JP6162778B2 - ワクチン免疫療法 - Google Patents
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- JP6162778B2 JP6162778B2 JP2015222533A JP2015222533A JP6162778B2 JP 6162778 B2 JP6162778 B2 JP 6162778B2 JP 2015222533 A JP2015222533 A JP 2015222533A JP 2015222533 A JP2015222533 A JP 2015222533A JP 6162778 B2 JP6162778 B2 JP 6162778B2
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Description
天然サイトカイン混合物(NCM)の調製
NCM(本明細書中においてIRX−2ともいう)は、フィトヘムアグルチニン(PHA)およびシプロフロキサシンによってヒトの末梢血単核細胞(PBMC)を刺激した後、GMP条件のもとで24時間かけて産生される規定のサイトカイン混合物である。PBMCの提供者をスクリーニングし、および試験済みの軟膜はFDAに認可された血液銀行から購入される。PHAの刺激の後、分裂促進因子を遠心分離および洗浄によって除去する。すべての細胞学的要素を遠心分離によって除去し、およびDNAを、陰イオン交換クロマトグラフィーによって除去する。細胞の存在しない上清を、フィルターを通して滅菌しナノフィルターで濾過してウイルスの除去を可能にし、および、これをIRX−2と指名する。生物学的試験およびサイトカイン濃度のELISAによる決定の両方を含む厳格なQC試験によって、IRX−2の一貫性が保証される。滅菌性、DNA、マイコプラズマ、エンドトキシンに関する安全性試験、および、CMVおよびEBVに対するウイルス試験もまたGMP工程の一部である。IRX−2はこれまで様々な臨床試験において150例を上回る患者に安全に投与されてきており、および、FDAによって承認されたINDのもと現在第I/II相試験にある。
頸部におけるNCMの局所外リンパ注射を、低用量のCY(300mg/m2)、INDO(25mgを経口で1日3回)、および亜鉛(元素亜鉛65mgを硫酸塩として、1日1回経口)による治療に加えることによって、頭頸部の扁平上皮細胞癌(H&N SCC)の患者の高い比率に臨床的退縮を誘起し(Hadden、1994;Meneses、1998;Barrera、2000;Hadden、2003;Menesis、2003)、無再発生存率の向上の徴候も伴った。全体としては、わずかな奏効(25%〜50%)、腫瘍の縮小、および病理組織標本中の腫瘍の縮小を含めると、90%を上回る患者に効果があり、およびその大半に50%を上回る腫瘍の縮小があった。
前述した臨床試験の臨床学的、病理学的および生存率のデータのさらなる分析によって、より多くの洞察が本発明の性質に提供される。その理由は、本発明は、自らの自己腫瘍抗原に対する患者の免疫、および、結果として生じる腫瘍の免疫の退化に関するからである。図6は、NCM(IRX−2)プロトコールによる治療が48ヶ月時点での生存率の増加に関連する(p<0.01)ことを示す。図7は、正の臨床反応が生存率と相関する、即ち、完全奏効(CR)または部分奏効(PR)の患者(50%を上回る腫瘍縮小)が、わずかな奏効(MR)(50%未満であるが25%を上回る腫瘍縮小)または無反応(NR)(25%未満)の患者よりも生存率が良好であった(p<0.01)ことを示す。図8は、病理反応がより強い患者(指標6〜9)のほうが、病理反応がより弱い患者よりも(6未満)、生存率が良好であった(p<0.02)ことを示す。図9は、腫瘍へのリンパ浸潤が単一の変数として生存率を予測する(p<0.01)ことを示す。臨床反応の病理反応との関係のカイ二乗分析は有意性の高い関係(p<0.01)を示し、このことは、この両者が生存率と相関するだけでなく、互いに相関し、従って、臨床反応、免疫の退化パラメータ、および生存率の間で相互に関連する、統計的なデータの三角関係を提供することを示している。このような関係は、ヒトの癌の免疫療法に対してこれまで全く示されてこなかった。
頭頸部のリンパ腫の患者2例を、上記に記載されたプロトコールに従って治療した。下記のスキームに従った。
患者は、左顎下腺領域の腫瘍の存在を示し、他に症状のない病歴3ヶ月の23歳の男性であった。緊急治療室にて患者は、左顎下腺領域に深いレベルに部分的に固定された堅い直径約6.5cmのリンパ節腫脹がみとめられた。残りの健康診断は正常であった。切開生検はホジキン・リンパ腫を示した。病変はECIIA期であった。NCMの一周期治療が施され、リンパ節腫脹の大きさが直径1cmだけ減少するわずかな奏効を得た。NCM治療の後に得られた生検報告は、病変の60%が正常なリンパ浸潤を示し、および、新生物の残り(40%)は壊死を示した。生存率する腫瘍細胞が見出されなかった。
