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- JPWO2021229234A5 JPWO2021229234A5 JP2022568691A JP2022568691A JPWO2021229234A5 JP WO2021229234 A5 JPWO2021229234 A5 JP WO2021229234A5 JP 2022568691 A JP2022568691 A JP 2022568691A JP 2022568691 A JP2022568691 A JP 2022568691A JP WO2021229234 A5 JPWO2021229234 A5 JP WO2021229234A5
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Description
配列番号１９；ＣＤＲ３ ＣＤ８α（残基１１８～１２３）
ＬＳＮＳＩＭ
以下に、本願の当初の特許請求の範囲に記載の発明を列挙する。
［発明１］
ＧＶＹＤＧＲＥＨＴＶ、配列番号２を含むＭＡＧＥ Ａ４のペプチド抗原に結合する異種Ｔ細胞受容体（ＴＣＲ）を発現または提示する有効量の改変された免疫応答性細胞を含む治療レジメンを被験体に投与することを含む、前記被験体において癌および／または腫瘍を治療するか予防するかまたはその進行を遅延させる方法であって、前記癌および／または腫瘍が頭頸部の癌および／もしくは腫瘍または肺の癌および／もしくは腫瘍である方法。
［発明２］
ＭＡＧＥ Ａ４の前記ペプチド抗原が配列ＧＶＹＤＧＲＥＨＴＶ、配列番号２を含む、発明１または２に記載の方法。
［発明３］
前記異種ＴＣＲが前記ペプチド抗原に特異的かつ／または選択的に結合する、発明１または２に記載の方法。
［発明４］
前記ペプチド抗原が、頭頸部の癌および／もしくは腫瘍もしくは肺の癌および／もしくは腫瘍に関連し、かつ／または腫瘍および／もしくは癌細胞もしくは組織によって提示される、発明１から３のいずれか一つに記載の方法。
［発明５］
前記癌および／または腫瘍が、ＭＡＧＥ Ａ４を発現する癌および／もしくは腫瘍であり、かつ／またはＭＡＧＥ Ａ４もしくはそのペプチド抗原、もしくはＧＶＹＤＧＲＥＨＴＶ、配列番号２を含むＭＡＧＥ Ａ４のペプチド抗原を発現する、発明１から４のいずれか一つに記載の方法。
［発明６］
前記ペプチド抗原が、ペプチド提示分子、任意により、主要組織適合性複合体（ＭＨＣ）またはヒト白血球抗原（ＨＬＡ）、任意により、クラスＩまたはクラスＩＩと複合体を形成している、発明１から５のいずれか一つに記載の方法。
［発明７］
前記ペプチド提示分子がＨＬＡ－Ａ＊０２であり、任意により、ＨＬＡ＊０２、ＨＬＡ－Ａ＊０２：０１、ＨＬＡ－Ａ＊０２：０２、ＨＬＡ－Ａ＊０２：０３、ＨＬＡ－Ａ＊０２：０４、ＨＬＡ－Ａ＊０２：０６、ＨＬＡ－Ａ＊０２：６４２またはＨＬＡ－Ａ＊０２：０７、好ましくはＨＬＡ－Ａ＊０２：０１またはＨＬＡ－Ａ＊０２から選択される、発明６に記載の方法。
［発明８］
前記異種ＴＣＲが、前記ペプチド抗原および／もしくは前記ペプチド提示分子ならびに／またはその複合体に特異的かつ／または選択的に結合する、発明１から６のいずれか一つに記載の方法。
［発明９］
前記ペプチド抗原がペプチド提示分子とは独立に提示される、発明１から５のいずれか一つに記載の方法。
［発明１０］
前記異種ＴＣＲがＴＣＲα鎖可変ドメインおよびＴＣＲβ鎖可変ドメインを含み、
（ｉ）前記α鎖可変ドメインが、配列
ＶＳＰＦＳＮ（αＣＤＲ１）、配列番号１１もしくは配列番号５のアミノ酸４８～５３、またはそれらに対して少なくとも５０％の配列同一性を有する配列、
ＬＴＦＳＥＮ（αＣＤＲ２）、配列番号１２もしくは配列番号５のアミノ酸７１～７６、またはそれらに対して少なくとも５０％の配列同一性を有する配列、および
ＣＶＶＳＧＧＴＤＳＷＧＫＬＱＦ（αＣＤＲ３）、配列番号１３もしくは配列番号５のアミノ酸１１１～１２５、またはそれらに対して少なくとも５０％の配列同一性を有する配列
を有するＣＤＲを含み、かつ
（ｉｉ）前記β鎖可変ドメインが、配列
ＫＧＨＤＲ（βＣＤＲ１）、配列番号１４もしくは配列番号７のアミノ酸４６～５０、またはそれらに対して少なくとも５０％の配列同一性を有する配列、
ＳＦＤＶＫＤ（βＣＤＲ２）、配列番号１５もしくは配列番号７のアミノ酸６８～７３、またはそれらに対して少なくとも５０％の配列同一性を有する配列、および
ＣＡＴＳＧＱＧＡＹＥＥＱＦＦ（βＣＤＲ３）、配列番号１６もしくは配列番号７のアミノ酸１１０～１２３、またはそれらに対して少なくとも５０％の配列同一性を有する配列
を有するＣＤＲを含む、
発明１から９のいずれか一つに記載の方法。
［発明１１］
前記異種ＴＣＲが、
（ａ）前記α鎖可変ドメインが配列番号９に対して少なくとも８０％の同一性を有するアミノ酸配列を含み、かつ／もしくは前記β鎖可変ドメインが配列番号１０に対して少なくとも８０％の同一性を有するアミノ酸配列を含み、
（ｂ）前記α鎖可変ドメインが配列番号９を含むアミノ酸配列を含み、かつ／もしくは前記β鎖可変ドメインが配列番号１０を含み、
