JP2019521099A - Her2/neuを含む、腫瘍ワクチン接種及び免疫療法のための組成物及び方法 - Google Patents
Her2/neuを含む、腫瘍ワクチン接種及び免疫療法のための組成物及び方法 Download PDFInfo
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Abstract
Description
本発明は、国立がん研究所(NCI)により授与されたSBIR助成金第1R43CA139663-01号、SBIR契約第HHSN261201100090C号、SBIR契約第HHSN261201300066C号、及び国防総省の奨学金W81XWH-12-1-0574;BC113107に基づく米国政府支援を受けてなされた。米国政府は本発明に関する一定の権利を有する。
ある特定の態様では、例えば本明細書に記述されるHER2/neu抗原又はエピトープなどの目的の標的タンパク質又は標的抗原を1つ以上コードする核酸配列を含む、発現構築物又はベクターが提供され得る。
本明細書において開示されるものには、HER2/neu抗原をコードする1つ以上の核酸配列、及び/又はCEAなどのムチンファミリー抗原をコードする1つ以上の核酸配列、及び/又はBrachyuryをコードする1つ以上の核酸配列、及び/又はMUC1-cをコードする1つ以上の核酸配列を同じ又は別の複製欠損型ベクターに含む、複製欠損型ベクターを含む組成物が含まれる。
本明細書において開示されるものには、HER2/neu抗原をコードする1つ以上の核酸配列、及び/又はMUC1などのムチンファミリー抗原をコードする1つ以上の核酸配列、及び/又はBrachyuryをコードする1つ以上の核酸配列、及び/又はCEAをコードする1つ以上の核酸配列を同じ又は別の複製欠損型ベクターに含む、複製欠損型ベクターを含む組成物が含まれる。
本明細書において開示されるものには、HER2/neu抗原をコードする1つ以上の核酸配列、及び/又はMUC1などのムチンファミリー抗原をコードする1つ以上の核酸配列、及び/又はBrachyuryをコードする1つ以上の核酸配列、及び/又はCEAをコードする1つ以上の核酸配列を同じ又は別の複製欠損型ベクターに含む、複製欠損型ベクターを含む組成物が含まれる。
ある特定の態様は、HER2/neu抗原又はエピトープなどの標的抗原を1つ以上コードする1つ以上の核酸配列を含む発現構築物を細胞に移入することを含む。ある特定の実施形態において、発現構築物の細胞への移入は、ウイルスベクターを使用して達成され得る。ウイルスベクターは、その中でクローニングされている組み換え遺伝子構築物を発現するために十分なウイルス配列を含むそれらの構築物を含むために使用され得る。
いくつかの実施形態において、アデノウイルスベクターなどのベクターは、免疫応答を調節することができる、HER2/neu抗原若しくはエピトープ、その融合物又はその断片などの1つ以上の腫瘍抗原をコードする異種核酸配列を含んでもよい。特定の態様において、HER2/neu抗原又はエピトープなどの1つ以上の腫瘍抗原をコードする異種核酸配列を含む、第二世代E2b欠失アデノウイルスベクターが提供され得る。
ある特定の態様では、免疫応答を発生させようとするHER2/neu抗原又はエピトープなどの腫瘍抗原を1つ以上コードする核酸配列を含む医薬組成物が提供され得る。例えば、腫瘍抗原は、HER2/neu抗原若しくはエピトープ、又は、本明細書に記述される若しくは当技術分野で利用可能である1つ以上のさらなる腫瘍抗原との組合せを含み得るが、これらに限定されない。
特定の実施形態において、ネイティブ又は工学操作されたNK細胞が、本明細書に記載されるアデノウイルスベクターベースの組成物又は免疫療法と組合せて、それを必要とする対象に投与されるために提供され得る。
ネイティブNK細胞に加えて、病変細胞がNK細胞の殺傷機能を逃れるためにしばしば利用するキラー抑制性受容体(KIR)を発現しない、患者へ投与するためのNK細胞が提供され得る。この独特の活性化NK細胞、又はaNK細胞は、これらの抑制性受容体を欠くが、病変細胞の選択的標的化及び殺傷を可能にする多岐にわたる活性化受容体を保持する。aNK細胞はまた、より大きな搭載量のグランザイム及びパーフォリン含有顆粒も有し、これによりはるかに大きな搭載量の致死的酵素を複数の標的に送達できるようにする。
キメラ抗原受容体(CAR)技術は、現在開発中の最も新規ながん治療アプローチの1つである。CARは、特異的表面抗原を提示するがん細胞を、免疫エフェクター細胞が標的化できるようにするタンパク質である。taNK(標的活性化ナチュラルキラー(target-activated Natural Killer))は、aNK細胞が1つ以上のCARと工学操作されてがんで見出されるタンパク質を標的化し、次いで広範なスペクトラムのCARと一体化されるプラットフォームである。この戦略は、自己T細胞などの患者又はドナー源エフェクター細胞を用いる他のCARアプローチと比べて、特に拡張性、品質管理、及び一貫性の点で複数の利点を有する。
研究は、おそらくヒト集団の20%のみがCD16の「高親和性」変異体(haNK細胞)を一律に発現し、該変異体は、「低親和性」CD16を有する患者と比べてより好ましい治療転帰と強く相関することを示している。さらに、多くのがん患者は、化学療法、疾患自体、又は他の要因のために免疫系がひどく弱まっている。
随所に記述されるHER2/neu抗原又はエピトープなどの腫瘍抗原をコードする核酸配列を含む、アデノウイルスベクター系ワクチン接種を含む組成物は、薬学的医薬に製剤化され、疾患、例えばがんの診断を受けた、それを必要とするヒト又は哺乳動物を処置するために使用され得る。これらの医薬は、1つ以上のさらなるワクチン又は他のがん療法とともに、ヒト又は哺乳動物に共投与されてもよい。
