JP2017520276A - T細胞認識を決定するための手段及び方法 - Google Patents
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Abstract
Description
- 少なくとも1つのB細胞において、BCL6の発現を誘導、増強及び/又は維持する工程、
- 前記少なくとも1つのB細胞において、抗アポトーシス核酸の発現を誘導、増強及び/又は維持する工程、
- 前記少なくとも1つのB細胞の、B細胞培養物への増殖を可能にする工程、
- 前記B細胞培養物のB細胞を、少なくとも1つの化合物と共にインキュベートする工程、
- 得られたB細胞を、T細胞と共にインキュベートする工程、及び
- 少なくとも1つのT細胞が、前記少なくとも1つの化合物の少なくとも1つのT細胞エピトープを認識するかどうかを決定する工程
を含む方法を提供する。
- 前記B細胞に、Bcl-6の発現を直接的又は間接的に増強することが可能な化合物を供給する工程、及び/又は
- Bcl-6の発現を直接的又は間接的に増強することが可能な化合物の存在下で、前記B細胞を培養する工程
により誘導、増強及び/又は維持される本発明による方法が更に提供される。
- 少なくとも1つのB細胞におけるSTAT5の発現を誘導、増強及び/又は維持する工程、
- 前記少なくとも1つのB細胞における抗アポトーシス核酸の発現を誘導、増強及び/又は維持する工程、
- B細胞培養物への前記少なくとも1つのB細胞の増殖を可能にする工程、
- 前記B細胞培養物のB細胞を、少なくとも1つの化合物と共にインキュベートする工程、
- 得られたB細胞を、T細胞と共にインキュベートする工程、及び
- 少なくとも1つのT細胞が、前記少なくとも1つの化合物の少なくとも1つのT細胞エピトープを認識するかどうかを決定する工程
を含む、本発明による方法が提供される。また、前記少なくとも1つのB細胞におけるBcl-6の発現が、前記B細胞に、STAT5を、又はそのホモログを、又はその機能性部分若しくは機能性誘導体を供給することにより誘導、増強及び/又は維持される本発明による方法が提供される。或いは、又は更に、前記少なくとも1つのB細胞におけるBcl-6の発現は、前記B細胞に、STAT5、又はそのホモログ、又はその機能性部分若しくは機能性誘導体をコードする核酸分子を供給することにより、或いはSTAT5の存在下で、又はそのホモログ、又はその機能性部分若しくは機能性誘導体の存在下で、前記B細胞を培養することにより誘導、増強及び/又は維持される。
- 前記B細胞に、Bcl-xL及び/又はMcl-1及び/又はBcl-2及び/又はA1及び/又はBcl-w及び/又はBcl2L10、或いはそれらのホモログの発現を直接的又は間接的に増強することが可能な化合物を供給する工程、及び/又は
- Bcl-xL及び/又はMcl-1及び/又はBcl-2及び/又はA1及び/又はBcl-w及び/又はBcl2L10、或いはそれらのホモログの発現を直接的又は間接的に増強することが可能な化合物の存在下で、前記B細胞を培養する工程
を含む本発明による方法が更に提供される。
- 前記B細胞に、Blimp-1の発現、又はBlimp-1ホモログの発現を直接的又は間接的に増加させることが可能な化合物を供給する工程、及び/又は
- Blimp-1の発現、又はBlimp-1ホモログの発現を直接的又は間接的に増加させることが可能な化合物の存在下で、前記B細胞を培養する工程
を更に含む、本発明による方法が更に提供される。
- STAT3又はその機能性部分若しくは機能性誘導体、及び/又は
- STAT3を活性化することが可能な化合物、及び/又は
- STAT3の発現を増強することが可能な化合物、及び/又は
- IL21、IL2、IL6、IL7、IL10、IL15、IL27、SOCSタンパク質、E-タンパク質E47、E12、E2-2又はHEBのうちの1つ、突然変異ヤヌスキナーゼ及び/又はSTAT3、或いはそのホモログ又は機能性部分若しくは機能性誘導体をコードする核酸配列
を含む。
- がん、好ましくは黒色腫又は上皮がん、及び
- 感染性疾患、好ましくはウイルス感染、細菌感染又は寄生虫感染、及び
- 自己免疫疾患、好ましくは多発性硬化症、糖尿病又はセリアック病
からなる群から選択される。
突然変異抗原に対する腫瘍内CD4+T細胞反応性は、ヒト黒色腫で一般的に観察される
方法
