JP6987390B2 - 細胞ベースの治療法を用いて癌および感染性疾患を処置する方法 - Google Patents
細胞ベースの治療法を用いて癌および感染性疾患を処置する方法 Download PDFInfo
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Description
本出願は、2016年4月8日に出願された米国仮特許出願第62/319,957号明細書の利益を主張する。この出願の全体は、あらゆる目的のために参照により本明細書に組み込まれる。
本発明は、国立衛生研究所によって授与されたRO1 HL116737−01AおよびRO1 CA188523の下、政府の支援を得てなされたものである。政府は、本発明に対する一定の権利を有する。
本出願に関する配列表は、紙のコピーの代わりにテキスト形式で提供され、参照により本明細書中に組み込まれる。配列表を含むテキストファイルの名称は、16094PCT_ST25.txtである。テキストファイルは、11KBであり、2017年4月5日に作成され、かつEFS−Web経由で電子的に提出されている。
を含む。特定の実施形態において、VIP分解酵素は、(配列番号3)
を有するヒト組換えエンケファリナーゼ(中性エンドペプチダーゼ、EC3.4.24.11)である。
生理学的老化中および化学療法のラウンドの繰り返しまたは慢性炎症状態に曝された個体において、T細胞は、それらがアネルギー性であるかまたは抗原刺激に応答して増殖能が制限される老化の状態を生じる。老化T細胞の表現型は、共刺激受容体CD27およびCD28を欠くか、または高レベルのCD57マーカーを有するT細胞として記載されてきた。さらに、プログラム死リガンドの受容体であるPD1の発現は、アネルギー状態と関連づけられてきた。アネルギー性T細胞の存在は、患者がワクチンに応答する能力、または慢性ウイルス感染もしくは癌に対する防御的で耐久性のある免疫応答を賦与する能力において重要な補因子である。慢性感染症および癌を有する患者に有効な細胞ベースの免疫療法の可能性を提供するには、T細胞老化およびアネルギーを反転させる新規アプローチが必要である。
特定の実施形態において、本開示は、抗CD3抗体および抗腫瘍抗体ならびに組換えマスト細胞キマーゼの有効量を注入、移植または投与することによってT細胞老化を反転させるインビボでの方法を企図する。特定の実施形態において、組換えマスト細胞キマーゼは、抗CD3抗体および腫瘍関連抗原に対する抗体を投与されている対象/患者に投与または静脈内注入される。
同種免疫応答におけるVIPシグナル伝達の役割を調べるために、VIPおよび/またはアンタゴニストVIPhybペプチドを含有する一方向混合リンパ球反応(MLR)を行った。VIPの添加は、ルシフェラーゼT細胞の増殖を用量依存的に減少させる一方、VIPhybの添加は、T細胞の増殖を増加させた。VIPhybは、MLRにおけるVIPの抑制効果を反転させ、T細胞増殖を対照培養物よりも高いレベルに回復させた。
びまん性大細胞型B細胞リンパ腫(DLBCL)は、主に高齢患者集団に影響を及ぼす高悪性度のB細胞悪性腫瘍である。強い処置レジメンが利用可能であるにもかかわらず、DLBCL患者のサブセットには治療抵抗性が高いリンパ腫が存在する。これらの患者の疾患は、現在の処置レジメンの実質的に全てに対して抵抗性であるという事実から、CART療法は、効果的な救援の選択肢として非常に有望であるが、多くの患者は、エクスビボでのT細胞増殖の失敗のために臨床試験で処置を受けることができなかった。この失敗は、患者の年齢に加え、多数のラウンドの治療によって与えられるダメージに大きく起因する。さらに、データは、NHLを有する患者がナイーブT細胞に対するメモリー細胞の偏った比率を有し、細胞免疫療法が損なわれていることを示す。
イデラリシブは、PI3キナーゼの阻害剤である。PI3キナーゼは、リンパ球活性化および分化の重要なシグナル伝達経路であり、AKTおよびmTOR1活性を調節する。イデラリシブは、慢性リンパ球性白血病および低悪性度B細胞悪性腫瘍を有する患者の治療についてFDAの承認を受けている。イデラリシブで治療された患者は、薬物治療が停止した後に抗癌応答を継続し、結腸炎および発疹を含む自己免疫様の徴候および症状を発症することが認められており、これは、イデラリシブが免疫系を調節し、Th1分極したT細胞を活性化または保存するという仮説を導く。
Claims (7)
- T細胞の増殖のためのインビトロ細胞培養物組成物であって、前記組成物が、精製されたT細胞およびVIP受容体アンタゴニストならびにビーズまたは固体表面上に任意選択により固定化された抗CD3抗体および抗CD28抗体を含み、前記VIP受容体アンタゴニストが、KPRRPYTDNYTRLRKQMAVKKYLNSILN)(配列番号1)を含むことを特徴とするインビトロ細胞培養物組成物。
- 請求項1に記載の組成物において、前記T細胞の15%超は、CD28に対して陰性であることを特徴とする組成物。
- 請求項1又は2に記載のインビトロ細胞培養物を用いて、CD28に対して陰性であるT細胞を増殖させ、複製T細胞を提供することを特徴とする方法。
- 請求項3に記載の方法において、前記複製T細胞は、複製前のレベルと比較してCD28の増加した発現を有することを特徴とする方法。
- 請求項4に記載の方法において、前記T細胞を増殖させる前、その間、またはその後、前記T細胞は、キメラ抗原受容体をコードする核酸を有するベクターと混合され、前記キメラ抗原受容体は、前記細胞が前記細胞の表面上に前記キメラ抗原受容体を発現する条件下において、癌標的配列、膜貫通ドメイン、T細胞共刺激分子ドメイン、およびT細胞抗原受容体ドメインのシグナル伝達成分を含むことを特徴とする方法。
- 対象の癌または慢性感染症を治療するための医薬の製造における単離されたT細胞の使用であって、前記単離されたT細胞を、前記T細胞が複製して、複製前のレベルと比較してCD28の増加した発現を有する複製T細胞を提供するような条件下において、VIP受容体アンタゴニストと組み合わせて、ビーズまたは固体表面上に任意選択により固定化された抗CD3抗体および抗CD28抗体と混合し、前記VIP受容体アンタゴニストが、KPRRPYTDNYTRLRKQMAVKKYLNSILN)(配列番号1)を含むことを特徴とする使用。
- 請求項6に記載の使用において、前記複製T細胞は、前記細胞の表面上にキメラ抗原受容体を発現することを特徴とする使用。
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