイルス(HHV)6、7、および8が挙げられる。HHV−8は、カポジ肉腫関連ヘルペスウイルスとしても知られる。
一態様では、癌、ウイルス誘導性癌、またはウイルス関連癌を処置および/または予防するための方法が、本明細書に提供される。いくつかの実施形態では、癌は潜伏ウイルス感染に関連する。ある実施形態では、方法は、HDAC阻害剤および免疫療法剤を投与する工程を含む。ある実施形態では、HDAC阻害剤および免疫療法剤は、同時配合される。いくつかの実施形態では、方法は、追加のHDAC阻害剤を投与する工程をさらに含む。他の実施形態では、方法は、追加の免疫療法剤を投与する工程をさらに含む。いくつかの実施形態では、方法は、追加の個体用量(individual doses)のHDAC阻害剤を投与する工程を含む。ある態様では、方法は、HDAC阻害剤および免疫療法剤を用いる癌の治療の前に、バルガンシクロビルまたはアシクロビルなどの、HDAC阻害剤およびチミジンキナーゼ阻害剤を投与する工程を含む。この前処置は、免疫療法剤の投与前に、腫瘍を縮小するか、または腫瘍を除去する役目を果たし得る。
「約」という用語は、明細書で使用されるように、規定の量の1%、5%、または10%以内の数を指す。
提供された発明の方法は、ウイルス感染細胞において遺伝子産物の発現を誘導するために、HDAC阻害剤を含む、本明細書において提供された1つ以上の医薬組成物の使用を含む。発現させられた遺伝子産物は、ウイルス酵素もしくは細胞酵素、またはウイルス感染細胞において大規模に発現させられる活性になり得る。標的となり得る発現産物は、例えば、ゲノムの修復もしくは複製、完全なウイルス粒子の組立て、ウイルス膜もしくは壁の生成、RNA転写もしくはタンパク質翻訳、またはこれらの活性の組み合わせのための、DNA複製に関連する酵素を含む。これらのプロセスに対しする干渉は、酵素,好ましくはプロセスにおいて重要な酵素を誘導し、その後、それに作用することにより行われる。提供された発明の方法および組成物において使用できる誘導剤は、例えば、米国特許第6,197,743号、および米国特許第6,677,302号において記載されており、これらは全体として引用により本明細書に組み込まれる。
本開示の免疫療法剤は、NK細胞を含む。細胞株および初代NK細胞の両方である。ある一実施形態では、そのNK細胞は、キメラ抗原受容体を発現するように改変されたものである。ある一実施形態では、NK細胞は、高親和性FC受容体、例えば、ヒトFcγRIIIaに158Vの突然変異を有する高親和性Fc受容体を保有するHaNK細胞を発現するように改変されたものである。ヒト中の初代ナチュラルキラー細胞は、細胞表面マーカーCD56を発現し、ある実施形態では、改変されたナチュラルキラー細胞は、非限定的な例として、フローサイトメトリーによって判定されるようなCD56陽性細胞から産生できる。ある実施形態では、ナチュラルキラー細胞は、自己由来の源(源細胞およびレシピエントの同じ遺伝的背景)、または異種起源の源(源細胞およびレシピエントの異なる遺伝的背景)由来であり得る。ある実施形態では、NK細胞は、細胞選別または磁気ビーズなどの方法を使用して処置される予定の、ドナーまたは個体の末梢血から単離される。ドナーから単離されたNK細胞は、7日超にわたって、インターロイキン2およびインターロイキン15中で培養することによって、エクスビボで増殖させることができる。NK細胞はまた、当技術分野における既知の方法を使用して、インビトロの培養物中の幹細胞または始原細胞から分化できる。ある実施形態では、NK細胞は、骨髄由来の幹細胞から分化される。ある実施形態では、NK細胞は、成人の多能性細胞から分化される。ある実施形態では、NK細胞は、胚性幹細胞から分化される。