TIL材料、腫瘍細胞株及びBcl-6/Bcl-xL形質導入B細胞の生成。PBMC及びTIL材料は、署名されたインフォームドコンセントを受けて、且つNKI-AVLでの医療倫理委員会(Medisch Ethische Toetsingscommissie)の承認後に適用可能である場合に、オランダのガイドラインに従って、ステージIVの黒色腫を有する個体から入手した。
NKI3.1
5'AGATCGGAAGAGCACACGTCTGAACTCCAGTCACNNNNNNATCTCGTATGC CGTCTTCTGCTTG/3'ddC/3'
NKI3.2
5'CAAGCAGAAGACGGCATACGAGATNNNNNNGTGACTGGAGTTCAGACGTGT GCTCTTCCGATCT/3'ddC/3'
P5プライマー:5'AATGATACGGCGACCACCGAGATCT3'、
P7プライマー:5'CAAGCAGAAGACGGCATACGAG3'。
ヒトのがんにおける突然変異の結果として生じる腫瘍特異的ネオ抗原1、2は、臨床上使用されるがん免疫療法の有効性にとって重要であると考えられる3〜5。腫瘍特異的CD4+T細胞応答は公知であり、増えてきた証拠により、ネオ抗原は、腫瘍内CD8+T細胞によりに一般的に認識され得ることが示唆される3、4、6一方で、ネオ抗原特異的CD4+T細胞が、ヒト腫瘍内に一般的に存在するかどうかは未知である。ここで、本発明者等は、不死化Bcl-6/Bcl-xL形質導入B細胞を使用して、腫瘍エクソームシーケンシングにより同定される推定ネオエピトープに対するCD4+T細胞応答の発生を測定する。このアプローチを使用して、本発明者等は、養子T細胞療法後の臨床応答を実証する黒色腫患者を含む、分析した5人の黒色腫患者のうち4人で、ネオ抗原反応性CD4+T細胞の存在を示す。
ネオ抗原特異的CD4+T細胞反応性が、がんエクソームデータに基づいて容易に検出できること(図3)、及び高頻度のネオ抗原特異的CD4+T細胞を含有するT細胞産物が、胆管細胞癌の部分的退縮を媒介することが近年示されたこと10の観察に基づいて、本発明者等は、ネオ抗原反応性CD4+T細胞区画がまた、養子T細胞療法時に臨床応答を受ける黒色腫患者に普及しているかどうかを分析した。
次に、本発明者等は、自己腫瘍細胞による末梢血単核球(PBMC)の刺激により得られるin vitroで増殖させた自己腫瘍特異的T細胞の多重注入を受容したステージIVの黒色腫患者(BO)におけるネオ抗原特異的CD4+T細胞反応性を分析した(ref 19)。治療後に、この患者は、完全な腫瘍寛解を受け、7年間今も継続している。更に、T細胞産物内に存在するCD4+T細胞は、自己黒色腫株の強力な認識を示した(図10c)。Bcl-6/Bcl-xL不死化B細胞は、この対象にはまだ利用可能でなかったため、より大きなバックグラウンドノイズにもかかわらず、自己EBV不死化B細胞を使用しなくてはならなかった。EBV不死化B細胞を、この患者で検出される発現遺伝子内の501個の非同義的突然変異を包含する31量体ペプチドで負荷した。EBV形質転換APCの使用に起因したより高いバックグラウンドノイズにもかかわらず、このスクリーンは、リボソームタンパク質S12の突然変異体バージョン(RPS12 V104I)に向けられた1つの顕著なCD4+T細胞応答(注入産物内の総CD4+T細胞の24%;即ち、26.0%-対照頻度1.98%)を同定した(図10c)。
前記データは、WO 2007/067046に従う方法で不死化されるB細胞が、T細胞エピトープのT細胞認識を試験するための好ましいAPCであることを示す。
ヒト黒色腫病巣におけるネオエピトープ特異的CD8+T細胞の検出
この実施例は、ネオエピトープ特異的CD4+T細胞応答の同定に関してこれまでの実施例で記載されるような、APCとしてのBcl-6/Bcl-xL不死化B細胞の使用がまた、ネオエピトープ特異的CD8+T細胞応答を同定するのにも適していることを示す。
Claims (35)
- T細胞がT細胞エピトープを認識するかどうかを決定する方法であって、
- 少なくとも1つのB細胞において、Bcl-6及び/又はSTAT5の発現を誘導、増強及び/又は維持する工程、
- 前記少なくとも1つのB細胞において、抗アポトーシス核酸の発現を誘導、増強及び/又は維持する工程、
- 前記少なくとも1つのB細胞の、B細胞培養物への増殖を可能にする工程、
- 前記B細胞培養物のB細胞を、少なくとも1つの化合物と共にインキュベートする工程、
