JP2014502970A - 腫瘍溶解性ワクシニアウイルスの投与による腫瘍抗原に対する抗体の生成および腫瘍特異的補体依存性細胞傷害の生成 - Google Patents
腫瘍溶解性ワクシニアウイルスの投与による腫瘍抗原に対する抗体の生成および腫瘍特異的補体依存性細胞傷害の生成 Download PDFInfo
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Abstract
Description
本出願は、2011年1月4日出願の、参照によりその全体が本明細書に組み込まれる米国仮特許出願第61/429622号の優先権の利益を主張するものである。
無し
本発明は、癌治療の介入のための新たな作用機序、ならびにこのような新たな作用機序に基づく癌治療のために考案された方法および組成物に関する。
新規な作用機序(MOA)を用いた新たな癌治療が必要とされている。現在の治療は、通常、単一薬剤として使用すると限られた有効性しか有さないので、実務上は最大効果のために組み合わせて使用されている。新規な薬剤は、理想的には承認された療法との交差耐性がなく、複数の相補的MOAを有するべきである1〜4。「遺伝子治療」(複製不全ウイルスへの治療用導入遺伝子の導入)5〜7および癌ワクチン(腫瘍抗原、同時刺激分子および/またはサイトカインの発現)8〜10を含む、異なるアプローチを用いる癌治療のための遺伝子組換えウイルスが開発されてきた。しかしながら、遺伝子治療は、十分な数の癌細胞への局所的および全身的な送達が非効率的であるために、現在まで患者では失敗している。対照的に、ウイルスに基づく癌ワクチンは、腫瘍免疫回避および進行した巨大な癌を有する患者における効果に関して宿主因子への排他的依存により限定されている。免疫回避は、単一腫瘍抗原および/または単一サイトカインの発現に依存するワクチンアプローチで最も可能性が高い。広範な治療用癌ワクチンは、複数の腫瘍抗原、サイトカイン、免疫細胞の動員と活性化、および免疫応答の危険信号を発現させるために必要とされる。
(a)複製能を有する腫瘍溶解性ウイルスを含む組成物を該患者に投与する工程であって、該組成物の投与によって、該患者内で該癌に特異的なCDC応答を媒介する抗体の産生が該患者において誘導される、工程;
(b)該患者から血液を単離する工程であって、該血液が、該癌に対する収集した抗体、収集したB細胞を含む、工程;
(c)該患者に特異的な免疫療法組成物を生成するために、該抗体を増大させるもしくは単離する工程、または該B細胞から抗体を産生する工程;および
(d)工程(c)の免疫療法組成物を該患者に投与する工程。
このような方法では、免疫療法組成物は、抗体の単離後直ちに投与されてもよい。あるいは、免疫療法組成物は、該患者のさらなる治療的処置用に保管される。
腫瘍溶解性ウイルスは、それらの作用の一次機序としてウイルス複製に依存する癌細胞溶解を引き起こすが、この癌特異的免疫の誘導は、前臨床モデルにおいても主要な活性メディエーターになり得る。しかし、抗癌免疫の機能的誘導は、これまで癌患者において示されなかった。JX−594は、抗癌免疫の誘導を増大させるためにヒト顆粒球マクロファージコロニー刺激因子(GM−CSF)を発現するように設計された標的化腫瘍溶解性ワクシニアウイルスである。JX−594は、臨床試験に参加した患者において腫瘍反応と関連した複製およびGM−CSF発現を示した。
