JP6257607B2 - 癌免疫療法のための組成物および方法 - Google Patents
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Description
本明細書でヒト、哺乳動物、哺乳動物対象、動物、獣医学対象、プラセボ対象、研究対象、実験対象、細胞、組織、器官または生体液に関して使用される「投与」は、外来性のリガンド、試薬、プラセボ、小分子、医薬品、治療剤、診断剤または組成物と対象、細胞、組織、器官または生体液などとの接触を非限定的に指す。「投与」は、例えば、治療法、薬物動態学的方法、診断法、研究法、プラセボ法および実験法を指す場合がある。細胞の治療は試薬と細胞との接触のほかにも、試薬と液体との接触を包含し、この場合、その液体は細胞と接触している。「投与」はこのほか、試薬、診断剤、結合組成物または別の細胞による、例えば細胞のインビボおよびエクスビボ治療を包含する。「〜とともに投与する」は、2つ以上の薬剤を単一組成物として投与することを意味するものではない。単一組成物としての投与が本発明により考慮されるが、このような薬剤は単一の対象に別個の投与として送達され得るものであり、このような投与は、同じ時間でも異なる時間でも実施され得るものであり、また同じ投与経路によっても異なる投与経路によっても実施され得るものである。
「不活化腫瘍細胞」は、細胞が分裂しないよう処理されている腫瘍細胞(患者に対して「自己」または「同種」のいずれか)を意味する。本発明の目的のため、このような細胞にはその免疫原性および代謝活性を維持させる。癌治療の一部として、このような腫瘍細胞は患者内で発現される導入遺伝子を発現するよう遺伝子を改変する。したがって、本発明の組成物またはワクチンは、治療を受けている患者に対して自己または同種の新生細胞(例えば、腫瘍細胞)を含み、最も好ましくは患者を冒している腫瘍細胞と同じ一般型の腫瘍細胞である。例えば、黒色腫に罹患している患者には通常、黒色腫由来の遺伝子改変細胞を投与する。本発明に使用する腫瘍細胞を不活性化する方法、例えば放射線照射の使用などは当該技術分野で周知である。
本明細書に記載される通り、上に挙げたような共刺激物質にはもう一つ、STINGと結合しSTING依存性TBK1活性化を誘導する環状プリンジヌクレオチドがある。これ以外に含まれ得る共刺激分子についてはのちに記載する。
上記不活化腫瘍細胞(1つまたは複数)および環状プリンジヌクロチド(dinuclotide)(1つまたは複数)に加えて、本発明の組成物は、アジュバント性を有することを理由に、不活化腫瘍細胞(1つまたは複数)上に存在する癌抗原に応答する免疫系を刺激するよう作用し得る1つまたは複数の追加の物質をさらに含み得る。このようなアジュバントとしては、特に限定されないが、脂質、リポソーム、自然免疫を誘導する不活性化細菌(例えば、不活化または弱毒化リステリア菌(Listeria monocytogenes))、Toll様受容体(TLR)を介して自然免疫活性化を仲介する組成物、(NOD)−様受容体(NLR)、レチノイン酸誘導遺伝子に基づく(RIG)−I様受容体(RLR)および/またはC型レクチン受容体(CLR)が挙げられる。PAMPの例としては、リポタンパク質、リポポリペプチド、ペプチドグリカン、ザイモサン、リポ多糖類、ナイセリアポリン、フラジェリン、プロフィリン、ガラクトセラミド、ムラミルジペプチドが挙げられる。ペプチドグリカン、リポタンパク質およびリポテイコ酸はグラム陽性の細胞壁成分である。リポ多糖類はほとんどの細胞によって発現され、MPLがその一例である。フラジェリンは、病原性細菌および共生細菌によって分泌される細菌鞭毛の構造成分を指す。α−ガラクトシルセラミド(α−GalCer)はナチュラルキラーT(NKT)細胞の活性化因子である。ムラミルジペプチドは全細菌に共通する生物活性ペプチドグリカンモチーフである。ここに挙げたものは限定することを意図するものではない。好ましいアジュバント組成物についてはのちに記載する。
CTLA−4は適応免疫応答の重要な負の調節因子であると考えられている。活性化T細胞がCTLA−4をアップレギュレートし、これがCD28よりも高い親和性で抗原提示細胞上のCD80およびCD86と結合することによりT−細胞刺激、IL−2遺伝子発現およびT細胞増殖を阻害する。CTLA4遮断の抗腫瘍効果が結腸癌、転移性前立腺癌および転移性黒色腫のマウスモデルで観察されている。
