JP2014520780A - 高静水圧によって死滅させた腫瘍細胞および樹状細胞を用いた活性細胞癌免疫療法のための手段および方法 - Google Patents
高静水圧によって死滅させた腫瘍細胞および樹状細胞を用いた活性細胞癌免疫療法のための手段および方法 Download PDFInfo
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Abstract
Description
WO2006/095330には、抗原性を有する細胞を熱的、機械的および/または化学的に損傷させ、この細胞を抗原提示細胞との凝集体として患者に導入することにより、細胞群の増殖を抑制する方法が記載されている。
ヒトの腫瘍、特に、卵巣癌細胞、前立腺癌細胞および急性リンパ芽球性白血病細胞のimmunogenic cell deathを近年報告されている化学療法薬よりもはるかに高程度に誘導する新規の方法および医薬組成物を開示する。この方法により死滅させた腫瘍細胞は樹状細胞によって捕捉されるとともに、immunogenic cell deathマーカーを高レベルに発現し、次いで、抗腫瘍免疫応答を抑制しうる制御性T細胞を誘導することなく多数の腫瘍特異的Tリンパ球を誘導する。本発明に従って処理された腫瘍細胞と樹状細胞との組み合わせにより得られる抗腫瘍免疫応答は、免疫原性の腫瘍細胞単独によって誘導される免疫応答の約10倍であることが明らかとなっている。
腫瘍細胞に対して免疫応答を誘導するための医薬組成物であって、
a)静水圧処理によってアポトーシスを起こした腫瘍細胞と、
b)樹状細胞と
を含む医薬組成物に関する。
高静水圧処理後のヒト癌細胞株およびヒト原発性腫瘍細胞のimmunogenic cell deathマーカーhsp70、hsp90およびカルレティキュリンの発現
白血病細胞株、卵巣癌細胞株、前立腺癌細胞株および原発性腫瘍細胞の高静水圧処理(HHP、200MPa)を21℃で10分間行い、公知のimmunogenic cell deathマーカーであるhsp70、hsp90およびカルレティキュリンの発現を6、12および24時間後に観察した。HHP処理の6、12および24時間後に、試験したすべての腫瘍モデルにおいて、カルレティキュリン、hsp70およびhsp90の有意な発現が検出された。これらの免疫原性分子の発現は、immunogenic cell deathの誘導因子として唯一知られているアントラサイクリン類によって誘導される発現よりも有意に高かった(図2)。HHP処理によりカルレティキュリンおよび熱ショックタンパク質の発現が増加したのと同時に、これらの分子は細胞表面へと移動した。また、HHP処理により、immunogenic cell deathの可溶性マーカーであるHMGB1の大量かつ急速な遊離が誘導された。遊離したHMGB1の量は、紫外線照射やアントラサイクリン類により処理を行った場合よりもはるかに多かった(図3)。
高静水圧処理された腫瘍細胞により増強された、抗原提示細胞による腫瘍細胞の貪食
カルレティキュリンはeat meシグナルとしての役割が実証されていることから、高静水圧により死滅させた腫瘍細胞が樹状細胞(DC)によって貪食される速度を調べた。樹状細胞(DC)は、免疫応答の開始に欠かせない抗原提示細胞として最も優れた細胞である。アントラサイクリン類や紫外線照射などの他の方法で死滅させた腫瘍細胞と比べて、高静水圧処理した腫瘍細胞ではより多くの細胞がより速い速度で貪食された。12時間後、貪食されたHHP処理白血病細胞の数は、紫外線照射により死滅させた細胞の4倍となった(図4aおよび図4b)。
高静水圧処理された腫瘍細胞の貪食によるDC成熟化の誘導
DCが免疫応答を活性化する能力は、DC自体の活性化状態と共刺激分子の発現とに左右される。通常の環境において、DCの成熟は、グラム陰性細菌由来のリポ多糖(LPS)などの病原体由来分子によって最も効率的に誘導される。高レベルの共刺激分子を発現している活性化(成熟)DCだけが免疫応答を開始することができる。本発明者らは、HHPにより死滅させた腫瘍細胞を貪食したDCの表現型を分析した。DCとHHP処理腫瘍細胞との相互作用による誘導によって、LPSによる活性化と同程度にまで共刺激分子(CD86、CD83)および成熟関連分子(HLA−DR)がアップレギュレートされた(図5)。従って、HHPによって死滅させた腫瘍細胞は、病原体由来LPSと同程度にDCの成熟化を誘導することができる。
高静水圧処理された腫瘍細胞を提示したDCによる腫瘍特異的T細胞および少数の抑制性・制御性T細胞の誘導