ウイルスおよび細胞系:本試験全般にわたって、JX−594、ワイス変種ワクシニアウイルス(チミジンキナーゼ[TK]−不活化、hGM−CSF発現)を用いて、以前に発表したように調製した24。SNU349、SUN482とSNU267(ヒト腎細胞癌;韓国細胞バンク[KCLB]から取得)およびSNU475とSNU398(ヒト幹細胞癌;KCLBから取得)をペニシリンとストレプトマイシンとともに10%FBS(HyClone社)を添加したRPMI1640(Gibco社)培地で培養した。HOP62、H157、H460とPC10(ヒト肺癌;アメリカン・タイプ・カルチャー・コレクション[ATCC]から取得)、HepG2(ヒト肝細胞癌;ATCCから取得)、SF−295(ヒト胆嚢癌;ATCCから取得)、PC−3(ヒト前立腺癌;ATCCから取得)、PANC−1(ヒト膵癌;ATCC)、MCF−7(ヒト乳癌;ATCC)をペニシリンとストレプトマイシンとともに10%FBSを含むDMEM培地で培養した。MRC−5非形質転換細胞(肺線維芽細胞;ATCC)およびHUVEC(内皮細胞;ATCC)MRC−5をペニシリンとストレプトマイシンとともに2%ウシ胎児血清(FBS)を添加した内皮細胞培地EBM−2(Lonza社,MD,USA)で培養した。
腫瘍を有し、JX−594で処置したウサギ由来の血清とともに腫瘍細胞をインキュベートした後、細胞生存率の低下が観察された。
ウサギモデルでCDCの誘導を調べるために、筋肉内に移植したVX2腺癌を有し、JX−594またはPBS対照で処置したウサギから血清を収集した。注射後28日目に収集した血清をin vitroで3%の濃度で、VX2細胞またはウサギ末梢血単核細胞(PBMC)に添加した。細胞生存率の有意な低下(約90%)は、JX−594で処置したVX2腫瘍を有するウサギ由来の血清とともにインキュベートした細胞でのみ観察された(図1A)。PBSで処置したVX2腫瘍を有するウサギ由来、またはJX−594で処置した腫瘍のないウサギ由来の血清とともにインキュベートしたVX2細胞は、細胞生存率の低下を示さなかった。さらに、PBMCでの生存率は、いずれの処置群に由来する血清とともにインキュベートしても、有意な低下を示さなかった。続いて、JX−594(またはPBS)での処置後の種々の時点で収集した血清とともにインキュベートして、VX2細胞生存率を評価した。VX2腫瘍を有し、JX−594で処置したウサギにおいて18日目以降から収集した血清とともにインキュベートすると、VX2細胞生存率は低下した(図1B)。血清濃度を上げると(2%まで)、VX2細胞生存率の用量依存的低下を示した(図1C)。2%血清とともに細胞をインキュベートすると、対照の正常なウサギ血清による処置と比較して、約20%のVX2細胞生存率がもたらされた。VX2を有しJX−594で処置したウサギ由来の血清が新規の抗原に結合するかどうかを評価するために、未処置ウサギおよび腫瘍を有しJX−594で処置したウサギに由来する血清を用いて、VX2細胞溶解物およびPBMC細胞溶解物でウエスタンブロット分析を行った。新規の抗原に対する強い反応性は、VX2細胞系の溶解物でのみ観察され、VX2腫瘍を有するウサギをJX−594で処置すると、複数の新しいバンドが認識され、VX2腫瘍抗原に対するポリクローナル抗体が誘導されたことを示していた(図1D)。
腫瘍を有しJX−594で処置したウサギ由来のウサギ血清とともにインキュベートすることでもたらされた細胞生存率の有意な低下が認められたので、JX−594で処置した患者から収集した血清においても同様な活性が観察されるかどうかを特定しようとした。本発明者らは、第1相の肝腫瘍試験で治療されている二人の患者由来の血清の試験を開始した。両患者は、JX−594処置後に有意な応答を示し、生存期間は長期であった(患者103:肺癌、生存期間24.5ヵ月;患者301:腎細胞癌、生存期間44.1+ヵ月)26。実際に、前臨床のモデルでの観察と同様に、JX−594で処置した患者の血清(5%)とともにインキュベートした癌細胞系は、細胞生存率の有意な低下をもたらした(図2A)。これらの患者の癌と同じ起源の癌細胞系を試験したところ、細胞生存率の時間依存的低下がほとんどの細胞系で観察された。明視野顕微鏡下で細胞を可視化することによって、膜侵襲複合体(MAC)の形成が明らかになり、細胞生存率の低下がCDCによってもたらされることを示した(図2B)。CSFEおよび7−AADの色素を用いて、生細胞と死細胞をそれぞれ染色した。7−AAD染色は、JX−594免疫患者由来の血清で処置した細胞が細胞死を起こしていることを示している。
