JP2015504423A - 腫瘍免疫療法のためのワクチン - Google Patents
腫瘍免疫療法のためのワクチン Download PDFInfo
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Abstract
Description
(i)抗原提示細胞(APC)、
(ii)腫瘍関連抗原(TAA)、及び
(iii)細菌ゴースト(BG)
を含む組成物を提供する。
(a)細菌細胞外被においてトンネル構造を形成することができる溶解タンパク質をコードする遺伝子を含むグラム陰性菌細胞を提供する工程、
(b)場合により、溶解遺伝子が発現しない条件下で細菌細胞を培養する工程、
(c)細菌細胞に、溶解遺伝子が発現せず、かつ細菌細胞の細胞質成分を遊離させる条件を受けさせる工程、並びに
(b)細菌ゴーストを得る工程。
(a)場合により、酵素遺伝子が発現しない条件下で細菌細胞を培養する工程、
(b)細菌細胞に、酵素遺伝子が発現せず、かつ細菌細胞の細胞質成分が分解されない条件を受けさせる工程。
実施例1. 細菌ゴースト
細菌ゴーストを、特許明細書PCT/EP2009/000272号に従って製造する。
癌患者から得られた腫瘍組織又は組織培養プレート(フラスコ)を、NACl(注入“Fresenius”のために水で0.9%の塩化ナトリウム)で満たした管に貯蔵する。腫瘍組織又は細胞を有する管を、+4℃で貯蔵し、そして手術の3日後までに加工する。その管を、組織の加工前に照射(120Gy)した。ドナー(患者)を、性的感染症(STD)、例えば、HIV、HCV、HBV、梅毒についてスクリーニングし、そして挙げたあらゆる疾患の陽性検出を有する患者を除外する。前記患者から得られた腫瘍組織を、5〜10mlの(Hanks’ Balanced Salt Solution;Lonza、No.:10−547F又は10−527F;cGMP調節に従って製造した)で満たした滅菌ペトリ皿に移す。壊死性組織及び結合組織の双方を、外科用メス及びピンセットによって取り出す。残りの腫瘍組織を、約5mmの小片に切断し、そして滅菌シリンジピストンによって研磨する。得られた細胞懸濁液を、さらに、均質な懸濁液が得られるまで数回、滅菌シリンジに取り付けた20G(0.9mm)針に懸濁液を通過することによって均質化する。続いて、細胞懸濁液を、ナイロンストレナー(100μm)を通して濾過し、そして滅菌50ml管に採取する。ペトリ皿を、残りのHBSSで洗浄し、ナイロンストレナーを通して濾過し、そして濾過した細胞と合する。その細胞懸濁液を、1600RPMで7時間+4℃で遠心沈殿する。その懸濁液を、素早く及び注意深くデカンテーションし、そしてペレットを、2mlのCellGro(登録商標)培養液中で再懸濁する。単一の細胞懸濁液を、マイクロチューブに均等に分ける。そのマイクロチューブを、液体N2中に、又はドライアイスとメタノールとの混合物中に、約3分間置く。続いて、凍結した細胞を、室温(RT)で15〜30分管、細胞ペレットが完全に溶けるまで溶解する(細胞は、腫瘍細胞タンパク質の破壊を妨げるために、RTで長時間保持すべきでない)。凍結融解の手順を5回繰り返す必要がある。そして、細胞溶解物を、超音波よく中で5分間超音波処理する。細胞破片を細胞溶解物と共に1つの管に採取し、10000〜15000RPMで10分間遠心沈殿し、続いてペレットを分離する細い針を使用して上澄み(細胞溶解物)を素早く及び注意深く採取する。細胞溶解物を濾過する必要はなく、すべての工程は、滅菌条件下で行うべきである。濾過していない細胞溶解物を、等分し、そしてさらに使用するまで−80℃で貯蔵する。その細胞溶解物を、10x DPBS(Dulbecco’s Phosphate Buffered Saline、10x PBS、Lonza、No.:17−515F)で希釈する。分光光度計を、タンパク質濃度の測定のために使用する。
患者の末梢血から得られた単核細胞を、溶離(Elutra Cell Separation System、CaridianBCT Europe NV/SA)又は磁器分離(CliniMACS、Miltenyi Biotec GmbH)によって単離する。GM−CSFを、CellGro(登録商標)培養液中で溶解して、1×105IU/mlの最終濃度を得て、マイクロチューブ中に等分し(1つのチューブあたり700μl)、そして−80℃で貯蔵する。IFN−α(Roche、ROFERON−A 12×106lU/ml)を、マイクロチューブ中に等分し(1つのチューブあたり17.5μl)、そして+2℃〜+8℃で貯蔵する。凍結保存で凍結した媒体CryoStor CS2又はCryoStor CS5を、マイクロチューブ中に滅菌条件下で等分する(1つのチューブあたり1.5ml)。分離した単核細胞を、培養液中で再懸濁し、そして培養フラスコ中に、培養液70ml中で約167×106個の単核細胞を加える。腫瘍溶解物の約150μgを、1つの培養フラスコについて、又は未成熟DC(単核細胞)の3倍の腫瘍細胞の数に対応する細胞からの腫瘍溶解物を要求する。培養液からの単核細胞細胞懸濁液を、RTで10分間1500RMで遠心分離する。上澄みのデカンテーション後に、細胞ペレットを、少量のCellGro(登録商標)培養液中で再懸濁し、そして35mlまでCellGro(登録商標)培養液で仕上げる。その細胞懸濁液を、培養フラスコに移す。35mlのCellGro(登録商標)培養液中でGM−CSF(700μl/7×104IU)及びIFN−α(17.5μl/2.1×105IU)を単核細胞細胞懸濁液に添加する。培養フラスコの含有物を、フラスコを左右に穏やかに動かすことによって注意深く混合する。細胞を、5% CO2加湿インキュベーター中で、+37℃で3日間インキュベートする。