- 得られたB細胞を、T細胞と共にインキュベートする工程、及び
- 少なくとも1つのT細胞が、前記少なくとも1つの化合物の少なくとも1つのT細胞エピトープを認識するかどうかを決定する工程
を含む方法。 - 前記B細胞を、少なくとも1つのペプチドと共にインキュベートする工程を含む、請求項1に記載の方法。
- 前記少なくとも1つのペプチドが、5から40の間のアミノ酸、好ましくは8から35の間のアミノ酸又は9から31の間のアミノ酸の長さを有する、請求項1又は2に記載の方法。
- 前記B細胞が、少なくとも2つ、好ましくは少なくとも5つ、好ましくは少なくとも10の異なるペプチドと共にインキュベートされる、請求項1から3のいずれか一項に記載の方法。
- 前記T細胞が、CD8+細胞障害性T細胞及び/又はCD4+ヘルパーT細胞を含む、請求項1から4のいずれか一項に記載の方法。
- 前記少なくとも1つのB細胞及び前記T細胞が、同じヒト個体由来である、請求項1から5のいずれか一項に記載の方法。
- 前記T細胞エピトープが、修飾自己抗原由来、又は非自己抗原由来、又は自己抗原由来である、請求項1から6のいずれか一項に記載の方法。
- 前記T細胞エピトープが、腫瘍特異的T細胞エピトープである、請求項1から7のいずれか一項に記載の方法。
- 前記腫瘍が、黒色腫又は上皮がんである、請求項8に記載の方法。
- 前記T細胞エピトープが、病原体由来である、請求項1から7のいずれか一項に記載の方法。
- 前記病原体が、ウイルス、細菌又は寄生虫である、請求項10に記載の方法。
- 前記T細胞エピトープが、自己抗原由来である、請求項1から7のいずれか一項に記載の方法。
- 少なくとも1つのT細胞が前記T細胞エピトープの少なくとも1つを認識したかどうかが、前記少なくとも1つのT細胞が活性化されるかどうかを決定することにより決定される、請求項1から12のいずれか一項に記載の方法。
- 前記T細胞活性化が、サイトカイン放出を測定することにより決定される、請求項13に記載の方法。
- 前記化合物の少なくとも1つのT細胞エピトープを認識するT細胞を含む医薬を調製する工程を更に含む、請求項1から14のいずれか一項に記載の方法。
- T細胞により認識される少なくとも1つのT細胞エピトープを同定する工程を更に含む、請求項1から15のいずれか一項に記載の方法。
- 前記少なくとも1つのT細胞エピトープを含む、免疫原性組成物、又は予防剤若しくはワクチンを調製する工程を更に含む、請求項16に記載の方法。
- 表面上に前記少なくとも1つのT細胞エピトープを表示する抗原提示細胞、好ましくはB細胞を含む、免疫原性組成物、又は予防剤若しくはワクチンを調製する工程を更に含む、請求項16に記載の方法。
- 前記B細胞が、障害に罹患しているか又は罹患していた個体由来のT細胞と共にインキュベートされる、請求項1から18のいずれか一項に記載の方法。
- 前記個体が、がん、好ましくは黒色腫又は上皮がんに罹患しているか又は罹患していた、請求項19に記載の方法。
- 前記個体が、病原体、好ましくはウイルス、細菌又は寄生虫に罹患しているか又は罹患していた、請求項19に記載の方法。
- 前記個体が、自己免疫疾患、好ましくは多発性硬化症、糖尿病又はセリアック病に罹患しているか又は罹患していた、請求項19に記載の方法。
- 前記T細胞が、前記個体由来の試料由来であり、前記試料において、又は前記試料のin vitroの増殖後のT細胞培養物において、T細胞の総量に対する、前記疾患と関連付けられるT細胞エピトープに特異的なT細胞の比率が、24%よりも低く、より好ましくは23%よりも低く、より好ましくは20%よりも低く、より好ましくは15%よりも低く、より好ましくは10%よりも低く、より好ましくは9%よりも低く、より好ましくは8%よりも低く、より好ましくは7%よりも低く、より好ましくは6%よりも低く、より好ましくは5%よりも低いことを特徴とする、請求項1から22のいずれか一項に記載の方法。
- 前記T細胞が、前記個体由来の試料由来であり、前記試料において、又は前記試料のin vitroの増殖後のT細胞培養物において、T細胞の総量に対する、目的の障害と関連付けられるT細胞エピトープに特異的なT細胞の比率が、1.9%よりも低く、より好ましくは1.8%よりも低く、より好ましくは1.7%よりも低く、より好ましくは1.6%よりも低く、より好ましくは1.5%よりも低いことを特徴とする、請求項1から23のいずれか一項に記載の方法。