ある実施形態では、本開示の方法は、癌の治療のためのものである。ある実施形態では、本開示の方法は、癌の治療を増強するためのものである。特定の実施形態では、癌は以下のものである:急性リンパ芽球性白血病、成人;急性リンパ芽球性白血病、小児期;急性骨髄白血病、成人;急性骨髄白血病、小児期;副腎皮質癌;副腎皮質癌、小児期;青年期、癌;エイズ関連の癌;エイズ関連のリンパ腫;肛門癌;虫垂癌;星細胞腫、小児期;非定型奇形腫様/横紋筋肉腫様腫瘍、小児期、中枢神経系;基底細胞癌;肝外胆管癌;膀胱癌;膀胱癌、小児期;骨肉腫、骨肉腫、および悪性線維性組織球腫;脳幹神経膠腫、小児期;脳腫瘍、成人;脳腫瘍、脳幹神経膠腫、小児期;脳腫瘍、中枢神経系非定型奇形腫様/横紋筋肉腫様腫瘍、小児期;脳腫瘍、中枢神経系胚芽腫、小児期;脳腫瘍、星細胞腫、小児期;脳腫瘍、頭蓋咽頭腫、小児期;脳腫瘍、上衣芽細胞腫、小児期;脳腫瘍、上衣腫、小児期;脳腫瘍、髄芽腫、小児期;脳腫瘍、髄様上皮腫、小児期;脳腫瘍、中間分化型の松果体実質腫瘍、小児期;脳腫瘍、テント上原始神経外胚葉腫瘍および松果体芽腫、小児期;脳および脊髄の腫瘍、小児期(他の);乳癌;乳癌および妊娠;乳癌、小児期;乳癌、男性;気管支腫瘍、小児期;バーキットリンパ腫;カルチノイド腫瘍、小児期;カルチノイド腫瘍、消化器系;原発不明癌;中枢神経系非定型奇形腫様/横紋筋肉腫様腫瘍、小児期;中枢神経系胚芽腫、小児期;中枢神経系(CNS)リンパ腫、原発性;子宮頚癌;子宮頚癌、小児期;小児癌;脊索腫、小児期;慢性リンパ球性白血病;慢性骨髄性白血病;慢性骨髄増殖症候群;結腸癌;大腸癌、小児期;頭蓋咽頭腫、小児期;悪性皮膚T細胞リンパ腫;胚芽腫、中枢神経系、小児期;子宮内膜癌;上衣芽細胞腫、小児期;上衣腫、小児期;食道癌;食道癌、小児期;感覚神経芽腫、小児期;ユーイング肉腫ファミリー腫瘍;頭蓋外胚細胞腫瘍、小児期;性腺外胚細胞腫瘍;肝臓外胆管癌;眼癌、眼内黒色腫;眼癌、網膜芽細胞腫;胆嚢癌;胃(Gastric)(胃(Stomach))癌;胃(Gastric)(胃(Stomach))癌、小児期;消化管カルチノイド腫瘍;消化管間質腫瘍(GIST);消化器間質細胞腫瘍、小児期;胚細胞腫瘍、小児、小児期;性腺外胚細胞腫;卵巣胚細胞腫;妊娠性絨毛腫瘍;神経膠腫、成人;神経膠腫、小児脳幹;ヘアリーセル白血病;頭頸部癌;心臓癌、小児期;肝細胞(肝臓)癌、成人(原発性);肝細胞(肝臓)癌、小児期(原発性);組織球増殖症、ランゲルハンス細胞;成人ホジキンリンパ腫;小児期ホジキンリンパ腫;下咽頭癌;眼内黒色腫;島細胞腫(内分泌膵);カポジ肉腫;腎臓(腎細胞)癌;腎癌、小児期;ランゲルハンス細胞組織球症;喉頭癌;小児期喉頭癌;白血病、急性リンパ芽球性、成人;白血病、急性リンパ芽球性、小児期;白血病、急性骨髄性、成人;白血病、急性骨髄性、小児期;白血病、慢性リンパ球性;白血病、慢性骨髄性;白血病、毛様細胞;***および口腔の癌;肝臓癌、成人(原発性);肝臓癌、小児期(原発性);肺癌、非小細胞性;肺癌、小細胞性;リンパ腫、エイズ関連;リンパ腫、バーキット;リンパ腫、皮膚T細胞;リンパ腫、ホジキン、成人;リンパ腫、ホジキン、小児期;リンパ腫、非ホジキン、成人;リンパ腫、非ホジキン、小児期;リンパ腫、原発性中枢神経系(CNS);マクログロブリン血症、ワルデンシュトレーム;骨および骨肉腫の悪性線維性組織球腫;髄芽腫、小児期;髄様上皮腫、小児期;黒色腫;黒色腫、眼内(目);メルケル細胞癌;中皮腫、成人悪性腫瘍;中皮腫、小児期;原発不明の転移性頸部扁平上皮癌;口腔癌;多発性内分泌腫瘍症候群、小児期;多発性骨髄腫/形質細胞腫瘍;菌状息肉腫;骨髄異形成症候群;骨髄異形成/骨髄増殖性腫瘍;骨髄性白血病、慢性;骨髄性白血病、成人急性;骨髄性白血病、小児期急性;多発性骨髄腫;骨髄増殖症候群、慢性;鼻腔および副鼻腔の癌;上咽頭癌;上咽頭癌、小児期;神経芽細胞腫;非ホジキンリンパ腫、成人;非ホジキンリンパ腫、小児期;非小細胞肺癌;口腔癌、小児期;口腔癌;***および口腔咽頭癌;骨肉腫および骨の悪性線維性組織球腫;卵巣癌、小児期;卵巣上皮癌;卵巣胚細胞腫瘍;卵巣低悪性度腫瘍;膵臓癌;膵臓癌、小児期;膵臓癌、島細胞腫;乳頭腫、小児期;副鼻腔および鼻腔の癌;副甲状腺癌;陰茎癌;咽頭癌;中間分化型の松果体実質腫瘍、小児期;松果体芽腫およびテント上原始神経外胚葉腫瘍、小児期;下垂体腫瘍;形質細胞腫瘍/多発性骨髄腫;胸膜肺芽腫、小児期;妊娠および乳癌;原発性中枢神経系(CNS)リンパ腫;前立腺癌;直腸癌;腎細胞(腎臓)癌;腎盂および尿管、移行上皮癌;第15染色体の変化が伴う呼吸器癌(Respiratory