本明細書で使用される「Toll様受容体」(または「TLR」)という用語は、微生物生成物を感知し、かつ/または適応免疫応答を開始させる、タンパク質のToll様受容体ファミリーのメンバーまたはそのフラグメントを指す。一実施形態では、TLRが樹状細胞(DC)を活性化する。Toll様受容体(TLR)は、最初は微生物病原体を認識する自然免疫系のセンサーとして認識されていたパターン認識受容体のファミリーである。TLRは、ロイシンリッチリピートの外部ドメイン、膜貫通ドメインおよび細胞内TIR(Toll/IL−1R)ドメインを含む保存された膜貫通分子のファミリーを含む。TLRは、多くの場合「PAMP」(病原関連分子パターン)と呼ばれる、微生物の独特な構造を認識する。リガンドがTLRと結合すると、炎症および免疫に関与する諸因子の産生を誘導する細胞内シグナル伝達経路のカスケードが起動する。
Pam3Cys、TLR−1/2アゴニスト;
CFA、TLR−2アゴニスト;
MALP2、TLR−2アゴニスト;
Pam2Cys、TLR−2アゴニスト;
FSL−1、TLR−2アゴニスト;
Hib−OMPC、TLR−2アゴニスト;
ポリリボシン酸:ポリリボシチジル酸(ポリI:C)、TLR−3アゴニスト;
ポリアデノシン−ポリウリジル酸(ポリAU)、TLR−3アゴニスト;
ポリ−L−リジンおよびカルボキシメチルセルロースで安定化したポリイノシン−ポリシチジル酸(Hiltonol(登録商標))、TLR−3アゴニスト;
モノホスホリル脂質A(MPL)、TLR−4アゴニスト;
LPS、TLR−4アゴニスト;
細菌フラジェリン、TLR−5アゴニスト;
シアリル−Tn(STn)、多数のヒト癌細胞上のMUC1ムチンに付随する炭水化物、TLR−4アゴニスト;
イミキモド、TLR−7アゴニスト;
レシキモド、TLR−7/8アゴニスト;
ロキソリビン、TLR−7/8アゴニスト;および
非メチル化CpGジヌクレオチド(CpG−ODN)、TLR−9アゴニスト。
リポソームは1層(「一枚膜」)または複数の層(「多重膜」)のリン脂質から形成される小胞である。リン脂質構成成分が両親媒性であることから、リポソームは通常、親水性の外面を示し親水性のコアを封入している親水性の層を含む。リポソームの親水性/疎水性成分の組込みにおける融通性、無毒性、生分解性、生体適合性、アジュバント性、細胞性免疫の誘導、徐放の特性およびマクロファージによる迅速な取込みにより、リポソームは抗原送達の魅力的な候補となっている。
a)水性媒体;
b)(i)ジミリストイルホスファチジルコリン(「DMPC」)と、
(ii)ジミリストイルホスファチジルグリセロール(「DMPG」)、ジミリストイルトリメチルアンモニウムプロパン(「DMTAP」)またはDMPGおよびDMTAPの両方と、
(iii)少なくとも1つのステロール誘導体とを含む、
リポソーム;ならびに
c)前記少なくとも1つのステロール誘導体の1%〜100%と共有結合した1つまたは複数の免疫原性ポリペプチド(1つまたは複数)または炭水化物(1つまたは複数)。
さらなる実施形態では、この方法は、患者の腫瘍に対する追加の治療として有効量の1つまたは複数の化学療法剤を対象に投与することをさらに含む。ある特定の実施形態では、1つまたは複数の化学療法剤は、酢酸アビラテロン、アルトレタミン、アンヒドロビンブラスチン、アウリスタチン、ベキサロテン、ビカルタミド、BMS184476、2,3,4,5,6−ペンタフルオロ−N−(3−フルオロ−4−メトキシフェニル)ベンゼンスルホンアミド、ブレオマイシン、N,N−ジメチル−L−バリル−L−バリル−N−メチル−L−バリル−L−プロリ−1−Lプロリン−t−ブチルアミド、カケクチン、セマドチン、クロラムブシル、シクロホスファミド、3’,4’−ジデヒドロ−4’−デオキシ−8’−ノルビン−カロイコブラスチン、ドセタキソル、ドキセタキセル、シクロホスファミド、カルボプラチン、カルムスチン、シスプラチン、クリプトフィシン、シクロホスファミド、シタラビン、ダカルバジン(DTIC)、ダクチノマイシン、ダウノルビシン、デシタビン ドラスタチン、ドキソルビシン(アドリアマイシン)、エトポシド、5‐フルオロウラシル、フィナステリド、フルタミド、ヒドロキシウレアおよびヒドロキシウレアタキサン、イホスファミド、リアロゾール、ロニダミン、ロムスチン(CCNU)、MDV3100、メクロレタミン(ナイトロジェンマスタード)、メルファラン、イセチオン酸ミボブリン、リゾキシン、セルテネフ、ストレプトゾシン、マイトマイシン、メトトレキサート、タキサン、ニルタミド、オナプリストン、パクリタキセル、プレドニムスチン、プロカルバジン、RPR109881、リン酸ストラムスチン(estramustine phosphate)、タモキシフェン、タソネルミン、タキソール、トレチノイン、ビンブラスチン、ビンクリスチン、硫酸ビンデシンならびにビンフルニンから選択される。