（ｃ）前記α鎖が配列番号５に対して少なくとも８０％の同一性を有するアミノ酸配列を含み、かつ／もしくは前記β鎖が配列番号６に対して少なくとも８０％の同一性を有するアミノ酸配列を含み、または
（ｄ）前記α鎖が配列番号５を含むアミノ酸配列を含み、かつ／もしくは前記β鎖が配列番号６を含むアミノ酸配列を含む
ＴＣＲを含む、発明１から１０のいずれか一つに記載の方法。
［発明１２］
異種ＴＣＲを発現または提示する前記改変された免疫応答性細胞が、異種共受容体をさらに発現または提示し、任意により、共受容体がＣＤ８共受容体である、発明１から１１のいずれか一つに記載の方法。
［発明１３］
前記異種ＣＤ８共受容体が、ヘテロ二量体またはホモ二量体、ＣＤ８αｂヘテロ二量体またはＣＤ８ααホモ二量体である、発明１２に記載の方法。
［発明１４］
前記異種ＣＤ８共受容体が、
（ａ）アミノ酸配列ＶＬＬＳＮＰＴＳＧ、配列番号１７に対して少なくとも８０％の配列同一性を有するＣＤＲ１、アミノ酸配列ＹＬＳＱＮＫＰＫ、配列番号１８に対して少なくとも８０％の配列同一性を有するＣＤＲ２、およびアミノ酸配列ＬＳＮＳＩＭ、配列番号１９に対して少なくとも８０％の配列同一性を有するＣＤＲ３、
（ｂ）アミノ酸配列ＶＬＬＳＮＰＴＳＧ、配列番号１７のＣＤＲ１、アミノ酸配列ＹＬＳＱＮＫＰＫ、配列番号１８のＣＤＲ２、およびアミノ酸配列ＬＳＮＳＩＭ、配列番号１９のＣＤＲ３、
（ｃ）配列番号３のアミノ酸番号２２～２３５、もしくは配列番号３の２２～１３５に対して少なくとも８０％の配列同一性を有するアミノ酸配列、または
（ｄ）配列番号３の配列のアミノ酸番号２２～２３５、または配列番号３の２２～１３５に対して１００％の配列同一性を有するアミノ酸配列
のうちのいずれか１つを含む、発明１０または１１に記載の方法。
［発明１５］
異種ＴＣＲを発現または提示する前記改変された免疫応答性細胞が、異種共刺激リガンド、任意により、４－１ＢＢＬまたはＣＤ８０をさらに発現または提示する、発明１から１４のいずれか一つに記載の方法。
［発明１６］
前記改変された免疫応答性細胞が、（ａ）Ｂ細胞、Ｔ細胞またはナチュラルキラー（ＮＫ）細胞、（ｂ）Ｔ細胞、任意によりＣＤ４
+
Ｔ細胞および／またはＣＤ８
+
Ｔ細胞である、発明１から１５のいずれか一つに記載の方法。
［発明１７］
前記改変された免疫応答性細胞が、ＣＤ４＋ Ｔ細胞の集団、もしくはＣＤ８＋ Ｔ細胞であるか、またはＣＤ４＋ Ｔ細胞およびＣＤ８＋ Ｔ細胞の混合集団である、発明１から１６のいずれか一つに記載の方法。
［発明１８］
前記改変された免疫応答性細胞が連続的または間欠的に投与される、発明１から１７のいずれか一つに記載の方法。
［発明１９］
前記改変された免疫応答性細胞が、複数用量として投与されるかまたは単一用量として投与される、発明１から１８のいずれか一つに記載の方法。
［発明２０］
前記単一用量または複数用量が１つまたは複数の投薬サイクルで投与され、任意により、前記用量が固定用量または可変用量であってよい、発明１９に記載の方法。
［発明２１］
前記改変された免疫応答性細胞が、約５億個～約１０億個の細胞、約２０億個～約５０億個の細胞、または約６０億個～約１００億個の細胞の間の用量で投与される、発明１から２０のいずれか一つに記載の方法。
［発明２２］
前記改変された免疫応答性細胞が、
（ａ）１つまたは複数の投薬サイクルのそれぞれで単一用量、
（ｂ）１つまたは複数の投薬サイクルのそれぞれで１つまたは複数の用量、
（ｃ）１つまたは複数の投薬サイクルのそれぞれの第１日に単一用量、
（ｄ）少なくとも１つの用量が各サイクルの第１日に行われる、１つまたは複数の投薬サイクルのそれぞれで１つまたは複数の用量、
（ｅ）少なくとも１つの用量が各サイクルの第１日に行われる、１つまたは複数の投薬サイクルのそれぞれで１つまたは複数の用量、
（ｆ）単一用量
として投与される、発明１から２１のいずれか一つに記載の方法。
［発明２３］
前記投薬サイクルが２カ月間～６カ月間の間であるかまたは疾患の進行で継続する、発明２０から２２のいずれか一つに記載の方法。
［発明２４］
前記投薬サイクルが、
（ａ）改変された免疫応答性細胞の以前の投与後の疾患進行、および前記改変された免疫応答性細胞の以前の投与から１２週間またはそれ以上の後で継続し、
（ｂ）前記腫瘍および／もしくは癌がＭＡＧＥ－Ａ４および／もしくはそのペプチド抗原を発現し、かつ／または
（ｄ）ＭＡＧＥ－Ａ４および／もしくはそのペプチド抗原が被験体の生体サンプル中に検出され、かつ／もしくは正常範囲を上回る、
発明２０から２３のいずれか一つに記載の方法。
［発明２５］
前記投薬サイクルが、
（ａ）改変された免疫応答性細胞の以前の投与後の完全もしくは部分奏効、または（ｂ）前記改変された免疫応答性細胞の以前の投与後に４カ月間以上の期間にわたる疾患安定、その後の疾患進行；および（ｃ）前記改変された免疫応答性細胞の以前の投与から１２週間以上後で継続し、
（ｄ）前記腫瘍および／もしくは癌がＭＡＧＥ－Ａ４および／もしくはそのペプチド抗原を発現し、かつ／または
（ｄ）ＭＡＧＥ－Ａ４および／もしくはそのペプチド抗原が被験体の生体サンプル中に検出され、かつ／もしくは正常範囲を上回る、