本明細書に記載されたウイルスベクター又は組成物は、HER2/neu抗原、又は本明細書に開示された任意の他の標的抗原などの標的抗原の免疫原性を高めることができるタンパク質、又は「免疫学的融合パートナー」をコードする核酸配列をさらに含んでもよい。これに関して、そのようなタンパク質を含有するウイルスベクターによる免疫後に産生されるタンパク質は、目的とする標的抗原の免疫原性を高めるタンパク質に融合された、目的とする標的抗原を含む融合タンパク質となり得る。さらに、HER2/neuをコードするAd5 [E1-, E2b-]ベクター、及び免疫学的融合パートナーによる併用療法は、両方の治療的部分の組合せが、HER2/neuをコードするAd5 [E1-, E2b-]ベクター単独、又は免疫学的融合パートナー単独のどちらかより、免疫応答を相乗的に追加刺激するように作用するような、免疫応答の追加刺激をもたらすことができる。例えば、HER2/neuをコードするAd5 [E1-, E2b-]ベクター、及び免疫学的融合パートナーによる併用療法は、抗原特異的エフェクターCD4+及びCD8+ T細胞の刺激、感染細胞の殺傷に対するNK細胞応答の刺激、抗体依存性T細胞媒介性細胞傷害(ADCC)、抗体依存性T細胞性抗体依存性細胞食作用(ADCP)機構を介した感染細胞の殺傷に対する好中球若しくは単球細胞応答の刺激、又はそれらの任意の組合せの相乗的増強をもたらすことができる。この相乗的追加刺激は、それを必要とする対象への投与後の生存転帰を著しく改善することができる。特定の実施形態において、HER2/neuをコードするAd5 [E1-, E2b-]ベクター及び免疫学的融合パートナーによる併用療法は、対照と比較して、アデノウイルスベクターを投与された対象において、約1.5〜20倍以上の標的抗原特異的CTL活性の増加を含む免疫応答の惹起をもたらすことができる。別の実施形態において、免疫応答の惹起は、HER2/neu抗原をコードするAd5 [E1-, E2b-]ベクター及び免疫学的融合パートナーを投与された対象における、対照と比較して約1.5〜20倍以上の標的特異的CTL活性の増加を含む。さらなる実施形態において、免疫応答の惹起は、インターフェロン-ガンマ(IFN-γ)、インターロイキン-2 (IL-2)、腫瘍壊死因子-アルファ(TNF-α)、又は他のサイトカインなどのサイトカイン分泌を測定するELISpotアッセイにより測定される場合、対照と比較して約1.5〜20倍以上の標的抗原特異的細胞性免疫活性の増加を含む。さらなる実施形態において、免疫応答の惹起は、本明細書に記載されるHER2/neu抗原をコードするAd5 [E1-, E2b-]ベクター及び免疫学的融合パートナーを投与された対象における、適当な対照と比較して1.5〜5倍の標的特異的抗体産生の増加を含む。別の実施形態において、免疫応答の惹起は、アデノウイルスベクターを投与された対象における、対照と比較して約1.5〜20倍以上の標的特異的抗体産生の増加を含む。
HER2/neu抗原又はエピトープなどの標的抗原を含有する組換えアデノウイルス系ベクターワクチンの使用に加えて、共刺激分子を当該ワクチンに組み込んで免疫原性を増大させることができる。免疫応答の開始は、APCによるネイティブT細胞の活性化のための少なくとも2つのシグナルを必要とする(DamleらJ Immunol 148:1985-92 (1992); GuinanらBlood 84:3261-82 (1994); HellstromらCancer Chemother Pharmacol 38:S40-44 (1996); HodgeらCancer Res 39:5800-07 (1999))。抗原特異的第一シグナルは、ペプチド/主要組織適合性複合体(MHC)を介してT細胞受容体(TCR)を通じて送達され、T細胞を細胞周期に入らせる。第二シグナル、又は共刺激物質シグナルは、サイトカイン産生及び増殖のために送達され得る。
ある特定の実施形態において、免疫経路チェックポイント阻害剤は、本明細書に開示されたアデノウイルスベクターを含む組成物と組み合わされる。ある特定の実施形態において、患者は、本明細書に記載されたワクチン又は医薬組成物と合わせて、免疫経路チェックポイント阻害剤を受け取った。さらなる実施形態において、組成物は、1つ以上の免疫経路チェックポイント調節因子と投与される。活性化シグナルと阻害シグナルのバランスは、Tリンパ球と病変細胞の相互作用を制御し、T細胞受容体(TCR)による抗原認識を通じてT細胞応答が開始される。阻害経路及びシグナルは、免疫経路チェックポイントと呼ばれる。正常な状況では、免疫経路チェックポイントは、自己免疫の制御及び防止において重要な役割を果たし、また病原性感染への応答における組織損傷から保護する。
いくつかの実施形態では、本開示の方法及び組成物は、それを必要とする対象のがんを処置するために使用される。特定の態様において、これらのがんは、HER2/neu標的抗原を過剰発現する。HER2/neuは、乳がん、卵巣がん、前立腺がん、胃がん、結腸がん、肺がん、及び骨がんをはじめとする、様々な異なるがんにおいて過剰発現する。HER2/neuの過剰発現は、がん処置における予後マーカーとして有用であり得る。
ある特定の態様では、HER2/neu抗原又はエピトープを含む複製欠損型ベクターを含む方法及び組成物は、乳がん、特に切除不能、局所進行、若しくは転移性の乳がんを有するか、有するリスクがあるか、又は有するものと診断される対象を処置するために使用される。
いくつかの実施形態では、HER2/neu抗原又はエピトープを含む複製欠損型ベクターを含む方法及び組成物は、骨がん、特に骨肉腫を有するか、有するリスクがあるか、又は有するものと診断される対象を処置するために使用される。ある特定の実施形態では、骨肉腫は、高グレード骨肉腫、中間グレード骨肉腫、又は低グレード骨肉腫であり得る。骨肉腫は、若年の対象において最も一般的に見られる骨のがんである。これらのがんは、新しい骨が成長する領域に起因するのが最も一般的である。いくつかの実施形態では、本開示の方法及び組成物は、あらゆるグレード又はタイプの骨肉腫を有する対象を処置するために投与され得る。