Tract Cancer);網膜芽細胞腫;横紋筋肉腫、小児期;唾液腺癌;唾液腺癌、小児期;肉腫、ユーイング肉腫ファミリー腫瘍;肉腫、カポジ;肉腫、軟部組織、成人;肉腫、軟部組織、小児期;肉腫、子宮;セザリー症候群;皮膚癌(非黒色腫);皮膚癌、小児期;皮膚癌(黒色腫);皮膚癌、メルケル細胞;小細胞肺癌;小腸癌;軟部組織肉腫、成人;軟部組織肉腫、小児期;扁平上皮癌;原発不明の頸部扁平上皮癌、転移性;胃癌;テント上原始神経外胚葉腫瘍、小児期;T細胞性リンパ腫、皮膚;精巣癌;咽喉癌;胸腺腫および胸腺癌;甲状腺癌;甲状腺癌、小児期;腎盂および尿管の移行上皮癌;絨毛腫瘍、妊娠性;原発部位不明、細胞腫、成人;原発部位不明、癌、小児期;小児の珍しい癌;尿管および腎盂、移行性細胞癌;尿道癌;子宮癌、子宮内膜;子宮肉腫;膣癌;外陰癌;ワルデンストレーム高ガンマグロブリン血症;またはウィルムス腫瘍。
1つ以上の薬剤(例えばHDAC阻害剤または免疫療法剤)の投与は、断続的となり得る;例えば、投与は、2日ごと、3日ごと、5日ごと、週1回、月に1回または2回などであり得る。量、形態、及び/又は異なる形態の量は、投与の異なる時間に変更され得る。
VRx−3996を、PC3(前立腺)およびMDA−MB−231(三種陰性乳癌)の癌細胞におけるHDAC活性を阻害する、その能力に関して試験した。免疫ブロットによりヒストンH3上のアセチルリジン9の存在に関して検査する前に、細胞を、VRx−3996(657nM)またはDMSOに対して2.5時間曝露した。図2は、VRX−3996が、両方の細胞株においてヒストンH3の脱アセチル化を阻害することを示す。
DMSO(ビヒクル)またはVRx−3996を用いた処置の後に、PC3またはMDA−MB−321の細胞を、それらの細胞表面の表現型に関して分析した。細胞を、継続的に4日にわたって、CHR−3996に対して毎日(657nM、2.5時間/日)、またはDMSO対照に対して曝露し;5日目に、細胞を、免疫の認識、刺激、および阻害に関連する、タンパク質の細胞表面の発現に関して、フローサイトメトリーにより検査した。PC3細胞の表現型を、表1に示す。MDA−MB−321細胞の表現型を、表2に示す。全体的に見て、VRx−3996が、両方の細胞株において、いくつかの変化をもたらした。
VRx−3996により処置された、腫瘍細胞株であるPC3およびMDA−MB−231を、様々な初代NK細胞およびそのNK細胞株HaNK(ヒトFcγRIIIaの158Vに突然変異を有する、高親和性Fc受容体を備えるNK細胞)によって破壊される予定のそれらの能力に関して試験した。PC3およびMDA−MB−231細胞を、一晩の標準的なIn−111放出溶解アッセイにおける直接NK破壊(direct NK killing)のために、5日目に標的として使用する前に、継続的に4日にわたって、DMSOに対して、またはCHR−3996に対して毎日(657nM、2.5時間/日)、曝露した。(負の選択により単離された)2人の健康的なドナーのヒトPBMCからの初代NK細胞と、37℃および5%のCO2で、24時間静止させられたNKか、または24時間ALT803(25ng/ml)に対して予め曝露されたNKと、を使用した。HaNK細胞を、24時間後に、10Gyの放射線曝露に使用した。NK細胞を播種し、結果として、PC3細胞(図3)およびMDA−MB−231細胞(図4)に対するエフェクター対標的比率(E:T)が変動した。
方法:転移性乳癌の7人の患者からの末梢血単核球(PBMC)を、VRx−3996に対して毎日(657nM、2.5時間/日)、またはDMSO対照に対して継続的に2日にわたって曝露し、その後それらを、以下の分析された様々な免疫細胞サブセットに関して、フローサイトメトリーにより検査した:9つの標準的な免疫細胞サブセット、成熟/機能に関する114のサブセット。表3は、VRx−3996が一般的なリンパ球サブセット有していた影響を示す。表4は、分析された最も変化したサブセットを示す。
