JP2018525343A - 短鎖ペプチド抗腫瘍ワクチンを用いて早期のtメモリー応答を誘発する方法。 - Google Patents
短鎖ペプチド抗腫瘍ワクチンを用いて早期のtメモリー応答を誘発する方法。 Download PDFInfo
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Abstract
Description
「エピトープ」は、免疫グロブリン、T細胞受容体又はHLA分子により認識される部位を一緒に形成する、一次、二次及び三次ペプチド構造、並びに電荷等の分子の総体的特徴である。或いは、エピトープは、特定の免疫グロブリンによる認識に関与する、又はT細胞に関するアミノ酸残基、T細胞受容体のタンパク質及び/又は主要組織適合性複合体(MHC)受容体による認識のために必要なこれらの残基の1組と定義することができる。エピトープは、天然に存在して、単離、精製するか又はヒトにより他の方法で調製若しくは誘導することができる。例えば、エピトープは、天然の供給源からの単離により調製することができ、又はそれらは、当技術分野における標準的プロトコルに従って合成することができる。本開示全体を通して、エピトープは、幾つかの場合に、ペプチド又はペプチドエピトープと称されることもある。
本発明の多エピトープT特異的がん免疫療法剤は、免疫系が、長く続く腫瘍特異的効果を有し得る免疫メモリーを発達させることを助けることができる。
RLLQETELV 配列番号1
YLQLVFGIEV 配列番号2
LLTFWNPPV 配列番号3
KVFGSLAFV 配列番号4
KLBPVQLWV 配列番号5、Bはα-アミノイソ酪酸を示す
SMPPPGTRV 配列番号6
IMIGHLVGV 配列番号7
KVAEIVHFL 配列番号8
YLSGADLNL 配列番号9
aKXVAAWTLKAAa 配列番号10、X及びaは、それぞれシクロヘキシルアラニン及びd-アラニンを示す。
ワクチンの投与レジメンは、初回刺激期間及び場合により維持期間を含む。
本発明の関係で、用語「処置」又は「処置すること」は、治癒的、症候的、及び予防的処置を表す。本発明の医薬組成物及び製剤は、がん又は腫瘍が存在する、好ましくはがんの進行の後期にあるヒトに使用することができる。本発明の医薬組成物及び製剤は、がんを有する患者を必ずしも治癒させるとは限らないが、疾患の進行を遅らせるか若しくは遅くするか又はさらなる進行を防止し、それにより患者の状態を緩和する。特に、本発明の医薬組成物及び製剤は、腫瘍の発達を縮小し、及び/又は転移の発生若しくは発達及びがんの再発を予防する。がんの処置において、本発明の医薬組成物は、治療有効量で投与される。
本発明の好ましい態様によれば、OSE-2101組成物によるワクチン接種の対象は、がんの患者である。好ましい実施形態では、患者のがんは、以下のがんの1つに起因する: NSCLC(非小細胞肺がん)及び小細胞肺がん等のがん癌、メラノーマ、中皮腫、乳がん、原発性脳がん、卵巣、子宮癌、特に子宮体部及び/又は子宮頸部の癌、頭部及び頸部、結腸、胃腸、腎臓のがん、肉腫、胚細胞腫瘍、白血病、リンパ腫、精巣がん並びに膀胱がん、好ましくはNSCLC、結腸がん、乳がん、卵巣がん、並びに頭部及び/又は頸部のがん、より好ましくはNSCLC。
場合により、該処置は、別の抗腫瘍薬を用いる処置、特に化学療法、ホルモン療法及び/又は免疫療法と組み合わせて使用される。
セントラルメモリーT細胞の関与による早期の免疫応答
フェーズ1/フェーズ2の臨床研究で、10種のペプチドにより強化されたエピトープの組合せ、OSE-2101の安全性及び免疫原性を、早期の結腸及びNSCLC患者で広い多エピトープCTL応答を誘発するように合理的に設計した。多エピトープの適用範囲に加えて、OSE-2101は、乳房、結腸及び非小細胞肺、卵巣の腫瘍で広範に発現される5種の腫瘍抗原(CEA、HER-2/neu、p53、MAGE2及びMAGE3)からのエピトープも標的として、この製品を、異なるがんの徴候に対する療法のために適するようにした。CTL誘発のためのT細胞ヘルパーの供給源として、普遍的なHTLエピトープPan DRエピトープも含まれて、鉱物油アジュバントがこのT特異的がん免疫療法剤の最終の剤形化のために使用された。
患者の特徴付け。試験に登録されたIII期の結腸がんを有する14名の患者及び6用量のOSE-2101を受けた後研究を完了した10名の患者。NSCLCの試験でIIB/IIIA期の疾患を有する10名の患者が登録されて、6名の患者が研究を完了した。