発明２０から２３のいずれか一つに記載の方法。
［発明２６］
前記改変された免疫応答性細胞が静脈内にまたは静脈内注入により投与される、発明１から２５のいずれか一つに記載の方法。
［発明２７］
治療の前に前記被験体が、米国東海岸癌臨床試験グループ（ＥＣＯＧ）が０～１であり、かつ／または固形癌効果判定基準（ＲＥＣＩＳＴ）１．１による測定可能な疾患および／または組織学的に確認された頭頸部または肺の癌／腫瘍を有する、発明１から２６のいずれか一つに記載の方法。
［発明２８］
治療の前に、前記被験体が、
（ａ）ＨＬＡ－Ａ遺伝子型がＨＬＡ－Ａ＊０２：０５陽性である、
（ｂ）ＨＬＡ－Ａ遺伝子型が唯一のＨＬＡ－Ａ＊０２アレルとしてＨＬＡ－Ａ＊０２：０７である（例えば、ＨＬＡアレルＡ＊０２：０４およびＡ＊０２：０７を有する被験体は適格である）、
（ｃ）ＨＬＡ－Ａ遺伝子型が唯一のＨＬＡ－Ａ＊０２アレルとして任意のＡ＊０２ヌルアレルのＨＬＡ－Ａ＊である、または
（ｄ）症候性ＣＮＳ転移
のうちのいずれか１つまたは複数を有する場合に、前記被験体が治療から除外される、発明１から２７のいずれか一つに記載の方法。
［発明２９］
前記被験体が、標準治療、任意により白金ベース全身化学療法治療に対して不耐容である、発明１から２８のいずれか一つに記載の方法。
［発明３０］
前記頭頸部または肺の癌および／または腫瘍が、標準治療、任意により白金ベース全身化学療法治療での治療に以前に不成功であった、発明１から２９のいずれか一つに記載の方法。
［発明３１］
前記頭頸部または肺の癌および／または腫瘍が、手術（切除）、放射線療法、標的療法、免疫療法もしくは化学療法、または手術（切除）、放射線療法、放射線療法標的療法、チェックポイント阻害剤もしくは免疫療法との併用化学療法のいずれかでの治療に以前に不成功であった、発明１から３０のいずれか一つに記載の方法。
［発明３２］
前記被験体が、頭頸部もしくは肺の癌および／もしくは腫瘍を有するか、または頭頸部もしくは肺の癌および／もしくは腫瘍が、原発癌、続発癌、再燃癌もしくは難治性癌もしくは再発癌もしくは局所再発癌もしくは転移性癌、切除不能癌もしくは外科的もしくは放射線療法の選択肢がない局所限局癌もしくは手術不能癌であり、任意により癌が移植もしくは局所領域療法の対象とならない、発明１から３１のいずれか一つに記載の方法。
［発明３３］
前記頭頸部の癌および／または腫瘍が、扁平上皮頭頸部癌または頭頸部扁平上皮癌（ＨＮＳＣＣ）であり、任意により、転移性および／または進行性および／または局所進行性および／または再発性の扁平上皮頭頸部癌または頭頸部扁平上皮癌（ＨＮＳＣＣ）である、発明１から３２のいずれか一つに記載の方法。
［発明３４］
前記肺の癌および／または腫瘍が、ＮＳＣＬＣ、扁平上皮ＮＳＣＬＣ、腺扁平上皮ＮＳＣＬＣまたは大細胞癌、任意により、転移性および／または進行性および／または局所進行性および／または再発性のＮＳＣＬＣ、扁平上皮ＮＳＣＬＣ、腺扁平上皮ＮＳＣＬＣまたは大細胞癌のうちのいずれか１つである、発明１から３２のいずれか一つに記載の方法。
［発明３５］
異種Ｔ細胞受容体（ＴＣＲ）を発現または提示する前記改変された免疫応答性細胞の投与の前に、前記被験体がリンパ球除去化学療法を受ける、発明１から３４のいずれか一つに記載の方法。
［発明３６］
前記リンパ球除去化学療法が、シクロホスファミドおよびフルダラビンの、任意により、５００ｍｇ／ｍ
2
／ｄ×３日のシクロホスファミドおよび２０ｍｇ／ｍ
2
／ｄ×３日のフルダラビンの用量での、または６００ｍｇ／ｍ
2
／ｄ×３日のシクロホスファミドおよび３０ｍｇ／ｍ
2
／ｄ×４日の用量での投与を含む、発明３５に記載の方法。
［発明３７］
異種Ｔ細胞受容体（ＴＣＲ）を発現または提示する前記改変された免疫応答性細胞の投与の７日～５日前または７日～４日前に、前記リンパ球除去化学療法が投与される、発明３５または３６に記載の方法。
［発明３８］
被験体が癌および／または腫瘍に対する前治療を受けていない、発明１から３７のいずれか一つに記載の方法。
［発明３９］
被験体が癌および／または腫瘍の前治療を受けており、かつ／または癌および／または腫瘍の前治療が奏効していない、発明１から３７のいずれか一つに記載の方法。
［発明４０］
前記前治療が、全身および／または局所療法、任意により、手術、放射線療法、凍結療法、レーザー療法、局部療法および／または全身療法のうちのいずれか１つまたは複数、例えば、化学療法、ホルモン療法、標的薬、標的化学療法または免疫療法のうちのいずれか１つまたは複数を含む、発明３９に記載の方法。
［発明４１］
前記前治療がＰＤ－Ｌ１結合アンタゴニストまたはＰＤ－１結合アンタゴニストを含み、任意により、ＰＤ－１軸結合アンタゴニストまたはＰＤ－Ｌ１結合アンタゴニストが抗体である、発明４０に記載の方法。
［発明４２］
前記前治療が上皮増殖因子受容体アンタゴニストを含み、任意により、セツキシマブ、エルロチニブ、ゲフィチニブまたはアファチニブのうちのいずれかを含む、発明４０に記載の方法。
［発明４３］