いくつかの実施形態では、HER2/neu抗原又はエピトープを含む複製欠損型ベクターを含む方法及び組成物は、胃がんを有するか、有するリスクがあるか、又は有するものと診断される対象を処置するために使用される。胃がんは、胃に起因するがんであり、そのうち90〜95%近くが腺がんである。ある特定の実施形態では、胃がんは、腺がん、リンパ腫、消化管間質腫瘍、又はカルチノイド腫瘍であり得る。胃がんは、ヘリコバクターピロリ(Helicobacter pylori)による感染から発生する場合もある。いくつかの実施形態では、本開示の方法及び組成物は、あらゆるグレード又はタイプの骨肉腫を有する対象を処置するために投与され得る。
本明細書に記述されるHER2/neu抗原又はエピトープなどの標的抗原を含む複製欠損型アデノウイルスベクターは、本明細書に記述される1つ以上の標的抗原に対する免疫応答を発生させるために、いくつかのワクチン設定で使用することができる。いくつかの実施形態では、HER2/neu抗原又はエピトープなどの任意の標的抗原に対する免疫応答を発生させる方法が提供される。
本明細書に記載された組成物、免疫療法又はワクチンは、キットの形態で供給することができる。本開示のキットは、治療レジメン情報を含む投与量及び投与に関する説明書をさらに含むことができる。
Ad5 [E1-, E2b-]ベクターの構築
Ad5 [E1-, E2b-]-HER2/neuワクチンの構築
この実施例では、Ad5[E1-,E2b-]-HER2/neuワクチンの構築を記述する。最小サイトメガロウイルスプロモーター/エンハンサーエレメント及びSV40由来ポリアデニル化シグナルと隣接する切断型HER2/neuトランスジーンを、シャトルpShuttleCMVにサブクローニングし、シャトルプラスミドpShuttleCMV/HER2/neuを生成した。シャトルプラスミドをPmeIで直鎖化し、プラスミドpAdΔppと相同組換え(大腸菌で)してpAdCMV/HER2/neu/Δpp生成した(図1)。
Ad5[E1-,E2b-]-HER2/neuの前臨床毒性学評価
この実施例では、Ad5[E1-,E2b-]-HER2/neuの前臨床毒性学評価を記述する。BALB/cマウスのGLP試験において、Ad5[E1-,E2b-]-HER2/neuの反復投与毒性を評価した。この研究は、4つのビヒクル対照群(第1群〜第4群)及び4つの試験品処置群(第5群〜第8群)の計8つの群からなった。1日目、22日目、及び43日目に1.7×108個のウイルス粒子(VP)/投与のAd5[E1-,E2b-]-HER2/neuでマウスを免疫化した。ヒトの体重を60kg、マウスの体重を0.02kgと仮定すると、1.7×108VP/投与(8.3×109VP/kg)の用量のAd5[E1-,E2b-]-HER2/neuが、ヒトにおいて提唱される最も高い用量である5×1011VP/投与(8.3×109VP/kg)のマウス対ヒト当量である。Ad5[E1-,E2b-]-HER2/neuはマウスの皮下に投与した。皮下投与は、患者に対して意図される投与経路でもある。
Ad5[E1-,E2b-]-HER2/neuワクチン(注射用懸濁液)の調製
この実施例では、Ad5[E1-,E2b-]-HER2/neuワクチン(注射用懸濁液)の調製を記述する。Ad5[E1-,E2b-]-HER2/neuワクチン(注射用懸濁液)は、複製欠損型アデノウイルスベクター系である。Ad5[E1-,E2b-]-HER2/neuは、Ad5[E1-,E2b-]ベクター及び改変されたHER2/neu遺伝子インサートを含むHER2/neu標的ワクチンである。HER2/neu遺伝子インサートは、細胞外ドメイン及び膜貫通領域からなる切断型ヒトHER2/neuタンパク質をコードする。発がん活性をもたらすキナーゼドメインを含有する細胞内ドメイン全体を除去した。
Ad5[E1-,E2b-]-HER2/neuは、E1遺伝子の除去、E2b及びE3遺伝子の欠失、並びに細胞外ドメイン及び膜貫通領域からなるヒトHER2/neuの切断型遺伝子の挿入によって改変された組換え複製欠損型Ad5ベクターである。発がん活性をもたらすキナーゼドメインを含有する細胞内ドメイン全体を除去した(Gabitzsch ES and Jones FR. J Clin Cell Immunol. 2011a;S4:001、Hartman ZC, Wei J, Osada T, et al. An adenoviral vaccine encoding full-length inactivated human HER2/neu exhibits potent immunogenicty and enhanced therapeutic efficacy without oncogenicity. Clin Cancer Res. 2010;16:1466-1477)。
Ad5[E1-,E2b-]-HER2/neuを、E1、E2b、及びE3領域における有意な欠失、並びにヒトHER2/neu遺伝子の挿入によって改変した。結果として得られる複製欠損型ウイルスベクターは、欠失したE1及びE2b遺伝子産物をトランスで供給することができる所有権のあるのヒト胎児由来腎臓293細胞株(E.C7)において増殖可能である。しかしながら、複製可能なアデノウイルスが、E.C7(293)細胞株に存在するE1及びE2b配列の組換えによるアデノウイルスのウイルス粒子の製造中に形成され得る理論的可能性が存在する。したがって、複製可能なアデノウイルスに関する高感度試験をこのワクチンのための遊離試験に組み込んだ。