本明細書で使用される「医薬品」という用語は、疾患の治癒、治療または予防に使用することを目的とし、処方医薬品または一般用医薬品として米国食品医薬品局(または米国以外のこれに相当する機関)による承認手続きを必要とする化学物質を指す。このような組成物の製剤化および投与の技術に関する詳細はRemington,The Science and Practice of Pharmacy 第21版(Mack Publishing Co.、Easton、PA)ならびにNielloudおよびMarti−Mestres,Pharmaceutical Emulsions and Suspensions:第2版(Marcel Dekker,Inc、New York)にみることができる。
目的とする抗原を含み、何らかの変性条件で処理して病原性の侵入力を備えるのに無効または非効率的にされた粒子の不活化細菌またはウイルス;
通常は病原体もしくは病原体を含む組織試料またはその組換え型の細胞培養物から精製された天然に産生される抗原である精製抗原;
対象の宿主細胞で抗原を発現および/または分泌するよう組換え操作された生ウイルスまたは生細菌送達ベクター。この戦略は、ウイルスまたは細菌ベクターを非病原性および無毒性に弱毒化すること(例えば、遺伝子工学により)依存するものである。
抗原を負荷した細胞または抗原をコードする核酸を含む組成物をトランスフェクトした細胞を含む、樹状細胞(DC)ベクター(例えば、去勢抵抗性転移性前立腺癌の治療のためのProvenge(登録商標)(Dendreon Corporation))などの抗原提示細胞(APC)ベクター;
リポソーム抗原送達媒体;ならびに
遺伝子銃、エレクトロポレーション、細菌ゴースト、マイクロスフェア、微粒子、リポソーム、ポリカチオンナノ粒子などにより投与され得る裸のDNAベクターおよび裸のRNAベクター。
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以下の実施例は本発明を説明する役割を果たすものである。これらの実施例は、本発明の範囲を限定することを一切意図するものではない。
広範なレパートリーのTAAに対する免疫を刺激する1つの方法が「GVAX」であり、これはDCの動員、分化および成熟を刺激する主要なサイトカイン、GM−CSFを分泌するよう遺伝子操作された同種ヒト腫瘍細胞系に基づくワクチンである。GVAXワクチンは、いくつかの癌適応における複数の臨床試験の基礎を形成しているものであり、安全性および優れた耐容性が示され、またいくつかの臨床的有用性が得られることが示されている。mCRPCを有する男性において前立腺GVAX免疫療法(G)とセタキセル/プレドニゾン(D+P)とを比較した第3相試験が、初期の事前に計画されていない無益性解析から、この試験が所定の全生存率改善の主要評価項目を満たす確率が30%未満であることが明らかになったため、試験依頼者によって早期に中止された。しかし、試験対象の600例を超える患者に対して継続された追跡および解析では、約21か月目にG治療群のカプラン・マイヤー生存曲線がD+P治療群のものに交差し上回ることが明らかになった。さらに、治療前のハラビィノモグラムによる予測生存期間が18か月を上回る患者にGVAXによる治療を実施した場合、化学療法に比して2.5か月の生存有益性がみられ、長期生存例の「テール」が30%であった。これらの結果から、GVAX前立腺免疫療法により化学療法を上回る生存有益性が得らることが示され、これはプラセボに比して約2か月の生存有益性に相当することを示すものである。
