JP6616295B2 - 抗ヒトパピローマウイルス抗原t細胞の調製方法 - Google Patents
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Description
本特許出願は、2013年7月15日出願の米国仮特許出願第61/846,161号(参照により、その全体が本明細書に組み込まれる)の利益を主張する。
いくつかのタイプの癌、例えば子宮頸癌などの主因は、ヒトパピローマウイルス(HPV)感染である。化学療法などの治療法の進歩にもかかわらず、HPV関連癌を含む多くの癌の予後は不良である場合がある。従って、癌、特にHPV関連癌に対して、満たされていない更なる治療の必要性が存在する。
本発明の一実施態様は、HPV特異的T細胞集団を調製する方法であって、HPV陽性腫瘍サンプルを複数(multiple)のフラグメントに分割すること;該複数のフラグメントを、1のみのサイトカインの存在下、別個に培養すること;培養された複数のフラグメントからT細胞を得ること;該T細胞を、特異的な自己HPV陽性腫瘍認識及びHPV抗原認識の一方又は両方について試験すること;特異的な自己HPV陽性腫瘍認識及びHPV抗原認識の一方又は両方を呈するT細胞を選択すること;並びに、選択されたT細胞の数を拡大(expanding)して、HPV特異的T細胞集団を作製することを含む、方法を提供する。
ヒトパピローマウイルス(HPV)特異的T細胞集団が、様々な適用のため、例えば養子細胞療法などのために調製され得ることを発見した。本発明の方法は、様々な病態(conditions)、例えば癌などを治療するのに有用である細胞を作製し得る。
本実施例は、養子細胞療法のためのHPV陽性腫瘍浸潤リンパ球(TIL)を調製する方法を実証する。
本実施例は、患者1由来のTILの反応性を実証する。
本実施例は、HPV 18 E7反応性のCD8陽性T細胞を単離するために、患者1の腫瘍フラグメント16由来のTILのクローニングを実証する。
本実施例は、患者12由来の実施例1で作製されるTILの反応性を実証する。
本実施例は、HPV 18 E6反応性のCD8陽性T細胞を単離するために、患者12の腫瘍フラグメント1及び15由来のTILクローンの反応性を実証する。
本実施例は、患者12のF15腫瘍フラグメントから作製されたクローンが、HLA-DRB1*15拘束性の様式で、HPV 18 E6121-135を認識することを実証する。
本実施例は、患者4及び8由来のTILの反応性を実証する。
本実施例は、HPV反応性のCD4及びCD8陽性T細胞を単離するために、患者4の腫瘍フラグメント由来のTILのクローニングを実証する。
本実施例は、抗HPV T細胞を用いた養子細胞療法が癌を治療することを実証する。
本実施例は、実施例9に記載の結果が得られてから9ヶ月後に得られた、実施例9に記載の臨床研究のアップデートされた結果を提供する。本実施例は、抗HPV T細胞を用いた養子細胞療法が癌を治療することを実証する。
本実施例は、抗HPV T細胞を用いた養子細胞療法による実施例10で得られた完全な腫瘍縮小効果をさらに説明する。
HPV-TILの作製:以前に記載されるように(Dudley et al., J. Immunother., 26(4):332-42(2003))、切除腫瘍の2 mmのフラグメントから腫瘍浸潤リンパ球(TIL)を増殖させた。リンパ球アウトグロース(outgrowth)の2週間から3週間後に、培養物をフローサイトメトリーにより細胞構成について評価し、以下のHPVオンコプロテイン反応性の評価セクションに記載するように、インターフェロン(IFN)-ガンマ産生アッセイによりHPVタイプ特異的E6及びE7に対する反応性について評価した。CD3、CD4、CD8及びCD56に対して特異的な蛍光抗体(BD Biosciences)を用いてフローサイトメトリー分析を実施した。HPVオンコプロテインに対する反応性、急速増殖、高T細胞純度、及び高頻度のCD8+ T細胞に基づき、更なる拡大のために培養物を選択した。治療のために使用される細胞数への拡大は、G-REXガス透過性フラスコを用いた急速拡大プロトコルにより達成された(Dudley et al., J. Immunother., 26(4):332-42(2003);Jin et al., J. Immunother., 35(3):283-92(2012))。注入産物は、生細胞数、T細胞純度(フローサイトメトリー)、能力(potency)(IFN-γ産生)、無菌性(微生物学的研究)、及び腫瘍細胞の不存在(細胞病理学)について証明された。
