JP2021521828A - ヒドロキシクエン酸および/またはその塩を使用してt細胞集団を産生する方法 - Google Patents
ヒドロキシクエン酸および/またはその塩を使用してt細胞集団を産生する方法 Download PDFInfo
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Abstract
【選択図】なし
Description
本特許出願は、2018年4月24日に出願された同時係属中の米国仮特許出願番号第62/661,941号(参照によりその全体が本明細書に取り込まれる)についての利益を主張する。
本発明は、国立衛生研究所、国立がん研究所によりプロジェクト番号Z01ZIA BC010763-07の下での政府の支援を受けてなされた。政府は、本発明に一定の権利を有する。
本明細書と同時に提出され、以下のように識別される、コンピュータで読み取り可能なヌクレオチド/アミノ酸の配列表は、参照により、その全体が本明細書に取り込まれる:2019年4月22日付け作成の「742111_ST25.txt」という名前の1つの739バイトのASCII(テキスト)ファイルである。
がん反応性T細胞を使用する養子細胞療法(adoptive cell therapy (ACT))は、一部のがん患者において利益を伴う臨床反応を生み出す可能性がある。しかし、がんおよび他の状態の治療のためのACTの使用の成功にはいくつかの障害も残っている。たとえば、インビボ(in vivo)におけるT細胞の持続性、生存、および抗腫瘍活性の1以上が、養子移入後に減少する場合がある。代替的または追加的に、場合によっては、T細胞のアポトーシスの増加は、がんおよび他の状態の治療に障害をもたらす可能性があり得る。したがって、ACTのための単離細胞集団を得るより良い方法が求められている。
本発明の一実施形態では、単離T細胞集団を産生する方法であって、ヒドロキシクエン酸および/またはその塩の存在下で、単離T細胞をインビトロ(in vitro)で培養することを含み、前記塩はヒドロキシクエン酸カリウムまたはヒドロキシクエン酸ナトリウムである、方法を提供する。
(研究の承認)
(T細胞のインビトロ活性化)
(マウスおよび細胞株)
細胞内サイトカイン染色、ホスホフローサイトメトリーおよびフローサイトメトリー
(養子細胞移入(ACT)と腫瘍免疫療法)
(実験的転移)
(レトロウイルス形質導入)
(AcCoAとクエン酸塩の定量化)
(ChIP-seq および ChIP-PCR)
(ChIP-Seqおよびピークコール分析(peak calling analysis))
(統計分析)
本実施例は、ヒドロキシクエン酸カリウムの曝露により、T細胞に、クエン酸塩の蓄積および細胞質AcCoAの欠乏が生じることを実証する。
本実施例は、ヒドロキシクエン酸カリウム処理によって、T細胞においてIFN-γプロモーターでの活性化ヒストンマーク(activating histone marks)が減少することを実証する。
本実施例は、T細胞をヒドロキシクエン酸カリウムで処理すると、オートファジーが増強することを実証する。
本実施例は、T細胞をヒドロキシクエン酸カリウムで処理すると、エフェクター分化が遮断されてアポトーシスが減少することを実証する。
本実施例は、T細胞をヒドロキシクエン酸カリウム処理することにより、TMemマーカーの獲得を元に戻すことを実証する。
本実施例は、T細胞をヒドロキシクエン酸カリウムで処理することにより、養子移入後のインビボ持続性が増強し、抗腫瘍効果が改善することを実証する。
本実施例は、T細胞をヒドロキシクエン酸カリウムで処理することにより、B16黒色腫モデルにおける抗腫瘍効果が改善するが、クエン酸塩ではしないことを実証する。
本実施例は、ヒドロキシクエン酸カリウム処理がヒト腫瘍浸潤リンパ球(tumor infiltrating lymphocytes)の多機能性を改善することを実証する。
本実施例は、T細胞をヒドロキシクエン酸カリウムで処理すると、CD62Lの発現が増加することを実証する。
Claims (20)
- 単離T細胞集団を産生する方法であって、ヒドロキシクエン酸および/またはその塩の存在下で、単離T細胞をインビトロで培養することを含み、前記塩はヒドロキシクエン酸カリウムまたはヒドロキシクエン酸ナトリウムである、
方法。 - 前記方法が、約1.0mMから約10.0mMのヒドロキシクエン酸ヒドロキシクエン酸および/またはその塩の存在下でT細胞を培養することを含む、請求項1に記載の方法。
- 前記塩がヒドロキシクエン酸カリウムである、請求項1または2に記載の方法。