前記前治療が、リポプラチン、シスプラチン、カルボプラチン、オキサリプラチン、ネダプラチン、四硝酸トリプラチン、フェナントリプラチン、サトラプラチン、ピコプラチンのうちのいずれかから任意により選択される、白金化合物を含む化学療法を含む、発明４０に記載の方法。
［発明４４］
前記前治療が、メトトレキサート、カペシタビン、タキサン、アントラサイクリン、パクリタキセル、ドセタキセル、パクリタキセルタンパク質結合粒子、ドキソルビシン、エピルビシン、５－フルオロウラシル、シクロホスファミド、アファチニブ、ビンクリスチン、エトポシドのうちのいずれかまたはこれらの組み合わせから選択される化学療法剤を含む化学療法を含む、発明４０に記載の方法。
［発明４５］
前記前治療が、ＦＥＣ：５－フルオロウラシル、エピルビシン、シクロホスファミド；ＦＡＣ：５－フルオロウラシル、ドキソルビシン、シクロホスファミド；ＡＣ：ドキソルビシン、シクロホスファミド；ＥＣ：エピルビシン、シクロホスファミドのうちのいずれかから選択される化学療法剤を含む化学療法を含む、発明４０に記載の方法。
［発明４６］
前記被験体が、最後の治療から１２カ月以内または最後の治療から６カ月以内の再発において前治療を受けていない、発明４０から４５のいずれか一つに記載の方法。
［発明４７］
前記被験体が、最後の治療から１２カ月以内の再発において、または最後の治療から６カ月以内の再発において、いかなる事前のアジュバント療法（例えば、手術の後の放射線および／または化学療法）も局所領域療法も受けていない、発明４０から４５のいずれか一つに記載の方法。
［発明４８］
プラセボ投与と比較して、または治療前と比較して、または無治療と比較して、または標準治療、任意により白金ベース全身化学療法治療を含む治療と比較して、前記治療が、
（ａ）無増悪生存期間、
（ｂ）無増悪期間、
（ｃ）奏効持続期間、
（ｄ）全生存率、
（ｅ）客観的奏効または客観的奏効率、
（ｆ）全奏効または全奏効率、
（ｇ）部分奏効または部分奏効率
（ｈ）完全奏功または完全奏功率；
（ｉ）疾患安定率または疾患安定中央値、
（ｊ）無増悪生存期間中央値、
（ｋ）無増悪期間中央値、
（ｌ）奏効持続期間中央値、または
（ｍ）全生存率中央値；
（ｎ）客観的奏効中央値または客観的奏効率中央値、
（ｏ）全奏効中央値または全奏効率中央値、
（ｐ）部分奏効中央値または部分奏効率中央値、
（ｑ）完全奏効中央値または完全奏効中央値、
（ｒ）疾患安定率中央値または疾患安定中央値
を効果的に延長または改善する、発明１から４７のいずれか一つに記載の方法。
SEQ ID NO:19; CDR3 CD8α (residues 118-123)
LSN SIM
The inventions described in the original claims of this application are listed below.
[Invention 1]
2. A method of treating, preventing or delaying the progression of cancer and/or tumors in a subject comprising administering to the subject a therapeutic regimen comprising an effective amount of modified immunoresponsive cells that express or display a heterologous T cell receptor (TCR) that binds to a peptide antigen of MAGE A4 comprising SEQ ID NO:2, wherein the cancer and/or tumor is a head and neck cancer and/or tumor or a lung cancer and/or tumor.
[Invention 2]
3. The method according to claim 1 or 2, wherein said peptide antigen of MAGE A4 comprises the sequence GVYDGREHTV, SEQ ID NO:2.
[Invention 3]
The method according to claim 1 or 2, wherein the heterologous TCR specifically and/or selectively binds to the peptide antigen.
[Invention 4]
4. The method according to any one of claims 1 to 3, wherein said peptide antigen is associated with head and neck cancer and/or tumours or lung cancer and/or tumours and/or is presented by tumour and/or cancer cells or tissues.
[Invention 5]