患者は、有痛性の中頸部腫瘤ならびに10kgの体重減少を提示した病歴2ヶ月の82歳の男性である。健康診断で、患者は、右口蓋扁桃に腫瘍を提示し、該腫瘍は約4×3cmまで肥大し、扁桃の中心に潰瘍があった。頸部では、右顎下リンパ節の測定値は約2×2cmであり、および、リンパ節腫瘤はレベルIIおよびIII、約5×5cmであった。健康診断の残りは正常であった。扁桃および一方の頸部リンパ節の切開生検は中等度の明確な非ホジキン・リンパ腫の混合物を示した。
臨床的にIB1期、IB2期およびIIA期の未治療の早期子宮頸癌の患者10例を、NCMの局所外リンパ注射(10日の連日注射)、その後、21日目の広範子宮全摘術によって治療した。NCM治療を開始する1日前に、患者は、300mg/mのCYの単回のIV投与を受けた。INDOないしイブプロフェン、および硫酸亜鉛が1日目から21日目まで経口で投与された。臨床反応ならびに病理反応、毒性ならびに無病生存率を評価した。
原発性肝細胞癌から肝転移した2例の患者を、脾臓内NCM(1回または3回の注射)によって治療した。プロトコールは、H&N SCC、子宮頸部、またはリンパ腫の症例について前述したとおりであった。進行性肝細胞癌の患者1例は部分奏効を示し、断層撮影によって確認された。残りの1例は、部分奏効を示し、外科手術によって確認された。組織学的試験は腫瘍の縮小、断片化、およびリンパ浸潤を示した。
(ヒト・パピローマ・ウイルスが関連する)陰茎の扁平上皮細胞癌の患者4例を、上記に記載したようなNCMプロトコールで治療した。4例はすべて臨床的に部分奏効し、および、外科標本はH&N SCC癌患者に特徴的にみられる腫瘍の縮小および断片化、およびリンパ浸潤を示した。
NCMによるTリンパ球減少症の改善
下記の実験の目的は、リンパ球減少症患者のリンパ球数(LC)に対する10日の連日注射(115単位IL−2当量/日)での、6つのサイトカインIL−1、IL−2、IL−6、IL−8、IFN−γ、およびTNF−αを含有するNCMによる治療の効果を評価することであった。これらの患者は、過去の頭頸部癌への外科手術および放射線治療から回復し、および、平均細胞数441個/mm3の持続性リンパ球減少症を患っていた。LCの正常レベルは2000個/mm3である。患者は治療時に癌はなかった。0日目および13日目にLCを得た。Tリンパ球(CD3+)およびT細胞サブセット(CD4+またはCD8+)を細胞蛍光測定法によって評価した。表IIは、応答した患者5例のデータを提示する。有意な増加がLC、CD3+、およびCD4+T細胞に観察された。
NCMは樹状細胞の成熟および活性化を刺激する
過去の実験において、NCMで治療したH&N SCC患者5例、および未治療H&N SCC対照患者5例からリンパ節を単離し、および、樹状細胞の細胞表面マーカー(即ち、CD83+、CD86+、およびCD68+)のパネルを用いて、フロー・サイトメトリーによって、細胞組成を分析した。上述したように、洞組織球症は、一部の癌患者に見られるリンパ節の病変であり、未熟な樹状細胞を代表する大きな組織球のリンパ節内で蓄積することを特徴とする。図11Aに示すように、SHを患う患者(SH+)はリンパ節内にCD68+、CD83+、CD86DCの蓄積を有するが、一方、顕著なSHのない患者はCD83+細胞がほとんどなかった。しかしながら、NCM治療によって、未治療の癌対照と比べると、CD86+(CD68+、CD83+と共存する)DCの数が5倍増加し、このことは「活性化された」DC表現型への変換を示している。対照は、NCMで治療した癌患者と比較するための、未治療のH&N SCC患者である(図11Bを参照)。
NCMによる単球/マクロファージの活性化の刺激
サイトカインIL−1、IL−2、IL−6、IL−8、IFN−γおよびTNF−αを含有する本発明のNCMは、単球/マクロファージの強力な活性化因子でもある。より具体的には、付着PBMC(90%まで単球)をX−VIVO10培地中(BioWhittaker Bioproducts)で一晩成長させ、NCM(IRX−2)で24時間刺激し(最終濃度1:3で)、および、活性化されたマクロファージ上に典型的にみとめられる様々な活性化マーカーの発現について、フロー・サイトメトリーによって試験した。対照として、細胞をNCMのない培地中で24時間インキュベートした。図19に示すように、サイトカインを添加しないものと比べて、NCMによる細胞の処理によって、陽性の染色を示した細胞のパーセント比率が統計学的に増加し(図19A)、および、HLA−CR、CD86、CD40およびCD80(すべて単球/マクロファージの活性化マーカーである)に対する平均蛍光指数(MFI)が増加した(p<.03)(図19B)。図19に示すデータは、3回の独立した実験/提供者からの平均値±SEMを表す。