次に、JX−594で処置した患者由来の血清が癌細胞の細胞傷害性を媒介する機序を評価するために、抗体および補体の寄与を試験した。JX−594で処置した患者由来の血清を熱不活化させて、全ての補体活性を阻害した。IgGを結合するカラムを用いて、血清由来の抗体を除去した(図3Aの実験概要を参照されたい)。ベースライン血清(JX−594処置前、血清A)、JX−594処置後92日目に得た血清(血清B)、血清Bを熱不活化させたもの(血清C)、および血清BをIgG樹脂に通したもの(血清E)を5%濃度で癌細胞系の単層に添加した。ベースラインで収集した血清は、細胞生存率の低下を示さなかったが、JX−594処置開始後92日目で収集した血清は、強い抗腫瘍活性を示した。しかし、細胞は熱不活化またはIgG欠乏後も生存可能な状態であった。さらに、(ベースラインで収集されそれ自体は細胞生存率の低下を示さない血清Aの添加によって)血清Cの機能的補体を回復させると、抗腫瘍活性の回復がもたらされた。第1相試験で治療された計3名の患者(301−腎細胞癌;103−肺癌;304−黒色腫)に由来する血清試料を用いて同様の観察を行った(図3B)。血清インキュベーション後の細胞系(患者301)の明視野像を図3Cに示す。最終的に、細胞生存率における時間依存的増加は、熱不活化の長さに関連して観察された(図3D)。
次に、JX−594で処置した患者由来の血清が、ex vivoで正常なヒト細胞に対して細胞傷害性を引き起こすことができるかどうかを調べた。HUVEC内皮細胞およびMRC−5肺線維芽細胞は、試験した5名の患者のいずれかに由来する血清とともにインキュベートした場合、細胞生存率の有意な低下を示さなかった。概して、細胞生存率の低下は、その起源が該患者の腫瘍型(腎細胞癌、黒色腫および肝細胞癌)に対応する細胞で観察された(図4A〜D)。生存期間対CDC第1相。
継続中の無作為第2相試験で処置された肝細胞癌の患者でのCDC誘導を分析した。JX−594で処置された患者由来の血清とともにインキュベートした肝細胞癌の細胞系において細胞生存率の低下が観察された。CDC活性は、時間とともに増加した(図4B概要、図4C〜4E個々の細胞系)。
患者血清が新規の抗原を結合するかどうかを評価するために、患者の腫瘍と同じ組織起源の癌細胞系からの細胞溶解物と、患者血清(第1相および第2相試験の患者に由来するもので、有意なCDCを示していた)とを用いて、ウエスタンブロット分析を行った。新規の抗原に対する強い反応性は、JX−594処置後の血清において観察され、患者の内在性腫瘍抗原に対するポリクローナル抗体が誘導されたことを示唆する(図6)。新規の標的抗原を同定するために、ヒト肝細胞癌の細胞系(SNU449)から生成されたcDNAライブラリー上で強いCDC活性を有する肝細胞癌の患者に由来するプールした血清を用いて、SEREXスクリーニングを行った。2ラウンドのスクリーニングの後、17の候補抗原を同定した(図7、表1)。抗原のサブセット、例えば、RecQタンパク質様(DNAヘリカーゼQ1様)(RECQL)およびレプチン受容体(LEPR)は、HCCまたは他の癌の標的として以前に同定されているが、その他[ERBB受容体フィードバック阻害因子1(ERRFI1)、リソソームタンパク質膜貫通4アルファ(LAPTM4A)およびRAS癌遺伝子ファミリー(RAB1B)を含む]は、推定のHCC抗原であり、HCC中の新規の標的に潜在的に相当する。JX−594処置の前に収集した患者の血清の反応性を、同定した11の抗原に対する反応性について試験した。抗原のサブセットに対する抗体は、JX−594処置の前に存在していたが、一般に、反応性はJX−594治療後に強くなり、複製能を有するポックスウイルスによる処置が腫瘍抗原を認識するポリクローナル抗体を誘導することを示唆している。