5. The method according to any one of claims 1 to 4, wherein said cancer and/or tumor is a cancer and/or tumor that expresses MAGE A4 and/or expresses MAGE A4 or a peptide antigen thereof, or a peptide antigen of MAGE A4 comprising GVYDGREHTV, SEQ ID NO:2.
[Invention 6]
6. A method according to any one of claims 1 to 5, wherein the peptide antigen is complexed with a peptide presenting molecule, optionally a major histocompatibility complex (MHC) or a human leukocyte antigen (HLA), optionally class I or class II.
[Invention 7]
7. The method according to invention 6, wherein said peptide presenting molecule is HLA-A*02, optionally selected from HLA*02, HLA-A*02:01, HLA-A*02:02, HLA-A*02:03, HLA-A*02:04, HLA-A*02:06, HLA-A*02:642 or HLA-A*02:07, preferably HLA-A*02:01 or HLA-A*02.
[Invention 8]
The method according to any one of claims 1 to 6, wherein the heterologous TCR specifically and/or selectively binds to the peptide antigen and/or the peptide presenting molecule and/or a complex thereof.
[Invention 9]
6. The method according to any one of claims 1 to 5, wherein the peptide antigen is presented independently of a peptide-presenting molecule.
[Invention 10]
the heterologous TCR comprises a TCR alpha chain variable domain and a TCR beta chain variable domain;
(i) the α chain variable domain has the sequence
VSPFSN (αCDR1), amino acids 48-53 of SEQ ID NO:11 or SEQ ID NO:5, or a sequence having at least 50% sequence identity thereto;
LTFSEN (αCDR2), amino acids 71-76 of SEQ ID NO:12 or SEQ ID NO:5, or a sequence having at least 50% sequence identity thereto; and
CVVSGGTDSWGKLQF (αCDR3), amino acids 111-125 of SEQ ID NO:13 or SEQ ID NO:5, or a sequence having at least 50% sequence identity thereto
and
(ii) the β chain variable domain has the sequence
KGHDR (βCDR1), amino acids 46-50 of SEQ ID NO:14 or SEQ ID NO:7, or a sequence having at least 50% sequence identity thereto;
SFDVKD (βCDR2), amino acids 68-73 of SEQ ID NO: 15 or SEQ ID NO: 7, or a sequence having at least 50% sequence identity thereto; and
CATSGQGAYEEQFF (βCDR3), amino acids 110-123 of SEQ ID NO: 16 or SEQ ID NO: 7, or a sequence having at least 50% sequence identity thereto
Including CDR with
The method according to any one of claims 1 to 9.