Ad5[E1-,E2b-]-HER2/neuがんワクチンの前臨床研究
この実施例では、Ad5[E1-,E2b-]-HER2/neuがんワクチンの前臨床研究を記述する。BALB/cマウスモデルにおいて、がんワクチンとしてのAd5[E1-,E2b-]-HER2/neuを評価するために研究を行った。Ad5[E1-,E2b-]-HER2/neuは、Ad5ナイーブマウス及びAd5免疫マウスにおいてHER2/neuに対する強力なCMIを誘導した。液性応答が誘導され、抗体は、インビトロの補体の存在下でHER2/neu発現腫瘍細胞を溶解する能力を示した。Ad5[E1-,E2b-]-HER2/neuは、Ad5ナイーブ及びAd5免疫マウスモデルにおいてHER2/neu発現腫瘍の確立を防止し、確立した腫瘍の進行を有意に阻害した。これらのデータは、Ad5[E1-,E2b-]-HER2/neuのインビボ送達が、抗HER2/neu免疫を誘導し、HER2/neu発現がんの進行を阻害し得ることを示す。
切除不能な局所進行又は転移性のHER2/neu発現乳がんを有する対象におけるAd5[E1-,E2b-]-HER2/neuワクチン接種の第I相研究
この実施例では、切除不能、局所進行、又は転移性のHER2/neu発現(IHC 1+又は2+)乳がんを有する対象におけるAd5[E1-,E2b-]-HER2/neuワクチン接種の第I相研究を記述する。HER2/neu発現乳がんを有する対象に、Ad5[E1-,E2b-]-HER2/neuワクチンを3週間にわたって1週間に1回皮下(SC)投与し(合計3回の注射)、その後、3カ月間隔で3回のブースター注射を行う。このワクチンレジメンの全体的な安全性を判定し、Ad5[E1-,E2b-]-HER2/neuワクチンの第2相における推奨用量を特定する。Ad5[E1-,E2b-]-HER2/neuで処置したHER2/neu発現乳がんを有する対象において、客観的奏効率(ORR)、疾患コントロール率(DCR)、奏効の持続期間、無増悪生存率(PFS)、及び全生存率(OS)の予備評価を行う。Ad5[E1-,E2b-]-HER2/neuの免疫原性を評価し、対象の腫瘍のゲノムプロファイル及びプロテオミクスプロファイルを判定して、遺伝子突然変異、遺伝子増幅、RNA発現レベル、及びタンパク質発現レベルを特定する。ゲノム/プロテオミクスプロファイルと有効性転帰との相関性も評価する。
切除不能な局所進行又は転移性のHER2/neu発現(IHC 1+又は2+)乳がんを有する対象を含む第I相治験を行う。この研究は2部構成で行う。第1部では3+3デザインを使用した用量漸増を用い、第2部では安全性、予備有効性、及び免疫原性をさらに評価するため最大耐用量(MTD)又は最高試験用量(HTD)の拡大を用いる。第1部では、用量コホート1から始めて3〜6名の対象を順次登録する。コホート1には5×1010個のウイルス粒子(VP)を与え、コホート2には5×1011VPを与え、必要に応じて、用量漸減コホート(コホート-1)に5×109VPを与える。対象の用量規制毒性(DLT)を評価する。用量拡大は、MTD又はHTDが判定されたときに行う。治験の用量拡大部分にさらに12名の対象を登録し、MTD又はHTDにおいて合計18名の対象とする。提唱される研究の概略を図2に示す。
この研究には最大30名の対象が登録される。対象は、HER2/neuを発現する切除不能な局所進行又は転移性の乳がん(IHC 1+又は2+)が組織学的に確認されたものである。HER2/neu IHC 3+腫瘍を有する対象は除外される。用量漸増部分では、用量コホート1から始めて3〜6名の対象を順次登録する。用量拡大部分では(すなわち、MTD又はHTDが特定されたら)、MTD/HTDコホートの対象が合計18名となるよう、さらに12名の対象を登録して、安全性、予備有効性、及び免疫原性に関するさらなるデータを得る。
各対象は、およそ42週間(第0週、第3週、及び第6週に注射を行い、第18週、第30週、及び第42週にブースター注射を行う)、又は各対象が進行性疾患若しくは許容不可能な毒性を経験するか、同意を撤回するか、若しくは処置の継続がもはや最善とは言えないと研究者が感じるまで、処置を受けることが期待される。対象の処置の推定持続期間は、対象の疾患、Ad5[E1-,E2b-]-HER2/neuを耐容する能力、研究に参加する意志、又は処置の継続がもはや最善とは言えないと研究者が感じるかどうかに応じて、延長又は短縮されてもよい。
次の理由のうちいずれかが生じた場合、Ad5[E1-,E2b-]-HER2/neuは保留される:CTCAEバージョン4.03に規定されるあらゆるグレード3以上の毒性、あらゆるグレード2以上の自己免疫反応又は即時型過敏反応、左室駆出率(LVEF)の処置前の値からの16%未満又は16%の絶対的低下、機関が規定した正常下限(LLN)未満のLVEF、及びLVEFの処置前の値からの10%超又は10%の絶対的低下。
第I相臨床治験の対象の適格性は、組み入れ基準及び除外基準によって定義される。組み入れ基準には次のものが含まれる:年齢18歳以上、男性又は女性、機関審査委員会(IRB、Institutional Review Board)のガイドラインを満たす署名済みインフォームドコンセントを理解し提供する能力、解析のために利用可能である最も新しい入手可能な転移性生検試料、腫瘍組織(ブロック又はスライド)及び全血試料(アーカイブ組織は許可される)に由来する、組織学的に確認されたHER2/neuを発現する、切除不能な局所進行又は転移性の乳がん(IHC 1+又は2+)、並びに0又は1のEastern Cooperative Oncology Group(ECOG)性能ステータス。