癌に対する第1の癌免疫療法(Provenge、Dendreon社,Seattle,WA)の承認により、癌治療に対するこの新規の方法が有効となった。自己由来の樹状細胞集団は、患者に再注入する前に、GM−CSFに融合させた前立腺癌の抗原に曝露され、この方法は、去勢抵抗性前立腺癌患者の生存を向上させることが示されている32。非特異的な免疫賦活方法も、免疫賦活サイトカイン、例えばIL−2による処置を含む癌免疫療法として評価されている。免疫賦活サイトカインまたは同時刺激分子と関連して、腫瘍抗原を発現する多くの複製不可能なウイルスワクチンが腫瘍ワクチンとして評価されている。腫瘍特異的免疫応答を誘導するのに有効ではあるが、これらの戦略が患者にとって有意な延命効果をもたらしたことはなく、ウイルスワクチンが規制機関によって承認されたことは未だない。腫瘍抗原に対する抗体の全般的な誘導は観察されているが9、33、これらの抗体が機能的であるかどうか、例えば該抗体がCDCを媒介するかどうかは不明である。
複製能を有する腫瘍溶解性ウイルスが、CDCを媒介する腫瘍特異的抗体を差次的に誘導することを示すように試験を設計した。抗体誘導は、免疫賦活サイトカインの発現によって促進させることができる。これらのうちまず、第一にCDC応答を媒介する腫瘍特異的抗体の誘導に対する腫瘍溶解性ワクシニア、GM−CSFおよびレオウイルスの効果を評価し、データを図9に示す。
次の一連の試験で、CDC応答を媒介する腫瘍特異的抗体の誘導に対する腫瘍溶解性ワクシニア、GM−CSFおよびVSVの効果を評価し、そのデータを図10に示す。
この一連の実験では、ヒト癌細胞におけるCDCを媒介する腫瘍特異的抗体の誘導に対する腫瘍溶解性HSVおよびVSV−GM−CSFの効果を評価し、そのデータを図11に示す。
この一連の実験では、in vivo標的腫瘍由来のウサギ癌細胞におけるCDCを媒介する腫瘍特異的抗体の誘導に対する腫瘍溶解性ワクシニア、GM−CSFおよびVSVの効果を評価し、そのデータを図12に示す。
本実施例において、マウス腫瘍モデルでCDCを媒介する腫瘍特異的抗体の誘導を媒介した腫瘍溶解性ワクシニアおよびマウスGM−CSFの効果を評価し、そのデータを図13に示す。
Claims (32)
- 以下の工程を含む、腫瘍を有する動物において腫瘍特異的抗体に媒介される補体依存性細胞傷害応答を誘導する方法:
複製能を有する腫瘍溶解性ウイルスを含む組成物を該動物に投与する工程であって、該組成物の投与によって、該腫瘍に特異的なCDC応答を媒介する抗体が該動物において誘導される、工程。 - 前記腫瘍溶解性ウイルスの投与が、腫瘍を有さない動物においてはCDC応答を誘導しない、請求項1に記載の方法。
- 前記腫瘍溶解性ウイルスが、ポックスウイルス、アデノウイルス、アデノ随伴ウイルス、単純ヘルペスウイルス、ニューカッスル病ウイルス、水疱性口内炎ウイルス、流行性耳下腺炎ウイルス、インフルエンザウイルス、パルボウイルス、麻疹ウイルス、ヒトハンタウイルス、粘液腫ウイルス、サイトメガロウイルス(CMV)、レンチウイルス、コクサッキーウイルス、エコーウイルス類、セネカバレーウイルスおよびシンドビスウイルスからなる群から選択される、請求項1に記載の方法。
- 前記腫瘍溶解性ウイルスが腫瘍溶解性ポックスウイルスである、請求項1に記載の方法。