下記に詳説する各実験は、本発明のNCM組成物が、外因性抗原と併用して作用して、マウス中の抗原に対する免疫応答の向上(細胞学的なおよび抗体の両方)を誘発する能力を示す。
マウス
該手順は、オブアルブミン(OVA)またはキーホール・リンペット・ヘモシアニン(KLH)のいずれかに共役させたPSMAの予測されたT細胞エピトープ(LLH&ALF)(各100μg)に基づいて、前立腺特異的膜抗原(PSMA)ペプチドでマウスに免疫することであった。単離された非共役ペプチドを用いたこれまでの試みはマウスで成功しなかった。低用量のCY(400μg/マウス)の後に、NCM(0.1ml)を両方の共役抗原と併用して単回免疫として提供した後、NCM(0.1ml)を抗原を伴わずに9日間連続注射した。一方、CpG、ミョウバン、またはRIBI−Corixaアジュバントは、OVA共役体と併用した単回一次免疫であった。追加免疫(上記の共役体およびアジュバント)を各群のマウスに21日目及び28日目に与えた。T細胞ペプチドに対するDTH応答は最後の追加免疫の9日後に測定し、および、15〜21日目の屠殺時に血清を採取した。
血清を指示どおりに希釈し、および、ペプチド(ALFもしくはLLH)またはオブアルブミンのいずれかで被覆したマイクロプレートのウェルに添加した。結果は、5つのマウス群に対して405での平均ODとして表される。データは下記の表IVに提示される。
前立腺特異的膜抗原ペプチド(ペプチド1:Leu−Leu−His−Glu−Thr−Asp−Ser−Ala−Val;ペプチド2:Ala−Leu−Phe−Asp−Ile−Glu−Ser−Lys−Val)は、BioSynthesis Inc.(ルイスヴィル、テキサス州)によって合成された。オブアルブミンおよびシクロフォスファミドはSigmaから、およびKLHはPierce Biochemicalsから得た。RASとも呼ばれるRIBIアジュバントシステム(R−700)はCorixaから購入し、およびミョウバン(各40mg/mlの水酸化アルミニウムおよび水酸化マグネシウム)はPierce Chemicalsから購入した。RASは、モノホスホリル脂質A(0.5mg)および合成トレハロース・ジコリミコレート(0.5mg)、および44μlのスクアレンおよびツイン−80から成る。CpGオリゴヌクレオチド(マウスに特異的な配列)はBioSynthesisによって合成された。CpG配列はTCCATGACGTTCCTGACGTTであり、および、チオフォスフォネート誘導体であった。マウス中のCpGの生物活性は、マウス脾臓細胞の増殖およびマウス付着細胞によるTNF−αの産生(データ表示なし)を測定することによって確認される。
上記に記載のペプチド1および2を、上記に記載したようなオブアルブミンまたはKLH担体などの担体分子に共役させた。両方のペプチドは各担体に、即ち、単一の製剤として共役させた。例えば、これらの試験に用いられたOVA−PSMA共役体またはKLH−PSMA共役体は、担体分子に結合した両方のペプチドを含有した。ペプチドは、カルボジイミド法を用いてそれぞれの担体に共役させた(ODC;ピアスEDCキット77502、ロックフォード、イリノイ州)。早期の試験では、グルタルアルデヒド(Sigma、セントルイス、ミズーリ州)を使用したが、この2方法の間に免疫原性の差(データ表示なし)はなかったので、その後の試験にはより管理された方法としてカルボジイミド結合が選択された。共役体は、セファデックス精製カラムからの画分中のOD280および215を測定することによって特徴付けた。カラムからの280ODピークはオブアルブミンまたはKLH共役体を表し、および、共役体として回収された。用量決定はカラムから回収した担体の濃度に基づいた。215を観測すると、遊離ペプチドを表すテーリングピークを示し、このことは、共役手順の間に過剰なペプチドが存在したことを確認した。