Claims (31)
- 必要とする個体の癌を処置するための方法であって、該方法は、治療上有効な量の:
a)HDAC阻害剤と;
b)免疫療法剤であって、ここで、免疫療法剤はNK細胞を含む、免疫療法剤と、
を投与する工程を含む、ことを特徴とする方法。 - HDAC阻害剤は、ボリノスタット/スベロイルアニリドヒドロキサム酸、JNJ−26481585(N−ヒドロキシ−2−(4―((((1−メチル−1H−インドール−3−イル)メチル)アミノ)メチル)ピペリジン−1−イル)ピリミジン−5−カルボキサミド)、R306465/JNJ−16241199(N−ヒドロキシ−5−(4―(ナフタレン−2−イルスルホニル)ピペラジン−1−イル)ピリミジン−2−カルボキサミド)、CHR−3996(2−(6−{[(6−フルオロキノリン−2−イル)メチル]アミノ}−3−アザビシクロ[3.1.0]ヘキサ−3−イル)−N−ヒドロキシピリミジン−5−カルボキサミド)、ベリノスタット/PXD101、パノビノスタット/LBH−589、トリコスタチンA/TSA(7−[4―(ジメチルアミノ)フェニル]−N−ヒドロキシ−4,6−ジメチル−7−オキソヘプタ−2,4−ジエンアミド)、ITF2357、CBHA、ギビノスタット/ITF2357、PCI−24781、デプシペプチド類、ロミデプシン、酪酸塩、フェニル酪酸、バルプロ酸、AN−9、CI−994、エンチノスタット/MS−275/SNDX−275、モセチノスタット/MGCD0103(N−(2−アミノフェニル)−4−((4−ピリジン−3−イルピリミジン−2−イルアミノ)メチル)ベンズアミド)、m−カルボキシケイ皮酸、ビスヒドロキサム酸、コルクビスヒドロキサム酸、オキサムフラチンABHA、SB−55629、ピロキサミド、プロペンアミド、アロイルピロリルヒドロキサミド、もしくはLAQ824(((E)−N−ヒドロキシ−3−[4―[[2−ヒドロキシエチル−[2−(1H−インドール−3イル)エチル]アミノ]メチル]フェニル]プロプ−2−エンアミド)、キダミド、または4SC−202を含む、請求項1に記載の方法。
- HDAC阻害剤は、クラスI HDACを阻害する、請求項1または2に記載の方法。
- HDAC阻害剤は、(2−(6−{[(6−フルオロキノリン−2−イル)メチル]アミノ}−3−アザビシクロ[3.1.0]ヘキサ−3−イル)−N−ヒドロキシピリミジン−5−カルボキサミド)を含む、請求項1から3のいずれか1つに記載の方法。
- HDAC阻害剤は経口投与される、請求項1から4のいずれか1つに記載の方法。
- HDAC阻害剤は、1日当たり80mg未満の用量で投与される、請求項1から5のいずれか1つに記載の方法。
- HDAC阻害剤は、1日当たり40mg未満の用量で投与される、請求項1から5のいずれか1つに記載の方法。
- HDAC阻害剤は、1日当たり20mg未満の用量で投与される、請求項1から5のいずれか1つに記載の方法。
- HDAC阻害剤は、免疫療法剤を投与する前に投与される、請求項1から8のいずれか1つに記載の方法。
- HDAC阻害剤は、免疫療法剤の投与中に投与される、請求項1から8のいずれか1つに記載の方法。
- HDAC阻害剤は、免疫療法剤を投与した後に投与される、請求項1から8のいずれか1つに記載の方法。
- NK細胞は、初代NK細胞である、請求項1から11のいずれか1つに記載の方法。
- NK細胞は、キメラ抗原受容体(NK−CAR)を含む、請求項1から11のいずれか1つに記載の方法。
- NK細胞は、高親和性Fc受容体FcγRIIIAを含む、請求項1から11のいずれか1つに記載の方法。
- 高親和性Fc受容体は、腫瘍抗原に対して特異的な抗体に結合される、請求項14に記載の方法。
- 腫瘍抗原は、CD38、CD319/SLAMF−7、TNFRSF17/BCMA、SYND1/CD138、CD229、CD47、Her2/Neu、上皮増殖因子受容体(EGFR)、CD123/IL3−RA、CD19、CD20、CD22、メソテリン、EpCAM、MUC1、MUC16、Tn抗原、NEU5GC、NeuGcGM3、GD2、CLL−1、またはHERV−Kを含む、請求項15に記載の方法。