- 前記腫瘍溶解性ウイルスが、JX−594、p53発現ウイルス、水疱性口内炎ウイルス(VSV)、ONYX−15、Delta24、VA1領域に変異を有するアデノウイルス、K3LまたはE3L領域に変異を有するワクシニアウイルス、テロメライシン、テロメライシン−GFP、OV20.0L遺伝子に変異を有するパラポックスウイルスorfウイルス、Geneluxウイルス、およびγ(1)34.5遺伝子に変異を有するヘルペスウイルスからなる群から選択される、請求項1に記載の方法。
- 前記腫瘍溶解性ポックスウイルスがワクシニアウイルスである、請求項4に記載の方法。
- 前記腫瘍溶解性ウイルスがJX−594である、請求項4に記載の方法。
- 前記腫瘍溶解性ウイルスが導入遺伝子を含む、請求項1に記載の方法。
- 異種核酸配列がGM−CSF、シトシンデアミナーゼ、カルボキシルエステラーゼ、NIS、ソマトスタチン受容体をコードする、請求項8に記載の方法。
- 前記腫瘍が、星状細胞腫、乏突起神経膠腫、髄膜腫、神経線維腫、神経膠芽腫、脳室上衣細胞腫、シュワン腫、神経線維肉腫、神経芽細胞腫、下垂体腺腫、髄芽腫、頭頚部癌、黒色腫、前立腺癌、腎細胞癌、膵癌、乳癌、肺癌、結腸癌、胃癌、膀胱癌、肝癌、骨癌、直腸癌、卵巣癌、肉腫、胃癌、食道癌、子宮頸癌、線維肉腫、扁平上皮癌、神経外胚葉腫瘍、甲状腺腫瘍、ホジキンリンパ腫、非ホジキンリンパ腫、肝細胞癌、中皮腫、類表皮癌および血液の腫瘍化疾患からなる群から選択される、請求項1に記載の方法。
- 以下の工程を含む、抗腫瘍CDC応答を媒介する抗体をin vivoで生成する方法:
複製能を有する腫瘍溶解性ウイルスを含む組成物を患者に投与する工程であって、該組成物の投与によって、該腫瘍に特異的なCDC応答を媒介する抗体の産生が誘導される、工程。 - 前記投与の後、前記患者から血液を採取する工程、および、CDC応答を生ずる抗体を該血液から単離する工程をさらに含む、請求項11に記載の方法。
- 請求項12に記載の方法によって単離されたCDC応答を生ずる抗体を含む、組成物。
- 前記組成物が前記患者から収集された血清である、請求項13に記載の方法。
- 癌細胞の増殖を阻害するかまたは癌細胞を殺傷する方法であって、該癌細胞を請求項13に記載の組成物と接触させる工程を含む、方法。
- 前記接触させる工程が、癌細胞を前記組成物とin vitroで接触させることを含む、 請求項15に記載の方法。
- 前記接触させる工程が、癌患者に、収集した抗体、収集したB細胞、該収集したB細胞が産生した抗体、またはそれらの組み合わせを含む組成物を注入することを含む、請求項15に記載の方法。
- 前記癌細胞がin vivoで患者の体内にあり、前記接触させる工程が、前記組成物を含む薬物を投与することを含む、請求項15に記載の方法。
- 前記患者にさらなる抗癌治療薬を投与する工程をさらに含む、請求項1、11または15に記載の方法。
- 癌患者を治療する方法であって、請求項13に記載の組成物を含む組成物を該患者に投与する工程を含む、方法。
- 前記組成物が、前記患者にとって自己由来であり、かつ前記癌患者から単離されて、該癌患者に再注入される、請求項20に記載の方法。
- 前記癌患者にとって異種である前記組成物が、該組成物を用いて治療される該癌患者とは異なる癌患者から単離される、請求項20に記載の方法。
- 前記患者が、さらなる抗癌治療薬を用いて治療される、請求項20に記載の方法。
- 前記癌患者が固形腫瘍を有し、前記組成物が、腫瘍内に、静脈内に、腹膜内に、またはそれらの組み合わせで投与される、請求項20に記載の方法。
- 前記癌患者が、請求項12に記載の組成物の投与の前に、投与と同時に、または投与の後に切除される固形腫瘍を有する、請求項24に記載の方法。
- 前記癌患者が固形腫瘍を有し、前記組成物が該腫瘍の大きさを低下させる、請求項20に記載の方法。
- 前記癌患者が固形腫瘍を有し、前記投与によって該固形腫瘍の転移拡散が減少する、請求項20に記載の方法。