[Invention 11]
The heterologous TCR is
(a) the α chain variable domain comprises an amino acid sequence having at least 80% identity to SEQ ID NO:9, and/or the β chain variable domain comprises an amino acid sequence having at least 80% identity to SEQ ID NO:10;
(b) the α chain variable domain comprises an amino acid sequence comprising SEQ ID NO:9, and/or the β chain variable domain comprises SEQ ID NO:10;
(c) the α chain comprises an amino acid sequence having at least 80% identity to SEQ ID NO:5, and/or the β chain comprises an amino acid sequence having at least 80% identity to SEQ ID NO:6, or
(d) the alpha chain comprises an amino acid sequence comprising SEQ ID NO:5, and/or the beta chain comprises an amino acid sequence comprising SEQ ID NO:6.
11. The method according to any one of claims 1 to 10, comprising a TCR.
[Invention 12]
12. The method according to any one of claims 1 to 11, wherein said modified immunoresponsive cell expressing or presenting a heterologous TCR further expresses or presents a heterologous co-receptor, optionally wherein the co-receptor is a CD8 co-receptor.
[Invention 13]
13. The method according to claim 12, wherein said heterologous CD8 co-receptor is a heterodimer or a homodimer, a CD8αb heterodimer or a CD8αα homodimer.
[Invention 14]
the heterologous CD8 co-receptor
(a) an amino acid sequence VLLSNPTSG, a CDR1 having at least 80% sequence identity to SEQ ID NO: 17, an amino acid sequence YLSQNKPK, a CDR2 having at least 80% sequence identity to SEQ ID NO: 18, and an amino acid sequence LSNSIM, a CDR3 having at least 80% sequence identity to SEQ ID NO: 19;
(b) the amino acid sequence VLLSNPTSG, CDR1 of SEQ ID NO: 17, the amino acid sequence YLSQNKPK, CDR2 of SEQ ID NO: 18, and the amino acid sequence LSNSIM, CDR3 of SEQ ID NO: 19;
(c) an amino acid sequence having at least 80% sequence identity to amino acid numbers 22 to 235 of SEQ ID NO:3, or 22 to 135 of SEQ ID NO:3; or
(d) an amino acid sequence having 100% sequence identity to amino acid numbers 22 to 235 of SEQ ID NO: 3, or 22 to 135 of SEQ ID NO: 3
12. The method according to claim 10 or 11, comprising any one of the steps:
[Invention 15]
15. The method of any one of claims 1 to 14, wherein said modified immunoresponsive cell expressing or presenting a heterologous TCR further expresses or presents a heterologous costimulatory ligand, optionally 4-1BBL or CD80.
[Invention 16]
16. The method of any one of claims 1 to 15, wherein the modified immunoresponsive cell is (a) a B cell, a T cell or a natural killer (NK) cell; (b) a T cell, optionally a CD4 + T cell and/or a CD8 + T cell.
[Invention 17]
17. The method of any one of claims 1 to 16, wherein the modified immunoresponsive cells are a population of CD4+ T cells, or CD8+ T cells, or a mixed population of CD4+ and CD8+ T cells.
[Invention 18]
18. The method according to any one of claims 1 to 17, wherein the modified immunoresponsive cells are administered continuously or intermittently.
[Invention 19]
19. The method of any one of claims 1 to 18, wherein the modified immunoresponsive cells are administered as multiple doses or as a single dose.
[Invention 20]
20. The method of claim 19, wherein said single dose or multiple doses are administered in one or more dosing cycles, optionally said doses being fixed doses or variable doses.
[Invention 21]
21. The method of any one of claims 1 to 20, wherein the modified immunoresponsive cells are administered at a dose of between about 500 million to about 1 billion cells, about 2 billion to about 5 billion cells, or about 6 billion to about 10 billion cells.
[Invention 22]
The modified immunoresponsive cell comprises:
(a) a single dose in each of one or more dosing cycles;
(b) one or more doses in each of one or more dosing cycles;
(c) a single dose on day 1 of each of one or more dosing cycles;
(d) one or more doses in each of one or more dosing cycles, with at least one dose occurring on day 1 of each cycle;
(e) one or more doses in each of one or more dosing cycles, with at least one dose occurring on the first day of each cycle;
(f) Single dose
22. The method according to any one of claims 1 to 21, wherein the compound is administered as a medicament.
[Invention 23]
23. The method according to any one of claims 20 to 22, wherein said dosing cycle lasts for between 2 months and 6 months or continues as the disease progresses.
