JP2018523996A - 改善または増大した抗腫瘍免疫応答を誘導する最適に活性化された樹状細胞 - Google Patents
改善または増大した抗腫瘍免疫応答を誘導する最適に活性化された樹状細胞 Download PDFInfo
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Abstract
Description
抗原提示細胞(APC)は、有効な免疫応答を誘起するにあたって重要である。それらは、抗原を抗原特異的T細胞レセプターとともにT細胞に提示するのみならず、T細胞活性化に必要なシグナルをも提供する。APCが抗原を提示しかつT細胞活性化のシグナルを送達する能力は、一般にアクセサリ細胞機能といわれる。単球およびB細胞は、免疫応答を起こし得るAPCであることが示されたが、それらのインビトロでの抗原提示能力は、以前に感作されたT細胞の再活性化に限定されるようである。従って、単球およびB細胞は、機能的にナイーブなまたは非感作T細胞集団を直接活性化することはできない。それらはまた、誘導された免疫応答、または誘導される場合の免疫応答を極性化し得るシグナルを送達できない。
本開示は、単離され、活性化されたヒト樹状細胞を生成するための方法を提供し、上記方法は、i)ヒトPBMCを含む細胞集団を末梢血から単離する工程;ii)ヒトPBMCを含む上記細胞集団を、ヒト単球性樹状細胞前駆体に関して富化する工程;iii)ヒト単球性樹状細胞前駆体に関して富化された上記細胞集団を、有効量の樹状細胞分化薬剤を補充した組織培養培地とともに、上記ヒト単球性樹状細胞前駆体を未成熟ヒト樹状細胞へと分化させるために十分な期間にわたって培養する工程;iv)未成熟ヒト樹状細胞に関して富化された上記細胞集団を、有効量の樹状細胞成熟化薬剤とともに培養して、上記未成熟ヒト樹状細胞を約10〜約19時間にわたって活性化する工程;ならびにv)上記活性化されたヒト樹状細胞を単離および洗浄する工程を包含する。
本明細書で記載される方法および組成物の前述の局面および付随する利点のうちの多くは、以下の詳細な説明を添付の図面とともに参照することによって、よりよく理解されるようになるにつれてより容易に認識される。
樹状細胞は、種々のリンパ性組織および非リンパ性組織で見出される抗原提示細胞の多様な集団である(Liu, Cell 106:259−262 (2001); Steinman, Ann. Rev. Immunol. 9:271−296 (1991)を参照のこと)。樹状細胞としては、脾臓のリンパ性樹状細胞、表皮のランゲルハンス細胞、および血液循環中のベール細胞が挙げられる。まとめると、樹状細胞は、それらの形態、高レベルの表面MHCクラスII発現、ならびにT細胞、B細胞、単球、およびナチュラルキラー細胞上で発現されるある特定の他の表面マーカーの非存在に基づく群として分類される。特に、単球由来樹状細胞(単球性樹状細胞ともいわれる)は、通常、CD11c、CD80、CD86を発現し、HLA−DR+であるが、CD14−である。
樹状細胞前駆体(例えば、活性化されていない樹状細胞前駆体、および種々の供給源(血液および骨髄が挙げられる)に由来する未成熟樹状細胞)に関して富化された細胞集団を単離するための方法は、当該分野で公知である。例えば、樹状細胞前駆体および未成熟樹状細胞は、ヘパリン添加血液を集めることによって、アフェレーシスもしくは白血球アフェレーシス(leukapheresis)によって、バフィーコートの調製、ロゼット形成、遠心分離、密度勾配遠心分離(例えば、Ficoll(登録商標)(例えば、FICOLL−PAQUE(登録商標)、PERCOLL(登録商標)(透析不能ポリビニルピロリドン(PVP)で被覆されたコロイド性シリカ粒子(15〜30nm直径))、スクロースなどを使用)、細胞の差次的溶解、濾過などによって、単離され得る。ある特定の実施形態において、白血球集団は、例えば、被験体から血液を集め、線維素除去して、血小板を除去し、赤血球を溶解することによって、調製され得る。樹状細胞前駆体および未成熟樹状細胞は、必要に応じて、例えば、PERCOLL(登録商標)勾配を介する遠心分離、抗体パニングなどによって、単球性樹状細胞前駆体に関して富化され得る。用語「富化される」とは、本明細書で使用される場合、その細胞集団中の単球性樹状細胞前駆体、未成熟樹状細胞、または部分的に成熟した樹状細胞が、その集団中の細胞の総数のうちの少なくとも25%、少なくとも30%、少なくとも50%、少なくとも60%、少なくとも70%、少なくとも80%または少なくともその細胞集団中の細胞の総数のうちの90%すらを構成することを意味する。代表的には、上記富化された細胞は、その集団中の細胞の総数のうちの少なくとも約50%を構成する。ある特定の実施形態において、その富化された細胞は、細胞集団中の細胞の総数のうちの少なくとも約90%および約100%までを構成する。