患者4は、HPV-TILでの治療14ヶ月前に、ステージ3Bの低分化子宮頸部扁平上皮癌と診断された。患者は、最初に、シスプラチン、ビンクリスチン及びブレオマイシンで治療され、それに続いて、ゲムシタビン+シスプラチンを用いた化学放射線療法、及び小線源療法で治療された。2ヶ月後、傍気管リンパ節(バイオプシーにより確認)、気管分岐部リンパ節及び両側肺門リンパ節に転移性癌が検出された。患者は、疾患の進行前に、トポテカン及びパクリタキセルを4サイクル受け、次いで、実施例9及び10に記載の臨床試験を施行された。HPV-TILは、切除した傍気管リンパ節から調製した。患者は、リンパ球枯渇化学療法を受け、それに続いて、152×109 HPV-TILの単回静脈内注入、及び2用量のアルデスロイキンを受けた。アルデスロイキンの投薬は、患者の疲労のために中止した。患者は、細胞注入から12日後、血液学的回復後に病院から退院した。
患者はともに、治療前に播種性の進行性疾患を有した(図12A〜F;図14A〜H;図15A〜B;図16A〜D;図21A〜H;及び図22A〜H)。患者4は、傍大動脈縦隔リンパ節、両側肺門(bilateral lung hila)リンパ節、気管分岐部リンパ節、及び腸骨リンパ節を侵す転移性腫瘍を有した(図15A;図12A〜F;及び図21A〜H)。患者8は、少なくとも7つの部位を侵す転移性癌を有した:肝臓表面上の2つの腫瘍、傍大動脈及び大動静脈(aortocaval)のリンパ節、腹壁、左骨盤における結腸周囲腫瘤、並びに右尿管を塞ぐ小結節(図15B;図14A〜H;図16A〜D;及び図22A〜H)。患者はそれぞれ、単回注入T細胞で治療され、数ヶ月にわたって生じる腫瘍退縮がもたらされた(図15A〜B)。患者はともに、客観的な完全腫瘍縮小効果を生じ、治療から18ヶ月後及び11ヶ月後において持続した(図21A〜H(患者4)及び図22A〜H(患者8))。右尿管を塞ぐ腫瘍の退縮後、以前に留置された尿管ステントを患者8から除去した(図22G及びH)。いずれの患者も追加の治療を受けなかった。患者はともに、フルタイムの雇用に復帰した。
細胞注入と関連する急性毒性は存在しなかった。自己免疫の有害事象は生じなかった。患者はともに、発熱と関連する一過性の血清サイトカインの上昇を呈したが(図17A〜B)、いずれの患者も重篤なサイトカイン放出症候群は発症しなかった。凍結保存された血清中のサイトカインレベルを決定した。試験は以下のサイトカインについて行った:IL-1β、IL-2、IL-4、IL-5、IL-6、IL-7、IL-8、IL-10、IL-12(p70)、IL-13、IL-17、G-CSF、顆粒球マクロファージコロニー刺激因子(GM-CSF)、IFN-γ、MCP-1、マクロファージ炎症性タンパク質1ベータ(MIP-1β)及びTNF-α。2の連続測定においてベースラインの2倍超のレベルを有するサイトカインを示す。アルデスロイキンは、細胞注入から8時間毎に投薬された(患者4は2用量を受け、患者8は8用量を受けた)。GCSFは、細胞注入翌日から開始して毎日投与され、好中球数が回復するまで継続された(患者4は11用量を受け、患者8は9用量を受けた)。
HPV-TILの作製のために切除された転移性腫瘍は、患者4由来の扁平上皮癌及び患者8由来の腺癌であった。悪性細胞は、ハイリスクHPV感染の高感度指標であるp16INK4Aを発現した。HPVタイプ、並びにHPV-TILの標的抗原であるE6及びE7の発現レベルを、リアルタイム逆転写ポリメラーゼ連鎖反応(RT-PCR)により各患者腫瘍について決定した。患者4はHPV-16+の癌を有し、患者8はHPV-18+の癌を有した。両方の患者由来の腫瘍におけるT細胞浸潤は、患者4ではCD8+細胞が、患者8ではCD4+細胞が多数を示す混合組成を示した。CD4+及びCD8+ T細胞はともに、切除腫瘍から増殖した。注入されるHPV-TILは、患者4では19%のCD4+及び79%のCD8+ T細胞から構成され、患者8では15%のCD4+及び87%のCD8+ T細胞から構成された。
患者4に投与されるHPV-TILは、インターフェロン(IFN)-γ産生及びELISPOTアッセイにより実証されるように、E6及びE7オンコプロテインの両方に対して反応性であった(図18A及びC)。ELISPOTアッセイにより、注入細胞の5%、及び7%超が、それぞれ、E6又はE7に対する応答を示した(図18C及びD)。E6応答は、CD8+ T細胞媒介性であり、E7応答は、CD4+及びCD8+ T細胞媒介性であった。CD137上方制御アッセイにより測定されるように、合計で注入細胞の14%がHPV反応性を示した。患者8について、HPV-TILはE7に対して反応性であり(図18B)、ELISPOTアッセイにより、T細胞の4%が抗原に応答した(図18D)。この応答は、CD4+ T細胞により主に媒介された。
