JP2020524164A - Nk−92細胞を用いてメルケル細胞癌(mcc)を治療するための方法 - Google Patents
Nk−92細胞を用いてメルケル細胞癌(mcc)を治療するための方法 Download PDFInfo
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Abstract
Description
この出願は、2017年6月20日に出願された米国仮特許出願第62/522,335号の恩典を主張するものである。この仮出願は、あらゆる目的のためにその全体が参照により本明細書に組み入れられる。
MCCは希少であるが、一般的になりつつある、侵襲性の強い皮膚癌であり(米国では100,000人年あたり0.79例(Fitzgerald, et al., Am. Surg. 81:802-6 (2015)(非特許文献1))、該疾患の発生率は過去15年間で3倍になっている(Banks, et al., J Oncol Pract. 12:637-46 (2016)(非特許文献2))。MCCは、皮膚の遅順応性(slowly adapting)の機械受容器であるメルケル細胞(Merkel cell)から生じることが最初に提案された;しかし、腫瘍細胞の供給源はほとんど解明されておらず、多能性幹細胞および表皮ケラチノサイト様細胞が癌細胞を生じさせる可能性がある(Tilling and Moll, J Skin Cancer. 2012:680410 (2012)(非特許文献3))。MCCは、白人、65歳以上の高齢者、男性、および後天性(例えば、HIV感染)または医原性の免疫抑制(例えば、自己免疫疾患の治療による)を示す患者に多く見られる(Becker, Ann Oncol. 21 Suppl 7:vii81-5 (2010)(非特許文献4))。紫外線曝露は、この疾患の独立したリスク因子であり、MCCの発生率上昇の一因であり得る。
本明細書では、メルケル細胞癌を治療する方法が提供される。この方法は、メルケル細胞癌を有する対象を選択する段階、および該対象に治療有効量のNK-92細胞を投与する段階を含み、該投与によって該対象におけるメルケル細胞癌を治療する。
この癌はウイルス起源であるため、免疫療法は、メルケル細胞癌の治療を研究するための有望な手段であり得る。本明細書では、メルケル細胞癌を治療する方法が提供される。この方法は、メルケル細胞癌を有する対象を選択する段階;および該対象に治療有効量のNK-92細胞を投与する段階を含み、該投与によって該対象におけるメルケル細胞癌を治療する。
NK-92細胞は、ポリオーマウイルス陽性MCC細胞株に対して細胞傷害活性を示す。図1および2は、NK-92細胞を異なるエフェクター対標的比で3種のMCC細胞株(MKL-1、WaGaおよびMS-1)に一晩曝露した後のNK-92細胞の細胞傷害性の結果を示している。ヒトCML細胞株であるK562は、NK-92細胞によって常に殺傷されるため、対照としての役割を果たす。具体的には、K562、MKL-1、MS-1、およびWaGa細胞(標的)をメンブレン色素PKH67-GLでメーカー(Sigma Aldrich, St. Louis, MO)の指示に従って事前染色し、細胞密度105/mlでRPMI 1640+10%FBS中に再懸濁した。NK-92細胞(エフェクター)を細胞密度106/mlでX-Vivo10+5%HS+IL-2(500IU/ml)中に再懸濁した。標的細胞とエフェクター細胞を、96ウェルプレートでエフェクター:標的(E:T)比10:1、5:1、2.5:1、1.25:1で最終容量200μl/ウェルにて混合した。バックグラウンド自然死を決定するために、標的のみの対照を含めた。プレートを37℃のCO2インキュベータ内で4時間または24時間インキュベートし、その後、細胞をヨウ化プロピジウム(0.1μg/ml)で10分間染色した。サンプルをフローサイトメトリーで解析し、細胞傷害のパーセントを次のように算出した:%殺傷=[(サンプルの%PKH+/PI+)−(標的のみの%PKH+/PI+)]/[100−(標的のみの%PKH+/PI+)]* 100。図1は4時間での細胞傷害性を示し、図2は24時間での細胞傷害性を示す。
頭皮に再発性の進行性MCCを有し、少なくとも3箇所に皮膚転移がある81歳の男性患者をNK-92細胞で治療した。以前の治療には、手術、補助放射線(RT)、病巣内インターフェロン(IFN)+RT+局所イミキモド、抗PD-1療法、病巣内TLR-4アゴニスト、中性子によるRT、およびオクトレオチド長時間作用型徐放性製剤(long-acting release:LAR)が含まれていた。患者は、最初のサイクルの1日目に、2×109細胞/m2のNK-92静脈内注入を受けた。最初のサイクルの2日目に、患者は、2×109細胞/m2の2回目のNK-92注入を受けた。各サイクルの間に2週間の間隔をおいて、このサイクルを8回繰り返した。患者は、MCC腫瘍が完全に消散して、完全奏効(CR)を達成した。NK-92療法は、重大な有害事象なしで容認された。