[Invention 24]
The dosing cycle comprises:
(a) disease progression following a previous administration of modified immunoresponsive cells and continuing 12 weeks or more after the previous administration of said modified immunoresponsive cells;
(b) the tumor and/or cancer expresses MAGE-A4 and/or a peptide antigen thereof, and/or
(d) MAGE-A4 and/or its peptide antigens are detected in the subject's biological sample and/or are above the normal range;
24. The method according to any one of claims 20 to 23.
[Invention 25]
The dosing cycle comprises:
(a) a complete or partial response following a previous administration of modified immunoresponsive cells, or (b) stable disease for a period of 4 months or more following a previous administration of said modified immunoresponsive cells, followed by disease progression; and (c) continuing 12 weeks or more after the previous administration of said modified immunoresponsive cells.
(d) the tumor and/or cancer expresses MAGE-A4 and/or its peptide antigens, and/or
(d) MAGE-A4 and/or its peptide antigens are detected in the subject's biological sample and/or are above the normal range;
24. The method according to any one of claims 20 to 23.
[Invention 26]
26. The method of any one of claims 1 to 25, wherein said modified immunoresponsive cells are administered intravenously or by intravenous infusion.
[Invention 27]
27. The method according to any one of claims 1 to 26, wherein prior to treatment, said subject has Eastern Cooperative Oncology Group (ECOG) 0-1 and/or measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and/or histologically confirmed head, neck or lung cancer/tumor.
[Invention 28]
Prior to treatment, the subject:
(a) the HLA-A genotype is HLA-A*02:05 positive;
(b) the HLA-A genotype is HLA-A*02:07 as the only HLA-A*02 allele (e.g., a subject with HLA alleles A*02:04 and A*02:07 is eligible);
(c) the HLA-A genotype is HLA-A* with any A*02 null allele as the only HLA-A*02 allele; or
(d) Symptomatic CNS metastases
28. The method according to any one of claims 1 to 27, wherein the subject is excluded from treatment if he/she has any one or more of the following:
[Invention 29]
29. The method according to any one of claims 1 to 28, wherein the subject is intolerant to standard treatment, optionally a platinum-based systemic chemotherapy treatment.
[Invention 30]
30. The method according to any one of claims 1 to 29, wherein said head and neck or lung cancer and/or tumour has previously failed treatment with standard therapy, optionally with platinum-based systemic chemotherapy treatment.
[Invention 31]
31. The method according to any one of claims 1 to 30, wherein said head and neck or lung cancer and/or tumour has previously been unsuccessfully treated with either surgery (resection), radiation therapy, targeted therapy, immunotherapy or chemotherapy, or combination chemotherapy with surgery (resection), radiation therapy, radiotherapy targeted therapy, checkpoint inhibitor or immunotherapy.
[Invention 32]
32. The method according to any one of claims 1 to 31, wherein the subject has a head, neck or lung cancer and/or tumor, or the head, neck or lung cancer and/or tumor is a primary cancer, a secondary cancer, a relapsed cancer or a refractory cancer or a recurrent cancer or a locally recurrent cancer or a metastatic cancer, an unresectable cancer or a locoregional cancer or an inoperable cancer with no surgical or radiotherapy options, and optionally the cancer is not amenable to transplantation or locoregional therapy.
[Invention 33]
33. The method according to any one of claims 1 to 32, wherein the head and neck cancer and/or tumour is squamous cell head and neck cancer or head and neck squamous cell carcinoma (HNSCC), optionally metastatic and/or progressive and/or locally advanced and/or recurrent squamous cell head and neck cancer or head and neck squamous cell carcinoma (HNSCC).
[Invention 34]
33. The method according to any one of claims 1 to 32, wherein the lung cancer and/or tumour is any one of NSCLC, squamous NSCLC, adenosquamous NSCLC or large cell carcinoma, optionally metastatic and/or progressive and/or locally advanced and/or recurrent NSCLC, squamous NSCLC, adenosquamous NSCLC or large cell carcinoma.
[Invention 35]
35. The method of any one of claims 1 to 34, wherein the subject undergoes lymphodepleting chemotherapy prior to administration of the modified immunoresponsive cells expressing or displaying a heterologous T cell receptor (TCR).
[Invention 36]
The method of invention 35, wherein said lymphodepleting chemotherapy comprises administration of cyclophosphamide and fludarabine, optionally at doses of 500 mg/m2 / d x 3 days of cyclophosphamide and 20 mg/m2 / d x 3 days of fludarabine, or at doses of 600 mg/m2 / d x 3 days of cyclophosphamide and 30 mg/m2 / d x 4 days.