- 前記T細胞が、前記個体由来の試料由来であり、前記試料において、又は前記試料のin vitroの増殖後のT細胞培養物において、T細胞の総量に対する、目的の障害と関連付けられるT細胞エピトープに特異的なT細胞の比率が、1.0%よりも低く、より好ましくは0.9%よりも低く、より好ましくは0.8%よりも低く、より好ましくは0.7%よりも低く、より好ましくは0.6%よりも低く、より好ましくは0.5%よりも低く、より好ましくは0.4%よりも低く、より好ましくは0.3%よりも低いことを特徴とする、請求項1から24のいずれか一項に記載の方法。
- 前記個体由来の試料が使用されるか、又は前記試料のin vitroの増殖後に得られたT細胞培養物のT細胞が使用され、前記試料において、又は前記得られたin vitroのT細胞培養物において、T細胞の総数に対する、前記疾患と関連付けられるT細胞エピトープに特異的なT細胞の割合が、24%よりも低く、より好ましくは23%よりも低く、より好ましくは20%よりも低く、より好ましくは15%よりも低く、より好ましくは10%よりも低く、より好ましくは9%よりも低く、より好ましくは8%よりも低く、より好ましくは7%よりも低く、より好ましくは6%よりも低く、より好ましくは5%よりも低い、請求項1から25のいずれか一項に記載の方法。
- 前記個体由来の試料が使用されるか、又は前記試料のin vitroの増殖後に得られたT細胞培養物のT細胞が使用され、前記試料において、又は前記得られたin vitroのT細胞培養物において、T細胞の総数に対する、目的の障害と関連付けられるT細胞エピトープに特異的なT細胞の割合が、1.9%よりも低く、より好ましくは1.8%よりも低く、より好ましくは1.7%よりも低く、より好ましくは1.6%よりも低く、より好ましくは1.5%よりも低い、請求項1から26のいずれか一項に記載の方法。
- 前記個体由来の試料が使用されるか、又は前記試料のin vitroの増殖後に得られたT細胞培養物のT細胞が使用され、前記試料において、又は前記得られたin vitroのT細胞培養物において、T細胞の総数に対する、目的の障害と関連付けられるT細胞エピトープに特異的なT細胞の割合が、1.0%よりも低く、より好ましくは0.9%よりも低く、より好ましくは0.8%よりも低く、より好ましくは0.7%よりも低く、より好ましくは0.6%よりも低く、より好ましくは0.5%よりも低く、より好ましくは0.4%よりも低く、より好ましくは0.3%よりも低い、請求項1から27のいずれか一項に記載の方法。
- 前記疾患又は前記障害が、がん、好ましくは黒色腫又は上皮がん、感染性疾患、好ましくはウイルス感染、細菌感染又は寄生虫感染、及び自己免疫疾患、好ましくは多発性硬化症、糖尿病又はセリアック病からなる群から選択される、請求項23から28のいずれか一項に記載の方法。
- 前記抗アポトーシス核酸が、好ましくはBCL2ファミリーの抗アポトーシス分子、好ましくは、Bcl-xL、Mcl-1、Bcl-2、A1、Bcl-w、Bcl2L10、又はそれらの機能性部分若しくはホモログ、最も好ましくはBcl-xL又はMcl 1をコードする遺伝子を含む、請求項1から29のいずれか一項に記載の方法。
- 請求項1から30のいずれか一項に記載の方法を用いて得られる場合の、障害関連T細胞エピトープ、好ましくは腫瘍特異的T細胞エピトープ又は病原体由来のT細胞エピトープ又は自己抗原由来のT細胞エピトープを認識するT細胞を含む医薬。
- 請求項1から30のいずれか一項に記載の方法を用いて得られる場合の、障害関連T細胞エピトープ、好ましくは腫瘍特異的T細胞エピトープ又は病原体由来のT細胞エピトープ又は自己抗原由来のT細胞エピトープを含む、免疫原性組成物、又は予防剤若しくはワクチン。
- 目的のエピトープを提示するためのB細胞の使用であって、前記B細胞のin vitroでの複製寿命が、前記B細胞において、Bcl-6及び/又はSTAT5の発現を誘導、増強及び/又は維持することにより、並びに前記B細胞において、抗アポトーシス核酸の発現を誘導、増強及び/又は維持することにより延長されることを特徴とする使用。
- 前記エピトープが、T細胞エピトープである、請求項33に記載の使用。
- 前記T細胞が、CD4+T細胞又はCD8+T細胞である、請求項1から34のいずれか一項に記載の方法又は使用。
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