第I相臨床治験の対象の適格性は、組み入れ基準及び除外基準によって定義される。除外基準には次のものが含まれる:HER2/neu IHC 3+腫瘍を有する対象、トラスツズマブ、ペルツズマブ、T-DM1、及びラパチニブを含むHER2/neu指向療法が進行中の対象、この研究のためのスクリーニングの30日以内の治験薬又はデバイス研究への参加、妊娠中及び授乳中の女性、並びにパルボシクリブ、エベロリムス、又は免疫応答の誘導に干渉する他の乳がん療法が進行中の対象。
Ad5[E1-,E2b-]-HER2/neuワクチンの製品名、剤形、単位用量、投与経路、物理的説明、及び製造元を表9にまとめる。
Ad5[E1-,E2b-]-HER2/neuは、合計3回の注射を第0週、第3週、及び第6週に投与した後、3カ月間隔(第18週、第30週、及び第42週)で3回のブースター注射を行う。試験薬投与処置はすべて、予定来院日の±5日以内に行う。ワクチン注射はすべて、部位をアルコールで準備した後、大腿へのSC注射によって1mL容量として与えられるべきである。初回注射にはいずれの大腿を使用してもよい。その後の注射は初回注射と同じ大腿に与えなければならず、少なくとも5cm離れていなければならない。
安全性エンドポイントには、DLT、MTD、又はHTDの評価、処置により発生したAE、SAE、並びに安全性の研究室試験、物理的検査、ECG、LVEF、及びバイタルサインの臨床的に有意な変化が含まれる。毒性は、National Cancer Institute(NCI)の有害事象共通用語基準(CTCAE)バージョン4.03を使用してグレーディングする。有効性を評価するためには、RECISTバージョン1.1;奏効の持続期間、PFS、及びOSに従って腫瘍応答(ORR及びDCR)を評価する。
Ad5[E1-,E2b-]-HER2/neuワクチンの有効性は、生存率及び抗腫瘍応答を評価することによって評価する。対象の治験終了又は参加中止後、12カ月間にわたって3カ月毎、その後12カ月間にわたっておよそ6カ月毎に、すべての対象の生存率を追跡調査する。
標的病変及び/又は非標的病変の抗腫瘍活性は、以下に概説するRECISTバージョン1.1(Eisenhauer EA, Therasse P, Bogaerts J, et al. Eur J Cancer. 2009;45:228-247)に従って評価される。
免疫応答は、フローサイトメトリーベースのアッセイ及び血清アッセイにおいて検出及び数量化する。T細胞頻度、活性化ステータス、サイトカインプロファイル、及び抗体レベルのフローサイトメトリー解析により、Ad5[E1-,E2b-]-HER2/neuの免疫原性を検出する。
Ad5[E1-,E2b-]-HER2/neuワクチンの薬力学評価は、末梢血の回収と回収した試料の免疫評価によって評価される。研究中及び/又は特定の注射後の特定の時点において、およそ80mLの末梢血を対象から採取し、試験薬が免疫応答に及ぼす影響を評価する。採血は、ベースライン、各注射の前、及び第3の注射のおよそ3週間後(第9週);並びに各ブースター注射(第18週、第30週、及び第42週)の前、及び各ブースター注射の3週間後(第21週、第33週、及び第45週)に行う。蓋が緑色の10mLヘパリンナトリウム管6本分をPBMC試料用に採取し、8mL血清分離管2本分を血清試料用に採取する。免疫評価は、フローサイトメトリーベースのアッセイ及び血清アッセイを含む。
応答又は疾患進行に寄与し得るゲノムの相違を特定し、分子異常を理解するために、全血由来の非腫瘍細胞に対する組織由来の腫瘍細胞のゲノムシーケンシングのプロファイリングを行う。RNAシーケンシングを行って発現データを作成し、DNA突然変異との関連性を明らかにする。定量的なプロテオミクス解析を行い、特定のタンパク質の精確な量を判定し、ワクチン免疫療法への応答及び疾患進行と相関する遺伝子の発現を確認する。
DLT率及びMTD又はHTDを評価する。処置により発生したAE、SAE、並びに安全性の研究室試験、物理的検査、ECG、LVEF、及びバイタルサインの臨床的に有意な変化という観点から、用量コホート内及び研究集団全体で、CTCAEバージョン4.03を使用したグレードによるAEの頻度集計表を使用した記述的解析により、全体的な安全性を評価する。RECISTバージョン1.1に従って用量コホート別及び全体のORR及びDCRを評価し、奏効の持続期間も評価する。カプランマイヤー法を使用し、用量コホート別及び全体のPFS及びOSを解析する。
Claims (83)
- ネイティブHER2/neuタンパク質の断片であるHER2/neu抗原をコードする核酸配列を含む複製欠損型ウイルスベクターを含む組成物。
- HER2/neu抗原が、ネイティブHER2/neuタンパク質の細胞内ドメインを有しない、請求項1に記載の組成物。
- HER2/neu抗原が、ネイティブHER2/neuタンパク質の膜貫通ドメイン及び細胞外ドメインを有する、請求項1又は2に記載の組成物。
- HER2/neu抗原が、配列番号1又は配列番号2と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を有し、核酸配列が、配列番号1、又は配列番号3の1033〜3107位と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を有し、及び/又は複製欠損型ウイルスベクターが、配列番号3と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を有する、請求項1〜3のいずれか一項に記載の組成物。
- 複製欠損型ウイルスベクターが、アデノウイルスベクターである、請求項1〜4のいずれか一項に記載の組成物。
- アデノウイルスベクターが、E1領域、E2b領域、E3領域、及びE4領域、又はその任意の組合せにおいて欠失を含む、請求項5に記載の組成物。
- アデノウイルスベクターが、E2b領域において欠失を含む、請求項5又は6に記載の組成物。
- アデノウイルスベクターが、E1領域、E2b領域、及びE3領域において欠失を含む、請求項5〜7のいずれか一項に記載の組成物。