[Invention 37]
37. The method of claim 35 or 36, wherein said lymphodepleting chemotherapy is administered 7 to 5 days or 7 to 4 days prior to administration of said modified immunoresponsive cells expressing or displaying a heterologous T-cell receptor (TCR).
[Invention 38]
38. The method according to any one of claims 1 to 37, wherein the subject has not undergone prior treatment for cancer and/or tumor.
[Invention 39]
38. The method according to any one of claims 1 to 37, wherein the subject has undergone prior treatment for cancer and/or tumor and/or has failed prior treatment for cancer and/or tumor.
[Invention 40]
40. The method of claim 39, wherein said pretreatment comprises systemic and/or local therapy, optionally any one or more of surgery, radiation therapy, cryotherapy, laser therapy, local therapy and/or systemic therapy, such as any one or more of chemotherapy, hormonal therapy, targeted drugs, targeted chemotherapy or immunotherapy.
[Invention 41]
41. The method of claim 40, wherein said pretreatment comprises a PD-L1 binding antagonist or a PD-1 binding antagonist, and optionally, the PD-1 axis binding antagonist or the PD-L1 binding antagonist is an antibody.
[Invention 42]
41. The method of claim 40, wherein said prior treatment comprises an epidermal growth factor receptor antagonist, optionally comprising any of cetuximab, erlotinib, gefitinib or afatinib.
[Invention 43]
41. The method of claim 40, wherein said prior treatment comprises chemotherapy comprising a platinum compound, optionally selected from any of the following: lipoplatin, cisplatin, carboplatin, oxaliplatin, nedaplatin, triplatin tetranitrate, phenanthriplatin, satraplatin, picoplatin.
[Invention 44]
41. The method of claim 40, wherein said prior treatment comprises chemotherapy comprising a chemotherapeutic agent selected from methotrexate, capecitabine, taxanes, anthracyclines, paclitaxel, docetaxel, paclitaxel protein-bound particles, doxorubicin, epirubicin, 5-fluorouracil, cyclophosphamide, afatinib, vincristine, etoposide, or any combination thereof.
[Invention 45]
41. The method of claim 40, wherein said pretreatment comprises chemotherapy comprising a chemotherapeutic agent selected from any of the following: FEC: 5-fluorouracil, epirubicin, cyclophosphamide; FAC: 5-fluorouracil, doxorubicin, cyclophosphamide; AC: doxorubicin, cyclophosphamide; EC: epirubicin, cyclophosphamide.
[Invention 46]
46. The method according to any one of claims 40 to 45, wherein the subject has not been previously treated within 12 months of the last treatment or within 6 months of the last treatment in relapse.
[Invention 47]
46. The method according to any one of claims 40 to 45, wherein the subject has not received any prior adjuvant therapy (e.g., radiation and/or chemotherapy after surgery) or locoregional therapy at recurrence within 12 months of the last treatment, or at recurrence within 6 months of the last treatment.
[Invention 48]
compared to placebo administration, or compared to prior treatment, or compared to no treatment, or compared to a standard of care, optionally including a platinum-based systemic chemotherapy treatment,
(a) progression-free survival,
(b) time to progression,
(c) duration of response,
(d) overall survival;
(e) objective response or objective response rate,
(f) overall response or overall response rate,
(g) partial response or partial response rate
(h) complete response or complete response rate;
(i) disease stability rate or median disease stability;
(j) median progression-free survival,
(k) median time to progression;
(l) median duration of response; or
(m) Median overall survival;
(n) median objective response or median objective response rate;
(o) median overall response or median overall response rate;
(p) median partial response or median partial response rate;
(q) median complete response or median complete response,
(r) Median disease stability rate or median disease stability
48. The method according to any one of claims 1 to 47, which effectively prolongs or improves
Claims (1)
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| US63/030,503 | 2020-05-27 | ||
| US202063089611P | 2020-10-09 | 2020-10-09 | |
| US63/089,611 | 2020-10-09 | ||
| PCT/GB2021/051157 WO2021229234A1 (en) | 2020-05-13 | 2021-05-13 | Method of treatment of cancer or tumour |
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| JP2023528206A JP2023528206A (en) | 2023-07-04 |
| JPWO2021229234A5 true JPWO2021229234A5 (en) | 2024-05-22 |
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| EP (1) | EP4149493A1 (en) |
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| KR20230169944A (en) | 2021-03-09 | 2023-12-18 | 씨디알-라이프 아게 | MAGE-A4 peptide-MHC antigen binding protein |
| GB202213051D0 (en) * | 2022-09-07 | 2022-10-19 | Adaptimmune Ltd | Method of treatment of head and neck cancer |
| GB202213052D0 (en) * | 2022-09-07 | 2022-10-19 | Adaptimmune Ltd | Method and treatment of bladder cancer |
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