3人の患者をNK-92細胞で治療した。これらの患者は全員、固形癌治療効果判定基準(Response Evaluation Criteria in Solid Tumors:RECIST)に基づいて切除不能なステージIII(IIIB)または遠隔転移(ステージIV)のMCCを有していた。NK-92細胞を、2×109細胞/m2の用量で連続2日間(=1サイクル)、2週間ごとに合計8サイクルのIV注入(16回の注入)により、患者に投与した。患者をモニタリングして、無増悪生存期間(Progression Free Survival)を治療開始から4ヶ月で評価した。予備データは、NK-92細胞療法が有益な臨床結果を達成したことを示した。
Claims (18)
- (a)メルケル細胞癌を有する対象を選択する段階;
(b)該対象に治療有効量のNK-92細胞を投与する段階であって、該投与によって該対象におけるメルケル細胞癌を治療する、段階
を含む、対象におけるメルケル細胞癌を治療する方法。 - 前記対象が、以前に放射線療法、手術、化学療法、抗PD-1療法、またはそれらの任意の組み合わせを受けている、請求項1に記載の方法。
- メルケル細胞癌が転移性である、請求項1または2に記載の方法。
- 1×103〜1×1010個/m2のNK-92細胞を前記対象に投与する、請求項1〜3のいずれか一項に記載の方法。
- 2×109個/m2のNK-92細胞を前記対象に投与する、請求項1〜3のいずれか一項に記載の方法。
- NK-92細胞を非経口的に投与する、請求項1〜5のいずれか一項に記載の方法。
- NK-92細胞を静脈内に投与する、請求項1〜5のいずれか一項に記載の方法。
- NK-92細胞を腫瘍周囲に投与する、請求項1〜5のいずれか一項に記載の方法。
- NK-92細胞を、ある期間にわたって注入により前記対象に投与する、請求項1〜8のいずれか一項に記載の方法。
- 前記期間が5〜130分である、請求項9に記載の方法。
- 前記期間が90〜120分である、請求項9に記載の方法。
- 前記期間が15〜30分である、請求項9に記載の方法。
- メルケル細胞癌が、メルケル細胞ポリオーマウイルスによって引き起こされる、請求項1〜12のいずれか一項に記載の方法。
- メルケル細胞癌が、メルケル細胞ポリオーマウイルスによって引き起こされるものではない、請求項1〜12のいずれか一項に記載の方法。
- 前記対象におけるメルケル細胞癌が化学療法に耐性である、請求項1〜14のいずれか一項に記載の方法。
- NK-92細胞を、1日1回、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20日間、またはそれより長く、前記対象に投与する、請求項1〜15のいずれか一項に記載の方法。
- NK-92細胞を1日1回、2日間のサイクルで投与する、請求項1〜15のいずれか一項に記載の方法。
- NK-92細胞を、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、またはそれを超えるサイクルで投与する、請求項17に記載の方法。
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HISTORY OF CHANGES FOR STUDY: NCT02465957, JPN6022023354, 23 May 2015 (2015-05-23), ISSN: 0004956910 * |
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CN110753551A (zh) | 2020-02-04 |
IL270838A (en) | 2020-01-30 |
WO2018236887A1 (en) | 2018-12-27 |
CA3066463A1 (en) | 2018-12-27 |
EP3641790A1 (en) | 2020-04-29 |
AU2018288712A1 (en) | 2019-12-12 |
KR20200017494A (ko) | 2020-02-18 |
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