- 癌は、白血病、リンパ腫、中枢神経系リンパ腫、ホジキンリンパ腫、バーキットリンパ腫、上咽頭癌、胃癌、粘液性類表皮癌、多形神経膠芽腫、または乳癌である、請求項1から16のいずれか1つに記載の方法。
- 癌は、ウイルスが感染した結果である、請求項1から16のいずれか1つに記載の方法。
- ウイルスは、ヘルペスウイルス科からである、請求項18に記載の方法。
- ヘルペスウイルス科のメンバーは、エプスタイン−バーウイルスである、請求項19に記載の方法。
- ヘルペスウイルス科のメンバーは、サイトメガロウイルスである請求項19に記載の方法。
- ヘルペスウイルス科のメンバーは、ヒトヘルペスウイルス8である、請求項19に記載の方法。
- 抗ウイルス剤を投与する工程をさらに含む、請求項1から22のいずれか1つに記載の方法。
- 抗ウイルス剤はバルガンシクロビルを含む、請求項23に記載の方法。
- 抗ウイルス剤は、治療上有効な量の(2−(6−{[(6−フルオロキノリン−2−イル)メチル]アミノ}−3−アザビシクロ[3.1.0]ヘキサ−3−イル)−N−ヒドロキシピリミジン−5−カルボキサミド)と、免疫療法剤とを用いる処置の前に投与される、請求項23に記載の方法。
- 第2の免疫療法剤を投与する工程をさらに含む、請求項1から25のいずれか1つに記載の方法。
- 第2の免疫療法剤は、抗体、またはその抗原結合性フラグメントを含む、請求項26に記載の方法。
- 抗体、またはその抗原結合性フラグメントは、チェックポイント阻害剤に結合する、請求項27に記載の方法。
- チェックポイント阻害剤は、PD−L1、PDL−2、CTLA−4、PD−1、PD−2、TIM−3、VISTA、KIR、IDO、A2AR、B7−H3、B7−H4、BTLA、TIGIT、またはCD155のうちの1つ以上を含む、請求項28に記載の方法。
- チェックポイント阻害剤は、PD−1、PD−2、PD−L1、PD−L2、またはCTLA−4のうちの1つ以上を含む、請求項28に記載の方法。
- 抗体、またはその抗原結合性フラグメントは、ニボルマブ、ペンブロリズマブ、イピリムマブ、ピディリズマブ、アテゾリズマブ、またはそれらの組み合わせを含む、請求項27に記載の方法。
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CN111836636A (zh) * | 2018-01-12 | 2020-10-27 | 维拉克塔治疗公司 | 用于细胞免疫疗法的表观遗传修饰剂 |
CN112334572A (zh) * | 2018-06-19 | 2021-02-05 | 南特细胞公司 | Hiv治疗组合物和方法 |
CN109306341B (zh) * | 2018-09-12 | 2022-01-28 | 华东师范大学 | Hdac11基因干扰的嵌合抗原受体t细胞及其应用 |
KR20230070075A (ko) * | 2018-10-31 | 2023-05-19 | 난트퀘스트, 인크. | Pd-l1 키메라 항원 수용체-발현 nk 세포에 의한 pd-l1-양성 악성종양의 제거 |
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TWI831999B (zh) * | 2019-08-28 | 2024-02-11 | 大陸商深圳微芯生物科技股份有限公司 | 一種西達本胺藥物組合物及其應用 |
TW202128169A (zh) * | 2019-10-07 | 2021-08-01 | 美商維拉克塔治療公司 | 具有降低副作用之hdac治療劑量 |
KR20220110808A (ko) | 2019-12-05 | 2022-08-09 | 비락타 서브시디어리 인크. | Hdac 억제제 고체상 형태 |
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