フェーズ2で確認された早期のメモリーT細胞の関与
培養されたElispotによって測定されるCTLの免疫応答。免疫原性は、フェーズ2臨床試験で、各テスト試料からの凍結保存されたPBMCについて、30μg/ml DNAアーゼを含有する5%ヒト培養培地(25mM HEPESを含み、5%ヒトAB血清、4mM L-グルタミン、0.5mMピルビン酸ナトリウム、0.1mM MEM非必須アミノ酸、100μg/mlストレプトマイシン、及び100U/mlペニシリンで補完されたRPMI-1640培地)中で解凍して測定した。1200rpmで5分間遠心分離した後、細胞ペレットを5%ヒト培養培地に再懸濁して2回洗浄した。セントラルメモリーT細胞の培養されたELISPOTアッセイのために、2×106/mlのPBMCを48ウェルプレート中のウェルに反復で入れ、10μg/mlの各ペプチドで10日間刺激した。陽性対照として、PBMCをリコールウイルスペプチドのプールでも刺激した。ヒトrIL2(10U/ml)を、第1日、第4日及び第7日に、ペプチドで刺激された培養物に加えた。10日後に、刺激された細胞を回収して5×104/ウェルの濃度でプレーティングした。アッセイウェルには、照射された自家PBMC(1×105/ウェル)及び10μg/mlのペプチド、ワクチンペプチド、関係のないペプチド又は陽性対照ペプチドのいずれかも入れた。インビトロで各アナログエピトープにより刺激された細胞も、対応する野生型エピトープに対してテストした。
患者の登録及び免疫モニタリングの基準。IIIB期、IV期又はフェーズ2試験における再発NSCLCの合計64名のHLA-A2+患者を、少なくとも1用量のOSE-2101で処置した。33名の患者が3週間間隔で投与された6用量のOSE-2101からなる研究の初期フェーズを完了して、エピトープにより誘発されたT細胞/メモリーT細胞応答についてモニターされた。この患者コホートからのテスト結果を、第9週(3回の注射の後)及び第18週(6回の注射の後)における早期の応答に特別の注意をして、下に記載する。
早期のメモリーT細胞の関与による無増悪期間(TTP)に対する影響。
少なくともファーストラインの不成功の後の進行したNSCLCにおける短鎖ペプチド組合せのTTP結果(OSE2101フェーズ2データの内部報告)。腫瘍学で臨床的に、免疫組織学化学的に評価された浸潤メモリーT細胞の高いレベルの存在は、切除された結腸直腸がんの959個の検体における早期の転移性侵襲の徴候の不在、比較的進行していない病理学的病期、及び増大した生存率と相関した(Pages, Fら、2005、N Engl J Med;353: 2654〜2666頁)。TTPは、長期及び無病生存について、整合した代理薬がエフェクターメモリーT細胞と相関したので、興味深い。
悪性の胸水貯留(MPE)を有する進行がん患者における結果
Claims (17)
- HLA-A2(ヒト白血球抗原A2)陽性患者のがんの処置における使用のための治療用ペプチドT特異的免疫療法剤であって、ペプチドaKXVAAWTLKAAa(配列番号10、X及びaは、それぞれシクロヘキシルアラニン及びd-アラニンを示す)並びにRLLQETELV(配列番号1)、YLQLVFGIEV(配列番号2)、LLTFWNPPV(配列番号3)、KVFGSLAFV(配列番号4)、KLBPVQLWV(配列番号5、Bはα-アミノイソ酪酸を示す)、SMPPPGTRV(配列番号6)、IMIGHLVGV(配列番号7)、KVAEIVHFL(配列番号8)、及びYLSGADLNL(配列番号9)からなる群から選択される少なくとも4、5、6、7、8又は9種のペプチドを含み、前記処置が、前記治療用ペプチドT特異的免疫療法剤の2回から3回の投与からなる初回刺激期間を含み、それによりセントラルメモリーT細胞応答を誘発する、治療用ペプチドT特異的免疫療法剤。