B16黒色腫腫瘍モデルは侵襲性で免疫原性が弱く、放射線照射したGM−CSF分泌B16黒色腫腫瘍細胞(B16−GM)による治療的ワクチン接種は、CTLA−4またはPD−1などの免疫チェックポイントの遮断と組み合わせない限り効果が認められていない。この実施例では、本発明者らは、腫瘍が触知可能になり確立されたB16腫瘍細胞移植後7日目にSTINGVAX(ジギトニンとともに製剤化し、放射線照射B16−GMとインキュベートしたCDN)の単回注射を実施したところ、確立された触知可能なB16腫瘍の成長が有意に阻害されたことを示す。
図9は、放射線照射GM−CSF発現同種腫瘍細胞とともに製剤化したSTING活性化環状プリンジヌクレオチドの「STINGVAX」(GVAX;STING+GVAX=STINGVAX)の作用の相乗的機序を図示している。GVAX腫瘍細胞ワクチンにより、免疫系に対して複数の腫瘍関連抗原の偏りのない提示がもたらされる。GVAXによって産生されたGM−CSFが注射部位に樹状細胞(DC)を動員する。CDNが動員されたDCを活性化し、これにより強力な抗原特異的CD4およびCD8 T細胞が活性化または抗原刺激され、腫瘍まで移動してこれを殺滅し、その結果、臨床的有用性がもたらされる。STINGVAXは、GM−CSFに動員されたDCの集積所としての役割を果たすことによって腫瘍応答を増強し得る、あるいはオートクリンシグナル伝達を介して、GM−CSFに動員されたDCを協働して活性化するTBK−1/IRF−3依存性のIFN−βおよびNF−κB炎症誘発性サイトカインをともに発現し得る。
Claims (15)
- STINGと結合しSTING依存性TBK1活性化を誘導する環状プリンジヌクレオチドと、
GM−CSFを発現し分泌する不活化腫瘍細胞と
を含む組成物。 - 薬学的に許容される添加剤をさらに含む、請求項1に記載の組成物。
- 前記不活化腫瘍細胞がCCL20、CCL3、IL−12p70もしくはFLT−3リガンドから選択される1つまたは複数のサイトカインをさらに発現し分泌する、請求項1または2に記載の組成物。
- 1つまたは複数のCTLA−4アンタゴニストおよびTLR−4アゴニストをさらに含む、請求項1〜3のいずれか1項に記載の組成物。
- 前記腫瘍細胞が、放射線処理によって不活性化されている、請求項1〜4のいずれか1項に記載の組成物。
- 前記環状プリンジヌクロチド(dinuclotide)が、c−ジAMP、c−ジGMP、c−ジIMP、c−AMP−GMP、c−AMP−IMPおよびc−GMP−IMPまたはその組合せからなる群より選択される、請求項1〜5のいずれか1項に記載の組成物。
- 前記プリンジヌクロチド(dinuclotide)が、1つまたは複数の脂質とともに製剤化されている、請求項1〜6のいずれか1項に記載の組成物。
- 前記1つまたは複数の脂質がジギトニンを含む、請求項7に記載の組成物。
- 前記1つまたは複数の脂質がリポソームを形成する、請求項7に記載の組成物。
- 1つまたは複数のアジュバントをさらに含む、請求項1〜9のいずれか1項に記載の組成物。
- 前記1つまたは複数のアジュバントがCpGおよび/またはモノホスホリル脂質Aを含む、請求項10に記載の組成物。
- 個体において癌に対する免疫応答を誘導する方法における使用のための請求項1〜11のいずれか1項に記載の組成物であって、
前記不活化腫瘍細胞または異なる腫瘍細胞の混合物が前記個体の癌と型が一致する、
組成物。 - 前記不活化腫瘍細胞または異なる腫瘍細胞の混合物が、1つまたは複数の同種腫瘍細胞系である、請求項12に記載の使用のための組成物。
- 前記不活化腫瘍細胞が自己腫瘍細胞である、請求項12に記載の使用のための組成物。
- 前記腫瘍細胞が、結腸直腸癌細胞、気道消化器扁平上皮癌細胞、肺癌細胞、脳癌細胞、肝臓癌細胞、胃癌細胞、肉腫細胞、白血病細胞、リンパ腫細胞、多発性骨髄腫細胞、卵巣癌細胞、子宮癌細胞、乳癌細胞、黒色腫細胞、前立腺癌細胞、膵臓癌細胞および腎臓癌細胞からなる群より選択される、請求項12〜14のいずれか1項に記載の使用のための組成物。
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HK1204302A1 (en) | 2015-11-13 |
CN104507538B (zh) | 2018-04-06 |
IN2014MN02492A (ja) | 2015-07-17 |
CA2876150A1 (en) | 2013-12-12 |
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