HHPで処理されたことによってimmunogenic cell deathマーカーを発現した腫瘍細胞が抗腫瘍免疫を誘導するかどうかを調べるために、本発明者らは、腫瘍細胞を取り込んだDCが腫瘍細胞特異的T細胞応答を活性化する能力を評価した。HHPによって死滅させた腫瘍細胞と未成熟DCとを共培養し、次いでLPSを用いて成熟させた場合と成熟させなかった場合とを設けた。次いで、これらのDCを自己T細胞の刺激物質として用い、腫瘍細胞を取り込んだDCにより再刺激を行った1週間後にIFN−γ産生T細胞の頻度を分析した。HHPで死滅させた腫瘍細胞をパルスしたDCは、紫外線を照射した細胞をパルスしたDCと比較してより多くの腫瘍特異的IFN−γ産生T細胞を誘導し、さらなる成熟刺激(LPS)の非存在下でもより多くの腫瘍特異的IFN−γ産生T細胞を誘導した。
手術または放射線療法による腫瘍の一次治療後に残された病変が微小である場合、単一治療法として活性細胞免疫療法を施すことができる。前立腺癌においては、生化学的再発の徴候(超高感度法で測定された末梢血中前立腺特異抗原(PSA)レベルの上昇)を示した患者に適用できる。
進行性癌患者においては、化学免疫療法の基本理念に従って、活性細胞免疫療法を化学療法(すなわち前立腺癌ではドセタキセル)と組み合わせて実施すべきである。
紫外線により死滅させた腫瘍細胞よりもHHPで死滅させた腫瘍細胞が優れていることを示すインビトロ実験
インビトロ実験において、未成熟樹状細胞、ポリI:Cで活性化した成熟樹状細胞、HHP処理した腫瘍細胞を取り込んだ樹状細胞、および紫外線照射した腫瘍細胞を取り込んだ樹状細胞について、腫瘍特異的免疫の誘導能を調べた。腫瘍特異的免疫は、腫瘍特異的Tリンパ球のパーセンテージとして測定した。
本発明による腫瘍ワクチン接種により得られたインビボデータ
上述した患者と類似した患者コホートから樹状細胞を得た。上述のように死滅させた腫瘍細胞を樹状細胞にパルスした。前立腺切除術または放射線療法による根治的治療後に前立腺癌の生化学的再発を呈した複数の患者に腫瘍ワクチンを4〜6週間の間隔で最大12回接種した。疾患の進行は個々の患者のPSA倍加時間によって評価した。「PSA倍加時間」とは、PSA値が2倍になるのに要する時間と理解される。PSA倍加時間は、前立腺癌を有する男性の全生存期間および転移を起こさずに生存できる期間の最も強力かつ信頼性の高い決定因子であることが示されている。PSA倍加時間が短いと、生存期間が短縮し、転移の発生までの時間が短縮する(Antonarakisら,BJU Int., 2012, 108 (3); pp 378-385)。
末期前立腺癌患者における臨床試験
この臨床試験では、本明細書に記載のように死滅させた腫瘍細胞を樹状細胞にパルスした。複数の末期前立腺癌患者に腫瘍ワクチン接種を繰り返し施した。これらの患者は去勢抵抗性転移性前立腺癌を患っていた。これらの患者において、一定間隔でドセタキセル化学療法を行いながら、癌免疫療法を実施した。
Claims (14)
- 腫瘍細胞に対して免疫応答を誘導するための医薬組成物であって、
a)高静水圧処理によってアポトーシスを起こした腫瘍細胞と、
b)樹状細胞と
を含む医薬組成物。 - 前記腫瘍細胞が、少なくとも200MPaの静水圧で少なくとも10分間処理されたものであることを特徴とする、請求項1に記載の医薬組成物。
- 前記腫瘍細胞が、200〜250MPaの静水圧で10分〜2時間処理されたものであることを特徴とする、請求項1に記載の医薬組成物。
- 前記アポトーシスを起こした腫瘍細胞が、ネクローシスを起こしていないことを特徴とする、請求項1〜3のいずれかに記載の医薬組成物。
- 前記腫瘍細胞が腫瘍細胞株由来であることを特徴とする、前記請求項のいずれかに記載の医薬組成物。
- 前記腫瘍細胞が、治療を受ける患者から単離された腫瘍由来であることを特徴とする、請求項1〜4のいずれかに記載の医薬組成物。
- 高静水圧処理によってアポトーシスを起こした腫瘍細胞が未成熟樹状細胞に取り込まれていることを特徴とする、請求項1〜6のいずれかに記載の医薬組成物。
- 前記未成熟樹状細胞が白血球除去により得られたものであることを特徴とする、請求項7に記載の医薬組成物。
- 前記未成熟樹状細胞が、白血球除去およびサイトカイン存在下におけるインビトロ培養により得られたものであることを特徴とする、請求項8に記載の医薬組成物。
- 早期癌患者および末期癌患者に使用するための、請求項1〜9のいずれかに記載の医薬組成物。
- ホルモン治療抵抗性転移性前立腺癌である末期癌を有する患者に使用するための、請求項10に記載の医薬組成物。
- 請求項1〜11のいずれかに記載の医薬組成物を調製する方法であって、
高静水圧処理によってアポトーシスを起こした腫瘍細胞を未成熟樹状細胞に取り込ませること、および
該樹状細胞を成熟させること
を特徴とする方法。 - 癌ワクチン接種によりヒトを治療する方法であって、
患者から未成熟樹状細胞を単離すること、
患者から腫瘍細胞を単離すること、
高静水圧処理によって該腫瘍細胞をアポトーシス段階へと移行させること、
該腫瘍細胞を該未成熟樹状細胞に取り込ませること、および