- 以下のペプチド、aKXVAAWTLKAAa(配列番号10、X及びaは、それぞれシクロヘキシルアラニン及びd-アラニンを示す)、RLLQETELV(配列番号1)、YLQLVFGIEV(配列番号2)、LLTFWNPPV(配列番号3)、KVFGSLAFV(配列番号4)、KLBPVQLWV(配列番号5、Bはα-アミノイソ酪酸を示す)、SMPPPGTRV(配列番号6)、IMIGHLVGV(配列番号7)、KVAEIVHFL(配列番号8)、及びYLSGADLNL(配列番号9)を含む、請求項1に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記処置が、前記治療用ペプチドT特異的免疫療法剤の3回の投与からなる初回刺激期間を含む、請求項1又は2に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記初回刺激期間中に、1〜4週間毎に、好ましくは2〜3週間毎に、より好ましくは3週間毎に投与される、請求項1から3のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記処置中に、初回刺激期間の後に、前記治療用ペプチドT特異的免疫療法剤の投与が、1年を通して2〜8カ月毎に、好ましくは2〜3カ月毎に、より好ましくは2カ月毎に、及び次に1年を通して3カ月毎に行われる維持期間が続く、請求項1から4のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記がんが、NSCLC(非小細胞肺がん)及び小細胞肺がん等の肺がん、メラノーマ、中皮腫、乳がん、原発性脳がん、卵巣がん、子宮癌、特に子宮体部及び/又は子宮頸部癌、頭部及び頸部がん、結腸又は結直腸直がん、胃腸がん、腎臓がん、肉腫、胚細胞腫瘍、白血病、リンパ腫、精巣がん並びに膀胱がんからなる群から選択される、好ましくはNSCLC、結腸がん、乳がん、卵巣がん、並びに頭部及び/又は頸部のがんからなる群から選択されるがん、より好ましくはNSCLCである、請求項1から5のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記患者が、進行した又は後期のがんを患っている、請求項1から6のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記患者が、転移、特に脳転移を患っている、請求項1から7のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記患者が、悪性の胸水貯留を有する、請求項1から8のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記患者がHTL(ヘルパーT細胞)陽性である、請求項1から9のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 非経口的に、好ましくは皮下に投与される、請求項1から10のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- ペプチドが、不完全フロイントアジュバント等、好ましくはMontanide ISA-51に乳化されている、請求項1から11のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- ペプチドの用量が、注射用量当たり0.1から10mgの範囲のペプチドである、請求項1から12のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 合計ペプチド用量が、各注射について5.0mgである、請求項13に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記患者が、治療用ペプチドT特異的免疫療法剤による処置に先立って幾つかのラインの処置をすでに受けている、請求項1から14のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記処置が、別の抗腫瘍薬及び/又は放射線療法による処置と組み合わせて使用される、請求項1から15のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
- 前記処置が、チェックポイント阻害剤、好ましくはCTLA-4及び/又はPD-1/PD-L1阻害剤、例えば、ペンブロリズマブ、ニボルマブ、ピジリズマブ、BMS936559、MEDI4736、AMP-224、AMP-514、MPDL328OA及びアベルマブによる処置と組み合わせて使用される、請求項1から15のいずれか一項に記載の使用のための治療用ペプチドT特異的免疫療法剤。
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