- 前記T細胞ががん抗原に対して抗原特異性を有する、請求項1〜3のいずれか一項に記載の方法。
- 細胞が外因性TCRを発現する条件下で、外因性TCRをコードする核酸を細胞に導入することをさらに含む、請求項1〜4のいずれか一項に記載の方法。
- 細胞がキメラ抗原受容体(CAR)を発現する条件下で、CARをコードする核酸を細胞に導入することをさらに含む、請求項1〜4のいずれか一項に記載の方法。
- 前記方法が、約2.0mMから約6.0mMのヒドロキシクエン酸および/またはその塩の存在下でT細胞を培養することを含む、請求項1〜6のいずれか一項に記載の方法。
- 前記方法が、ヒドロキシクエン酸および/またはその塩の存在下でT細胞を非特異的に刺激することを含む、請求項1〜7のいずれか一項に記載の方法。
- 前記方法が、ヒドロキシクエン酸および/またはその塩の存在下でT細胞を特異的に刺激することを含む、請求項1〜7のいずれか一項に記載の方法。
- 前記方法が、(i)ヒドロキシクエン酸および/またはその塩、ならびに(ii)一方または両方の(a)1以上のサイトカインおよび(b)1以上の非特異的T細胞刺激の存在下で、細胞数を増加させることを含む、請求項1〜9のいずれか一項に記載の方法。
- ヒドロキシクエン酸および/またはその塩の存在下で細胞を培養すると、対照細胞に比べて、T細胞によるCD62L、インターロイキン(IL)-2、および腫瘍壊死因子(TNF)の1以上の発現が増加し、対照細胞をヒドロキシクエン酸および/またはその塩の存在下で培養しないことを除いて、対照細胞がヒドロキシクエン酸および/またはその塩の存在下で培養した細胞と同一である、請求項1〜10のいずれか一項に記載の方法。
- ヒドロキシクエン酸および/またはその塩の存在下で培養した細胞を哺乳動物に投与することが、対照細胞を投与することに比べて、より大きな持続性およびより大きな抗腫瘍活性の一方または両方を提供し、対照細胞をヒドロキシクエン酸および/またはその塩の存在下で培養しないことを除いて、対照細胞がヒドロキシクエン酸および/またはその塩の存在下で培養した細胞と同一である、請求項1〜11のいずれか一項に記載の方法。
- ヒドロキシクエン酸および/またはその塩の存在下で培養した細胞を哺乳動物に投与することが、対照細胞を投与することに比べて、アポトーシスが減少することを提供し、対照細胞をヒドロキシクエン酸および/またはその塩の存在下で培養しないことを除いて、対照細胞がヒドロキシクエン酸および/またはその塩の存在下で培養した細胞と同一である、請求項1〜12のいずれか一項に記載の方法。
- 前記T細胞ががん新生抗原に対して抗原特異性を有し、ならびに前記方法が、
がん新生抗原に対して抗原特異性を有するT細胞について、哺乳動物から得られた細胞をスクリーニングすること、および
哺乳動物から得られた細胞から、がん新生抗原に対して抗原特異性を有するT細胞を単離すること、
により単離T細胞を取得することをさらに含む、
請求項1〜13のいずれか一項に記載の方法。 - 請求項1〜14のいずれか一項に記載の方法によって産生した単離T細胞集団。
- 請求項15に記載の単離T細胞集団および薬学的に許容される担体を含む医薬組成物。
- 哺乳動物のがんの治療または予防における使用のための、請求項1〜14のいずれか一項に記載の方法に従って産生した細胞、または請求項15に記載の単離細胞集団、または請求項16に記載の医薬組成物。
- 前記使用が哺乳動物における転移を減少させる、請求項17に記載の使用のための細胞または単離細胞集団。
- 前記細胞または単離細胞集団が哺乳動物に対して自家である、請求項17に記載の使用のための細胞または単離細胞集団。
- 前記細胞または単離細胞集団が、哺乳動物に対して同種異系である、請求項17に記載の使用のための細胞または単離細胞集団。
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CA3097858A1 (en) | 2019-10-31 |
EP3784774A1 (en) | 2021-03-03 |
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AU2019260656A1 (en) | 2020-12-10 |
AU2019260656A2 (en) | 2020-12-17 |
CN112262212A (zh) | 2021-01-22 |
JP7342030B2 (ja) | 2023-09-11 |
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