部分的に成熟し、かつ最適に活性化された樹状細胞、またはこのような細胞を富化して含む細胞集団を、例えば、がんまたは腫瘍を有する被験体に投与するための方法および組成物が、提供される。ある特定の実施形態において、このような方法は、樹状細胞前駆体または未成熟樹状細胞を得、樹状細胞成熟化薬剤(例えば、BCGおよびIFNγ)または任意の他の樹状細胞成熟化薬剤(例えば、上記で列挙されるもの)の存在下でそれら細胞を分化および部分的に成熟させることによって行われる。その部分的に成熟し、かつ最適に活性化された樹状細胞は、生理学的に受容可能なキャリア、賦形剤、緩衝液および/または希釈剤とともに、当業者に周知の方法および組成物を使用して製剤化され得る。その部分的に成熟し、かつ最適に活性化された樹状細胞は、免疫刺激の必要性のある被験体へと直接投与され得る。代表的には、約102〜約1010 細胞が、薬学的に受容可能なキャリア中に懸濁される。その細胞は、腫瘍へと直接、あるいは、腫瘍もしくは腫瘍床の近くの領域、腫瘍もしくは腫瘍床と隣接する領域、または腫瘍もしくは腫瘍床との循環性もしくはリンパ性の接触にある領域へのいずれかに注射され、その細胞ががんもしくは腫瘍抗原へのアクセスを有することが担保される。
排他的所有権もしくは権利が特許請求される本発明の実施形態は、以下のとおり規定される:
Claims (20)
- 単離され、部分的に成熟し、かつ最適に活性化されたヒト樹状細胞を生成するための方法であって、該方法は、
i)ヒトPBMCを含む細胞集団を末梢血から単離する工程;
ii)ヒトPBMCを含む該細胞集団を、ヒト単球性樹状細胞前駆体に関して富化する工程;
iii)ヒト単球性樹状細胞前駆体に関して富化された該細胞集団を、有効量の樹状細胞分化薬剤を補充した組織培養培地とともに、該ヒト単球性樹状細胞前駆体を未成熟ヒト樹状細胞へと分化させるために十分な期間にわたって培養する工程;
iv)未成熟ヒト樹状細胞に関して富化された該細胞集団を、有効量の樹状細胞成熟化薬剤とともに培養して、該未成熟ヒト樹状細胞を約10〜約19時間にわたって活性化する工程;ならびに
v)該活性化されたヒト樹状細胞を単離および洗浄する工程、
を包含する方法。 - 単離され、部分的に成熟し、かつ活性化されたヒト樹状細胞を生成するための方法であって、該方法は、
i)ヒト単球性樹状細胞前駆体を含む細胞集団を単離する工程;
ii)ヒト単球性樹状細胞前駆体に関して富化された該細胞集団を、有効量の樹状細胞分化薬剤を補充した組織培養培地とともに、該ヒト単球性樹状細胞前駆体を未成熟ヒト樹状細胞へと分化させるために十分な期間にわたって培養する工程;
iii)未成熟ヒト樹状細胞に関して富化された該細胞集団を、有効量の樹状細胞成熟化薬剤とともに培養して、該未成熟ヒト樹状細胞を約10〜約19時間にわたって活性化する工程;ならびに
iv)該活性化されたヒト樹状細胞を単離および洗浄する工程、
を包含する方法。 - 前記単球性樹状細胞前駆体は、皮膚、脾臓、骨髄、胸腺、リンパ節、臍帯血、または末梢血から得られる、請求項2に記載の方法。
- 前記単球性樹状細胞前駆体細胞は、活性化されていない単球性樹状細胞前駆体である、請求項1〜3のいずれか1項に記載の方法。
- 前記単球性樹状細胞前駆体は、処置される個々の被験体から得られる、請求項1〜4のいずれか1項に記載の方法。
- 前記単球性樹状細胞前駆体は、前記処置される個々の被験体にHLAマッチした健康な個々の被験体から得られる、請求項1〜4のいずれか1項に記載の方法。
- 前記樹状細胞分化薬剤は、いかなる他のサイトカインもなしのGM−CSF、またはIL−4、IL−7、IL−13もしくはIL−15との組み合わせでのGM−CSFである、請求項1および2のいずれか1項に記載の方法。
- 前記樹状細胞成熟化薬剤は、不活性化カルメットゲラン桿菌(BCG)、インターフェロンγ(IFNγ)、リポポリサッカリド(LPS)、腫瘍壊死因子α(TNFα)、イミダゾキノリン化合物、合成2本鎖ポリリボヌクレオチド、Toll様レセプター(TLR)のアゴニスト、樹状細胞の成熟化を誘導することが公知の非メチル化CpGモチーフを含む核酸の配列、またはこれらの任意の組み合わせである、請求項1および2のいずれか1項に記載の方法。
- 前記不活性化BCGは、全BCG、BCGの細胞壁構成要素、BCG由来リポアラビノマンナン、またはBCG成分を含む、請求項8に記載の方法。
- 前記不活性化BCGは、熱不活性化BCG、ホルマリン処理BCG、または熱不活性化かつホルマリン処理BCGである、請求項9に記載の方法。