- 少なくとも1×109〜少なくとも5×1012個のウイルス粒子を含む、請求項1〜8のいずれか一項に記載の組成物。
- 少なくとも5×109個のウイルス粒子を含む、請求項1〜9のいずれか一項に記載の組成物。
- 少なくとも5×1010個のウイルス粒子を含む、請求項1〜10のいずれか一項に記載の組成物。
- 少なくとも5×1011個のウイルス粒子を含む、請求項1〜11のいずれか一項に記載の組成物。
- 少なくとも5×1012個のウイルス粒子を含む、請求項1〜12のいずれか一項に記載の組成物。
- 複製欠損型ウイルスベクターが、共刺激分子をコードする核酸配列をさらに含む、請求項1〜13のいずれか一項に記載の組成物。
- 複製欠損型ウイルスベクターが、免疫学的融合パートナーをコードする核酸配列をさらに含む、請求項1〜14のいずれか一項に記載の組成物。
- 共刺激分子が、B7、ICAM-1、LFA-3、又はその組合せを含む、請求項15に記載の組成物。
- 共刺激分子が、B7、ICAM-1、及びLFA-3の組合せを含む、請求項15又は16に記載の組成物。
- 同じ複製欠損型ウイルスベクターに位置する複数の共刺激分子をコードする複数の核酸配列をさらに含む、請求項1〜17のいずれか一項に記載の組成物。
- 別の複製欠損型ウイルスベクターに位置する複数の共刺激分子をコードする複数の核酸配列をさらに含む、請求項1〜17のいずれか一項に記載の組成物。
- 1つ以上の標的抗原又はその免疫学的エピトープをコードする核酸配列をさらに含む、請求項1〜19のいずれか一項に記載の組成物。
- 複製欠損型ウイルスベクターが、1つ以上の標的抗原又はその免疫学的エピトープをコードする核酸配列をさらに含む、請求項1〜20のいずれか一項に記載の組成物。
- 1つ以上の標的抗原が、腫瘍ネオ抗原、腫瘍ネオエピトープ、腫瘍特異的抗原、腫瘍関連抗原、組織特異的抗原、細菌抗原、ウイルス抗原、酵母抗原、真菌抗原、原虫抗原、寄生虫抗原、マイトゲン、又はその組合せである、請求項20又は21に記載の組成物。
- 1つ以上の標的抗原が、葉酸受容体アルファ、WT1、p53、MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A10、MAGE-A12、BAGE、DAM-6、-10、GAGE-1、-2、-8、GAGE-3、-4、-5、-6、-7B、NA88-A、NY-ESO-1、MART-1、MC1R、Gp100、チロシナーゼ、TRP-1、TRP-2、ART-4、CAMEL、CEA、Cyp-B、HER2/neu、BRCA1、BRACHYURY、BRACHYURY(TIVS7-2、多型)、BRACHYURY(IVS7 T/C多型)、T BRACHYURY、T、hTERT、hTRT、iCE、MUC1、MUC1(VNTR多型)、MUC1-c、MUC1n、MUC2、PRAME、P15、RU1、RU2、SART-1、SART-3、WT1、AFP、β-カテニン/m、カスパーゼ-8/m、CEA、CDK-4/m、HER3、ELF2M、GnT-V、G250、HSP70-2M、HST-2、KIAA0205、MUM-1、MUM-2、MUM-3、ミオシン/m、RAGE、SART-2、TRP-2/INT2、707-AP、アネキシンII、CDC27/m、TPI/mbcr-abl、ETV6/AML、LDLR/FUT、Pml/RARα、若しくはTEL/AML1、若しくはその改変変異体、スプライス変異体、機能的エピトープ、エピトープアゴニスト、又はその組合せである、請求項20〜22のいずれか一項に記載の組成物。
- 1つ以上の標的抗原が、CEA、Brachyury、MUC1、MUC1-c、又はその任意の組合せである、請求項20〜23のいずれか一項に記載の組成物。
- 1つ以上の標的抗原がCEAである、請求項20〜24のいずれか一項に記載の組成物。
- 1つ以上の標的抗原がBrachyuryである、請求項20〜24のいずれか一項に記載の組成物。
- 1つ以上の標的抗原が、MUC1又はMUC1-cである、請求項20〜24のいずれか一項に記載の組成物。
- 1つ以上の標的抗原がHER3である、請求項20〜23のいずれか一項に記載の組成物。
- CEAが、配列番号30、配列番号31、又は配列番号29の1057〜3165位と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を含む、請求項23〜25のいずれか一項に記載の組成物。
- MUC1-cが、配列番号32又は配列番号33と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を含む、請求項23〜25のいずれか一項に記載の組成物。
- Brachyuryが、配列番号34と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を含む、請求項23〜25のいずれか一項に記載の組成物。
- HER3が、配列番号27と、少なくとも80%、少なくとも85%、少なくとも90%、少なくとも92%、少なくとも95%、少なくとも97%、又は少なくとも99%同一である配列を含む、請求項28に記載の組成物。
- 複製欠損型ウイルスベクターが、選択可能マーカーをさらに含む、請求項1〜32のいずれか一項に記載の組成物。
- 選択可能マーカーが、lacZ遺伝子、チミジンキナーゼ、gpt、GUS、若しくはワクシニアK1L宿主域遺伝子、又はその組合せである、請求項33に記載の組成物。
- 請求項1〜34のいずれか一項に記載の組成物及び薬学的に許容される担体を含む医薬組成物。
- 請求項1〜34のいずれか一項に記載の組成物を含む宿主細胞。
- 腫瘍ワクチンを製造する方法であって、請求項35に記載の医薬組成物を製造するステップを含む方法。