HPV-TIL注入に続いて、末梢血CD4+及びCD8+ T細胞が急速に増加したが、NK及びB細胞はしなかった(図19A〜B)。注入T細胞の数の拡大は、IFN-γ産生、ELISPOT、及びCD137上方制御アッセイにより測定されるように、HPVオンコプロテインに対する末梢血T細胞反応性の確立及び持続と関連した(図19C〜F)。患者はともに、治療前には、たとえ存在するとしても、E6又はE7に対する反応性を殆ど有さなかった。治療の後、患者4は、E6及びE7のロバストなT細胞認識を獲得した。患者8については、この認識は弱かったが、それにもかかわらず検出可能であり、注入T細胞と一致して、E7のみに対して向けられた。治療から1ヶ月後、患者4の末梢血T細胞の12%が、オンコプロテイン反応性であった(E6に対して7%及びE7に対して5%)(図19E)。これらの抗原に対する反応性は、細胞注入から4ヶ月後及び13ヶ月後において持続され、末梢血T細胞の1%がオンコプロテイン認識を示した(図19E)。患者8は、治療から1ヶ月後において、0.4%のHPV反応性T細胞を示した(図19F)。この反応性は、治療から3ヶ月後及び6ヶ月後において、低レベルにもかかわらず持続された(図19D及びF)。注入HPV-TILにおけるT細胞サブセットの反応性と一致して、患者で再増殖(repopulated)したHPV特異的T細胞は、主に、患者4についてはE6及びE7反応性CD8+ T細胞であり、患者8についてはE7反応性CD4+ T細胞であった。
本実施例は、実施例10及び11に記載の結果が得られてから4ヶ月後に得られた、実施例10及び11に記載の臨床研究からの、患者4及び8のアップデートされた結果を提供する。本実施例は、抗HPV T細胞を用いた養子細胞療法が癌を治療することを実証する。
Claims (13)
- ヒトパピローマウイルス(HPV)特異的T細胞集団を調製する方法であって、
HPV陽性腫瘍サンプルを複数のフラグメントに分割すること;
該複数のフラグメントを、1のみのサイトカインの存在下、別個に培養すること、ここで前記サイトカインは、インターロイキン(IL)-2、IL-7、IL-15又はIL-12である;
培養された複数のフラグメントからT細胞を得ること;
複数のフラグメントに由来する該T細胞を、特異的な自己HPV陽性腫瘍認識及びHPV抗原認識の一方又は両方について別個に試験すること;
特異的な自己HPV陽性腫瘍認識及びHPV抗原認識の一方又は両方を呈するT細胞を選択すること;並びに
選択されたT細胞の数を拡大して、HPV特異的T細胞集団を作製すること
を含む、方法。 - 選択されたT細胞の数を拡大することが、(i)放射線照射された同種異系フィーダー細胞及び(ii)放射線照射された自己フィーダー細胞の一方又は両方、並びに(iii)OKT3抗体及び(iv)インターロイキン(IL)-2の一方又は両方、を用いて細胞の数を拡大することを含む、請求項1に記載の方法。
- サイトカインがIL-2である、請求項1又は2に記載の方法。
- HPV特異的T細胞集団を調製する方法であって、
HPV陽性腫瘍サンプルを複数のフラグメントに分割すること;
該複数のフラグメントを、インターロイキン(IL)-2、IL-7、IL-15及びIL-12からなる群から選択される1以上のサイトカインの存在下、別個に培養すること;
培養された複数のフラグメントからT細胞を得ること;
複数のフラグメントに由来する該T細胞を、特異的な自己HPV陽性腫瘍認識及びHPV抗原認識の一方又は両方について別個に試験すること;
特異的な自己HPV陽性腫瘍認識及びHPV抗原認識の一方又は両方を呈するT細胞を選択すること;並びに
(i)OKT3抗体及び(ii)インターロイキン(IL)-2の一方又は両方を用いて、選択されたT細胞の数を拡大し、HPV特異的T細胞集団を作製すること
を含む、方法。 - 複数のフラグメントを別個に培養することが、複数のフラグメントを、1のみのサイトカインの存在下で培養することを含む、請求項4に記載の方法。
- サイトカインがIL-2である、請求項5に記載の方法。
- 選択されたT細胞の数を拡大することが、放射線照射された同種異系フィーダー細胞及び放射線照射された自己フィーダー細胞の一方又は両方を用いることをさらに含む、請求項4〜6のいずれか一項に記載の方法。
- HPV特異的T細胞集団が、HPV 16陽性癌細胞を認識する、請求項1〜7のいずれか一項に記載の方法。
- HPV特異的T細胞集団が、HPV 16 E6を認識する、請求項1〜8のいずれか一項に記載の方法。
- HPV特異的T細胞集団が、HPV 16 E7を認識する、請求項1〜9のいずれか一項に記載の方法。
- HPV特異的T細胞集団が、HPV 18陽性癌細胞を認識する、請求項1〜7のいずれか一項に記載の方法。
- HPV特異的T細胞集団が、HPV 18 E6を認識する、請求項1〜7及び11のいずれか一項に記載の方法。
- HPV特異的T細胞集団が、HPV 18 E7を認識する、請求項1〜7及び11〜12のいずれか一項に記載の方法。
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