医薬組成物を患者に投与する前に該樹状細胞を成熟させること
を含む方法。 - 癌ワクチン接種によってヒトを治療する方法であって、
患者から未成熟樹状細胞を単離すること、
高静水圧処理によってアポトーシス段階へと移行させた腫瘍細胞株から得られた腫瘍細胞を該樹状細胞に取り込ませること、および
医薬組成物を患者に投与する前に必要に応じて該樹状細胞を成熟させること
を含む方法。
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CN110392574A (zh) * | 2017-02-17 | 2019-10-29 | 艾维塔生物医学公司 | 使用经修饰的肿瘤细胞和经修饰的树突细胞增强肿瘤免疫原性的方法和用于自体癌症免疫治疗产品的组合物 |
JP2021029180A (ja) * | 2019-08-26 | 2021-03-01 | 学校法人関西医科大学 | 細胞又は組織にアポトーシスを誘導する方法 |
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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CN110392574A (zh) * | 2017-02-17 | 2019-10-29 | 艾维塔生物医学公司 | 使用经修饰的肿瘤细胞和经修饰的树突细胞增强肿瘤免疫原性的方法和用于自体癌症免疫治疗产品的组合物 |
JP2020507616A (ja) * | 2017-02-17 | 2020-03-12 | アイビタ バイオメディカル インコーポレイテッド | 改変された腫瘍細胞および改変された樹状細胞を使用して、腫瘍免疫原性を増強する方法および自己癌免疫療法製品の組成物 |
JP2021029180A (ja) * | 2019-08-26 | 2021-03-01 | 学校法人関西医科大学 | 細胞又は組織にアポトーシスを誘導する方法 |
JP7340240B2 (ja) | 2019-08-26 | 2023-09-07 | 学校法人関西医科大学 | 細胞又は組織にアポトーシスを誘導する方法 |
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EA030061B1 (ru) | 2018-06-29 |
BR122019026627B1 (pt) | 2021-01-12 |
PT2691110E (pt) | 2014-12-22 |
SMT201400188B (it) | 2015-03-05 |
ES2525759T3 (es) | 2014-12-30 |
NZ618000A (en) | 2014-12-24 |
US20140086957A1 (en) | 2014-03-27 |
KR102035873B1 (ko) | 2019-10-23 |
KR20140040734A (ko) | 2014-04-03 |
CN103648524B (zh) | 2016-08-17 |
EP2691110B1 (en) | 2014-10-29 |
BR112013031084A2 (pt) | 2016-11-29 |
CA2833946A1 (en) | 2013-01-10 |
EA201301089A1 (ru) | 2014-05-30 |
EP2691110A1 (en) | 2014-02-05 |
WO2013004708A1 (en) | 2013-01-10 |
PL2691110T3 (pl) | 2015-03-31 |
DK2691110T3 (en) | 2014-11-17 |
EP2543386A1 (en) | 2013-01-09 |
BR112013031084B1 (pt) | 2021-01-12 |
JP5986196B2 (ja) | 2016-09-06 |
SI2691110T1 (sl) | 2015-01-30 |
CN109125347A (zh) | 2019-01-04 |
CN103648524A (zh) | 2014-03-19 |
CN102861103A (zh) | 2013-01-09 |
RS53713B1 (en) | 2015-04-30 |
AU2016234915B2 (en) | 2017-08-31 |
RU2012127685A (ru) | 2014-01-20 |
UA111738C2 (uk) | 2016-06-10 |
AU2012280322B2 (en) | 2016-07-21 |
AU2016234915A1 (en) | 2016-10-20 |
SG194201A1 (en) | 2013-11-29 |
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