- それを必要とする対象における免疫応答を増強する方法であって、請求項1〜34のいずれか一項に記載の組成物又は請求項35に記載の医薬組成物の治療有効量を対象に投与するステップを含む方法。
- それを必要とする対象におけるがんを治療する方法であって、請求項1〜34のいずれか一項に記載の組成物又は請求項35に記載の医薬組成物の治療有効量を対象に投与するステップを含む方法。
- 前記医薬組成物を対象に再投与するステップをさらに含む、請求項38又は39に記載の方法。
- 免疫チェックポイント阻害剤を対象に投与するステップをさらに含む、請求項38〜40のいずれか一項に記載の方法。
- 免疫チェックポイント阻害剤が、PD1、PDL1、PDL2、CD28、CD80、CD86、CTLA4、B7RP1、ICOS、B7RPI、B7-H3、B7-H4、BTLA、HVEM、KIR、TCR、LAG3、CD137、CD137L、OX40、OX40L、CD27、CD70、CD40、CD40L、TIM3、GAL9、ADORA、CD276、VTCN1、IDO1、KIR3DL1、HAVCR2、VISTA、又はCD244を阻害する、請求項41に記載の方法。
- 免疫チェックポイント阻害剤が、PD1又はPDL1を阻害する、請求項41又は42に記載の方法。
- 免疫チェックポイント阻害剤が、抗PD1又は抗PDL1抗体である、請求項41〜43のいずれか一項に記載の方法。
- 免疫チェックポイント阻害剤が、抗PDL1抗体である、請求項41〜44のいずれか一項に記載の方法。
- 投与が、静脈内、皮下、リンパ内、腫瘍内、皮内、筋肉内、腹腔内、直腸内、膣内、鼻腔内、経口、膀胱内注入による、又はスカリフィケーションによる、請求項38〜45のいずれか一項に記載の方法。
- 増強される免疫応答が、細胞性又は液性応答である、請求項38〜46のいずれか一項に記載の方法。
- 増強される免疫応答が、B細胞増殖の増強、CD4+ T細胞増殖の増強、CD8+ T細胞増殖の増強、又はその組合せである、請求項38〜47のいずれか一項に記載の方法。
- 増強される免疫応答が、IL-2産生の増強、IFN-γ産生の増強、又はその組合せである、請求項38〜48のいずれか一項に記載の方法。
- 増強される免疫応答が、抗原提示細胞増殖の増強、機能の増強、又はその組合せである、請求項38〜49のいずれか一項に記載の方法。
- 対象が、アデノウイルスベクターを過去に投与されている、請求項38〜50のいずれか一項に記載の方法。
- 対象が、アデノウイルスベクターに対して既存の免疫を有する、請求項38〜51のいずれか一項に記載の方法。
- 対象が、アデノウイルスベクターに対して既存の免疫を有すると決定される、請求項38〜52のいずれか一項に記載の方法。
- 化学療法剤、放射線、異なる免疫療法、又はその組合せを対象に投与するステップをさらに含む、請求項38〜53のいずれか一項に記載の方法。
- 対象がヒト又は非ヒト動物である、請求項38〜54のいずれか一項に記載の方法。
- 対象が、がんに関して過去に治療されている、請求項38〜55のいずれか一項に記載の方法。
- 治療有効量を投与するステップが、少なくとも3回繰り返される、請求項38〜56のいずれか一項に記載の方法。
- 組成物が、少なくとも1×109〜少なくとも5×1012個のウイルス粒子を含む、請求項38〜57のいずれか一項に記載の方法。
- 治療有効量を投与するステップが、1用量あたり5×109個のウイルス粒子を含む、請求項38〜58のいずれか一項に記載の方法。
- 治療有効量を投与するステップが、1用量あたり少なくとも5×1010個のウイルス粒子を含む、請求項38〜59のいずれか一項に記載の方法。
- 治療有効量を投与するステップが、1用量あたり少なくとも5×1011個のウイルス粒子を含む、請求項38〜60のいずれか一項に記載の方法。
- 治療有効量を投与するステップが、1用量あたり少なくとも5×1012個のウイルス粒子を含む、請求項38〜61のいずれか一項に記載の方法。
- 治療有効量を投与するステップが、2週間又は3週間毎に繰り返される、請求項38〜62のいずれか一項に記載の方法。
- 治療有効量を投与するステップの後に、同じ組成物又は医薬組成物を含むブースター免疫を行う、請求項38〜63のいずれか一項に記載の方法。
- ブースター免疫が1カ月、2カ月、又は3カ月毎に投与される、請求項64に記載の方法。
- ブースター免疫が3回以上繰り返される、請求項64に記載の方法。
- 治療有効量を投与するステップが、初回免疫を、1週間毎、2週間毎、又は3週間毎に3回繰り返した後に、ブースター免疫を、1カ月毎、2カ月毎、又は3カ月毎に3回以上繰り返すことである、請求項38〜66のいずれか一項に記載の方法。
- 工学操作されたナチュラルキラー(NK)細胞の集団を含む医薬組成物を対象に投与するステップをさらに含む、請求項38〜67のいずれか一項に記載の方法。
- 工学操作されたNK細胞が、KIR(キラー抑制性受容体)の発現を本質的に欠如するように改変された1つ以上のNK細胞、高親和性CD16変異体を発現するように改変された1つ以上のNK細胞、及び1つ以上のCAR(キメラ抗原受容体)を発現するように改変された1つ以上のNK細胞、又はその任意の組合せを含む、請求項68に記載の方法。
- 工学操作されたNK細胞が、KIRの発現を本質的に欠如するように改変された1つ以上のNK細胞を含む、請求項68に記載の方法。
- 工学操作されたNK細胞が、高親和性CD16変異体を発現するように改変された1つ以上のNK細胞を含む、請求項68に記載の方法。
- 工学操作されたNK細胞が、1つ以上のCARを発現するように改変された1つ以上のNK細胞を含む、請求項68に記載の方法。