- 前記癌が、星状細胞腫、乏突起神経膠腫、髄膜腫、神経線維腫、神経膠芽腫、脳室上衣細胞腫、シュワン腫、神経線維肉腫、神経芽細胞腫、下垂体腺腫、髄芽腫、頭頚部癌、黒色腫、前立腺癌、腎細胞癌、膵癌、乳癌、肺癌、結腸癌、胃癌、膀胱癌、肝癌、骨癌、直腸癌、卵巣癌、肉腫、胃癌、食道癌、子宮頸癌、線維肉腫、扁平上皮癌、神経外胚葉腫瘍、甲状腺腫瘍、ホジキンリンパ腫、非ホジキンリンパ腫、肝細胞癌、中皮腫、類表皮癌および血液の腫瘍化疾患からなる群から選択される、請求項20に記載の方法。
- 以下の工程を含む、癌療法を癌患者に適合させる方法:
(a)複製能を有する腫瘍溶解性ウイルスを含む組成物を該患者に投与する工程であって、該組成物の投与によって、該患者内で該癌に特異的なCDC応答を媒介する抗体の産生が該患者において誘導される、工程;
(b)該患者から血液を単離する工程であって、該血液が、該癌に対する収集した抗体、収集したB細胞を含む、工程;
(c)該患者に特異的な免疫療法組成物を生成するために、該抗体を増大させるもしくは単離する工程、または該B細胞から抗体を産生する工程;および
(d)工程(c)の免疫療法組成物を該患者に投与する工程。 - 前記免疫療法組成物が、前記抗体の単離後直ちに投与される、請求項29に記載の方法。
- 前記免疫療法組成物が、前記患者のさらなる治療的処置用に保管される、請求項29に記載の方法。
- 以下の工程を含む、腫瘍特異抗原を同定する方法:
(a)癌細胞から調製されたcDNAライブラリーを発現ベクターにクローニングする工程;
(b)請求項11に記載の患者に由来する血清と該発現ベクターを接触させることによって一次免疫スクリーニングを行う工程であって、該血清が該腫瘍溶解性ウイルスの投与後に該患者から単離される、工程;および
(c)該血清によって認識される該cDNAライブラリーから抗原を単離する工程。
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AU2012204467B2 (en) | 2016-08-18 |
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US20180214538A1 (en) | 2018-08-02 |
EP2661278A4 (en) | 2015-10-07 |
KR20140032991A (ko) | 2014-03-17 |
US9919047B2 (en) | 2018-03-20 |
WO2012094386A9 (en) | 2013-08-15 |
JP6457003B2 (ja) | 2019-01-23 |
EP2661278B1 (en) | 2019-06-19 |
WO2012094386A1 (en) | 2012-07-12 |
KR101942237B1 (ko) | 2019-01-25 |
AU2012204467A2 (en) | 2013-10-24 |
JP6121910B2 (ja) | 2017-04-26 |
CA2824277A1 (en) | 2012-07-12 |
CN103429258A (zh) | 2013-12-04 |
US20150037355A1 (en) | 2015-02-05 |
CN103429258B (zh) | 2016-03-09 |
CA2824277C (en) | 2021-08-31 |
US10434169B2 (en) | 2019-10-08 |
EP2661278A1 (en) | 2013-11-13 |
HK1191874A1 (zh) | 2014-08-08 |
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