実施例3で得られた刺激したDCを有する培養フラスコを、完全に撹拌してフラスコ壁に付着した細胞を落とす。その細胞懸濁液を、ラベルした50ml管に完全に移す。培養フラスコを、腫瘍溶解物配合物のために使用したさらに2倍の同一のHBSS(10ml)で洗浄し、適宜、HBSSの全容量を、細胞懸濁液を有する管に移す。元の培養フラスコを、5mlのHBSSで見たし、インキュベーターに戻す。細胞懸濁液の容量を、HBSSで50mlまで満たし、そして管をひっくり返すことにより穏やかに混合した。その細胞懸濁液を、1500RPMで10分間+4℃で遠心沈殿する。その上澄みを、素早くかつ注意深くデカンテーションし、その細胞ペレットを、最初に5mlのHBSSで再懸濁し、続いてさらに45mlのHBSSを添加して、管をひっくり返すことによりよく混合する。10μlの細胞懸濁液を、Buerkner計数チャンバーを使用して、細胞数を測定するために使用する。懸濁液内での細胞の濃度が1.4×106個/ml未満である場合に、アクターゼを使用して、残りの細胞を培養フラスコから放し、又はそれぞれ5×106個の細胞を含む細胞アリコートを、患者にさらに投与するために凍結する。患者への投与のために少なくとも6アリコート、品質管理のために1アリコート、免疫監視のために1アリコート、マイコプラズマの試験のために1アリコート、及びアービトラージ(arbitrage)のために3アリコートを製造することが必須である。その細胞懸濁液を、1500RPMで10分間+4℃で遠心沈殿する。凍結管を、予め冷却したMiniCoolerに移す。その懸濁液を、素早く及び注意深くデカンテーションし、そして細胞ペレットを、凍結保存で凍結した媒体CryoStor CS2中で再懸濁し、そして凍結管に移す。抗腫瘍ワクチン配合物の等分後すぐに、全ての凍結管を、−80℃でのイソプロパノールボックスに置く。−80℃で24時間後に、全ての凍結したワクチン配合物を、液体窒素で満たしたDewar容器に移し、抗腫瘍ワクチン配合物について目的の使用のみに特定に設定する。
Claims (17)
- 以下、
(i)抗原提示細胞、
(ii)腫瘍関連抗原、及び
(iii)細菌ゴースト
を含む組成物。 - 腫瘍免疫治療のためのワクチンとしての使用のための、請求項1に記載の組成物。
- 前記抗原提示細胞が単核細胞を含む、請求項1又は2に記載の組成物。
- 前記抗原提示細胞が樹状細胞を含む、請求項1から3までのいずれか1項に記載の組成物。
- 1つ以上の腫瘍溶解物を含む、請求項1から4までのいずれか1項に記載の組成物。
- 溶解タンパク質をコードする遺伝子を含む細菌細胞から得られる細菌ゴーストを含む、請求項1から5までのいずれか1項に記載の組成物。
- β−プロピオラクトンで処理された細菌ゴーストを含む、請求項1から6までのいずれか1項に記載の組成物。
- グラム陰性菌、特に大腸菌、及びより好ましくは大腸菌 Nissle 1917からの細菌ゴーストを含む、請求項1から7までのいずれか1項に記載の組成物。
- 免疫系の活性剤又はサイレンサー、薬剤及び/又はDNAを有する細菌ゴーストを含む、請求項1から8までのいずれか1項に記載の組成物。
- 組換え腫瘍関連抗原を提供する細菌ゴーストを含む、請求項1から9までのいずれか1項に記載の組成物。
- 前記細菌ゴーストが、腫瘍関連抗原を有する、請求項10に記載の組成物。
- 前記細菌ゴーストが、腫瘍関連抗原を組み換えて発現する細菌に由来する、請求項10に記載の組成物。
- 抗原提示細胞1個あたり、1〜10000個、特に10〜1000個の細菌ゴーストを含む、請求項1から12までのいずれか1項に記載の組成物。
- 1投与量あたり1〜1000万個の抗原提示細胞を含む、請求項1から13までのいずれか1項に記載の組成物。
- 腫瘍抗原認識、及びT細胞による腫瘍特異性の死滅を誘発する抗原提示細胞を有する、請求項2に記載の組成物。
- 自己抗原提示細胞を含む、請求項2に記載の組成物。
- 請求項1から16までのいずれか1項に記載の組成物を含む治療用ワクチン。
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- 2011-11-09 EP EP11188494.6A patent/EP2591798B1/en active Active
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- 2012-11-07 CN CN201280055046.2A patent/CN104066443A/zh active Pending
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2015
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Also Published As
Publication number | Publication date |
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ES2525205T3 (es) | 2014-12-18 |
US20130115245A1 (en) | 2013-05-09 |
EP2591798A1 (en) | 2013-05-15 |
US9790260B2 (en) | 2017-10-17 |
NZ624069A (en) | 2015-10-30 |
AU2012334095B2 (en) | 2017-10-12 |
WO2013068406A1 (en) | 2013-05-16 |
HK1202070A1 (en) | 2015-09-18 |
CN104066443A (zh) | 2014-09-24 |
PL2591798T3 (pl) | 2015-04-30 |
EP2776060A1 (en) | 2014-09-17 |
EP2591798B1 (en) | 2014-11-19 |
JP6029677B2 (ja) | 2016-11-24 |
AU2012334095A1 (en) | 2014-05-29 |
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