- CARが、腫瘍ネオ抗原、腫瘍ネオエピトープ、WT1、p53、MAGE-A1、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A10、MAGE-A12、BAGE、DAM-6、DAM-10、葉酸受容体アルファ、GAGE-1、GAGE-2、GAGE-8、GAGE-3、GAGE-4、GAGE-5、GAGE-6、GAGE-7B、NA88-A、NY-ESO-1、MART-1、MC1R、Gp100、チロシナーゼ、TRP-1、TRP-2、ART-4、CAMEL、CEA、Cyp-B、HER2/neu、HER3、BRCA1、Brachyury、Brachyury(TIVS7-2、多型)、Brachyury(IVS7 T/C多型)、T Brachyury、T、hTERT、hTRT、iCE、MUC1、MUC1(VNTR多型)、MUC1c、MUC1n、MUC2、PRAME、P15、RU1、RU2、SART-1、SART-3、AFP、β-カテニン/m、カスパーゼ-8/m、CDK-4/m、ELF2M、GnT-V、G250、HSP70-2M、HST-2、KIAA0205、MUM-1、MUM-2、MUM-3、ミオシン/m、RAGE、SART-2、TRP-2/INT2、707-AP、アネキシンII、CDC27/m、TPl/mbcr-abl、ETV6/AML、LDLR/FUT、Pml/RARα、TEL/AML1、又はその任意の組合せのCARである、請求項68又は72に記載の方法。
- 複製欠損型アデノウイルスベクターが、細胞内に含まれる、請求項38〜73のいずれか一項に記載の方法。
- 細胞が樹状細胞(DC)である、請求項74に記載の方法。
- IL-15の治療有効量、又はIL-15をコードする核酸配列を含む複製欠損型ベクターの治療有効量を含む医薬組成物を投与するステップをさらに含む、請求項38〜75のいずれか一項に記載の方法。
- 対象が、HER2/neu発現がんを有する、請求項38〜76のいずれか一項に記載の方法。
- 対象が、HER2/neu発現乳がんを有する、請求項77に記載の方法。
- 対象が、HER2/neu発現骨がんを有する、請求項77に記載の方法。
- がんが骨肉腫である、請求項79に記載の方法。
- 対象が、HER2/neu発現胃がんを有する、請求項77に記載の方法。
- 対象が、切除不能、局所進行、又は転移性がんを有する、請求項77〜81のいずれか一項に記載の方法。
- 追加のがん治療剤を対象に投与するステップをさらに含む、請求項38〜82のいずれか一項に記載の方法。
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EP3596108A4 (en) | 2017-03-15 | 2020-12-23 | Pandion Operations, Inc. | TARGETED IMMUNOTOLERANCE |
BR112019024127A2 (pt) | 2017-05-24 | 2020-06-23 | Pandion Therapeutics, Inc. | Imunotolerância alvejada |
US10636512B2 (en) * | 2017-07-14 | 2020-04-28 | Cofactor Genomics, Inc. | Immuno-oncology applications using next generation sequencing |
CA3073045A1 (en) * | 2017-08-15 | 2019-02-21 | Nantcell, Inc. | Hank cetuximab combinations and methods |
US10174092B1 (en) | 2017-12-06 | 2019-01-08 | Pandion Therapeutics, Inc. | IL-2 muteins |
US10946068B2 (en) | 2017-12-06 | 2021-03-16 | Pandion Operations, Inc. | IL-2 muteins and uses thereof |
WO2019133760A1 (en) * | 2017-12-28 | 2019-07-04 | NEUGATE PHARMA, LLC aka NEUGATE THERANOSTICS | Compositions and formulations for treatment of malignancies |
TW202345890A (zh) * | 2018-04-23 | 2023-12-01 | 美商南特細胞公司 | 新抗原表位疫苗及免疫刺激組合物及方法 |
US11564980B2 (en) | 2018-04-23 | 2023-01-31 | Nantcell, Inc. | Tumor treatment method with an individualized peptide vaccine |
CN110856751A (zh) | 2018-08-24 | 2020-03-03 | 合成免疫股份有限公司 | 包含核酸及tcr修饰的免疫细胞的治疗剂及其应用 |
EP3972992A4 (en) | 2019-05-20 | 2023-07-19 | Pandion Operations, Inc. | ANTI-MADCAM IMMUNE TOLERANCE |
CN110922487B (zh) * | 2019-12-26 | 2021-04-02 | 河南赛诺特生物技术有限公司 | 一种抗人her-2单克隆抗体,抗原、杂交瘤细胞株及免疫组化试剂盒 |
US11981715B2 (en) | 2020-02-21 | 2024-05-14 | Pandion Operations, Inc. | Tissue targeted immunotolerance with a CD39 effector |
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