- 前記有効量のBCGは、約105〜107cfu/ミリリットル 組織培養培地であり、前記有効量のIFNγは、約100〜約1,000ユニット/ミリリットル 組織培養培地である、請求項8〜10のいずれか1項に記載の方法。
- 前記イミダゾキノリン化合物は、イミダゾキノリン−4−アミン化合物である、請求項8に記載の方法。
- 前記イミダゾキノリン−4−アミン化合物は、4−アミノ−2−エトキシメチル−α,α−ジメチル−1H−イミダゾール[4,5−c]キノリン−l−5 エタノールまたは1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−4−アミン、またはこれらの誘導体である、請求項12に記載の方法。
- 前記合成2本鎖ポリリボヌクレオチドは、ポリ[I]:ポリ[C(12)U]である、請求項8に記載の方法。
- 前記部分的に成熟し、かつ最適に活性化された樹状細胞は、腫瘍へと直接、該腫瘍の外科的除去または切除の後に腫瘍床へと、該腫瘍を取り囲む組織領域に、腫瘍領域から直接排出するリンパ節へと、該腫瘍もしくは腫瘍罹患器官へと血液もしくはリンパを送達する循環性脈管に直接、または該腫瘍もしくは腫瘍罹患器官に該細胞が送達されるように循環系へと投与される、請求項1〜14のいずれか1項に記載の方法。
- 前記部分的に成熟し、かつ最適に活性化された樹状細胞は、放射線療法、化学療法、もしくはこれらの組み合わせに対する補助的手段として投与される、請求項1〜15のいずれか1項に記載の方法。
- 前記活性化された樹状細胞は、放射線療法、化学療法、もしくはこれらの組み合わせの前に、同時に、または後に投与される、請求項1〜15のいずれか1項に記載の方法。
- 抗腫瘍免疫応答を生成するための方法であって、該方法は、ヒト樹状細胞成熟化薬剤とともに約10〜約19時間にわたってインビトロで部分的に成熟させかつ最適に活性化させたヒト樹状細胞に関して富化した細胞集団および薬学的に受容可能なキャリアを含む組成物を投与する工程を包含し;ここで該組成物は、このような処置の必要性のある個体において、腫瘍、腫瘍床もしくは腫瘍を取り囲む組織領域へと投与される、方法。
- 未成熟樹状細胞をヒト樹状細胞成熟化薬剤とともに約10〜約19時間にわたって培養することによって成熟を誘導された、部分的に成熟し、かつ最適に活性化されたヒト樹状細胞を含む組成物であって、ここで該部分的に成熟し、かつ最適に活性化された樹状細胞は、炎症応答と関連するサイトカインを生成する、組成物。
- 前記サイトカインは、腫瘍壊死因子α(TNFα)、インターロイキン6(IL−6)、および/またはインターロイキン8(IL−8)である、請求項19に記載の組成物。
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WO2014149871A1 (en) * | 2013-03-14 | 2014-09-25 | Icahn School Of Medicine At Mount Sinai | Autologous tumor lysate-loaded dendritic cell vaccine for treatment of liver cancer |
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US11124768B2 (en) | 2021-09-21 |
AR106496A1 (es) | 2018-01-24 |
KR20180022949A (ko) | 2018-03-06 |
WO2017004230A1 (en) | 2017-01-05 |
AU2016286112B2 (en) | 2023-02-16 |
CN107849537A (zh) | 2018-03-27 |
JP6985939B2 (ja) | 2021-12-22 |
BR112017028602A2 (pt) | 2018-09-04 |
MX2018000056A (es) | 2018-05-28 |
PL424035A1 (pl) | 2019-01-02 |
EP3317403A4 (en) | 2019-07-03 |
AU2016286112A1 (en) | 2018-02-15 |
RU2018103235A (ru) | 2019-07-31 |
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MX2023001622A (es) | 2023-03-09 |
HK1255084A1 (zh) | 2019-08-02 |
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