Balb/cマウスを、Charles RiverまたはHarlanのいずれかから購入し、Cold Spring Harbor Animal Facility(CSHL)によって飼育した。すべての手順はCSHLのALAC委員会によって承認された。いくつかの実験では、シクロフォスファミド(400または2000μg/100μl、腹腔内)をIRX−2による処理の3日前に注射した。その後の試験は、シクロフォスファミドが、マウスにおけるNCM(IRX−2)による応答の増強に対して、統計学的に有意な効果を及ぼさなかったことを示した(データ表示なし)。免疫を下記のように実施した。PSMA共役体100μl、および、100μgのNCMないしミョウバンなどアジュバント、または、PBSを含有する200μl/マウスを、尾の付け根の皮下に注射して、局所リンパ節への急速な流入を与えた。一次免疫の後に、常に9回の(2、3、4、5、8、9、10、11および12日目に)追加的なNCMの注射(100μl=6〜8IUのIL−2当量)を行った。ミョウバンまたはRIBIとは異なり、NCM(IRX−2)を反復して同一部位に注射しても、該部位に顕著な炎症をきたさなかった(未公開の所見)。DTH活性を評価する前に、共役体およびアジュバントによる(14日目および28日目の)追加免疫を2回実施した。追加免疫では、追加のNCMは与えなかった。
DTH検定のためのin vivoでの抗原惹起は、該2個のPSMAペプチドの混合物(担体を含まない)(20μl中100μg)または担体単独(オブアルブミンまたはKLH)(20μl中50〜100μg)のいずれかによって行った。マウスには、追加免疫の9日後に、惹起抗原を左肢足蹠におよびPBSを右肢足蹠に皮下に注射した。24時間後、右肢および左肢足蹠の厚さをデジタル読み取りノギス(Preisser DIGI−METモデル18314、Stofiting Co.、ウッド デール 、イリノイ州)を用いて測定した。腫脹応答を左肢足蹠の厚さ(実験的応答)から右肢足蹠の厚さ(ベースライン)を減算することによって計算した。データは、各マウスの腫脹ならびに平均±平均の標準誤差として表した。統計学的解析はスチューデントt検定または分散分析により行った。
これら試験のために、追加免疫の14〜21日後に脾臓を採取し、および、金網を通して分散させて単離した。脾臓細胞を採取しおよびプラスチックに90分間付着させることによって付着細胞を得た。単離した付着細胞はプールされ、その後培養に添加されて、追加的な抗原提示細胞を提供した。2×104個の付着細胞を1ウェルあたり約6×105個のリンパ球に添加した。
屠殺時の血清は、ELISA検定で後に使用するために凍結させた。ELISAプレート(イムノロン−4、Nunc、デンマーク)を興味のある抗原(オブアルブミン、KLH、共役体または個々のペプチド)で一晩被覆した。血清の希釈液をブロックされおよび洗浄されたウェルに添加して、一晩インキュベートした。抗マウス・ビオチンおよびビオチン−アルカリ・フォスファターゼ(Southern BioTech、バーミングハム、アラバマ州)を順次添加し、およびpNPP基質の添加の後、ODを測定しおよび血清の希釈に対してプロットした。
若齢マウスに、OVA−PSMAまたはKLH−PSMA共役体と併用した、NCM(または陰性対照としてのPBSのいずれか)で、上述したように(例えば、共役体100μg、およびNCMまたはPBS100μlを含む200μl/マウスを)免疫した。免疫は、尾の付け根に皮下注射として投与され、局所リンパ節への急速な流入を提供した。マウスは後に、上記に記載したようなDTH検定において、惹起抗原として、PSMAペプチド(図24A)、または、共役体の免疫にそれぞれ用いられる担体(図24B)のいずれかを用いて惹起した。
出願人らは最初に、分裂促進因子(PHA)で刺激した老齢マウスの脾臓細胞が、若齢マウスの応答と比べて、二つの主要なT細胞サイトカイン、IL−2およびIFN−γの分泌において劣っていた(IL−2:285対75pg/ml、およびIFN−γ:1535対128pg/ml)ことを示すことによって、老齢マウス(>18月齢)におけるT細胞免疫応答が若齢マウス(8〜16週齢)における応答と比べて不完全であることを確認した。
従って、NCMおよびPSMA共役体で免疫したマウスに対するNCM処理のアジュバント効果を、免疫したマウス由来の脾臓細胞によるIFN−γの分泌を測定することによって決定した。より具体的には、KLH−PSMA共役体(上記に記載したような)およびNCM(IRX−2)で免疫したマウスから脾臓細胞を採取し、共役体(KLH−PSMA)、担体(KLH)、またはペプチド(PSMA)でex vivoでインキュベートした。培養の6日後に脾臓細胞からの上清を回収し、および、上記方法および材料の節に記載されているようにIFN−γの分泌を測定した。図28に示すように、共役体およびNCMで免疫したマウスにおけるIFN−γ(pg/ml中)の産生形態でのT細胞応答は、3抗原すべてについて、未感作マウスよりも大きかった。
さらに、NCM処理がin vivoで抗体産生に対するアジュバント効果を有したか否かを決定するために実験を実施した。より具体的には、マウスを、上記に記載したようなPSMA−共役体、および、アジュバントであるNCM、ミョウバンまたはCpGで免疫した。アジュバントに対する陰性対照としてPBSを用いた。マウスからの血清を、3回目の免疫から15日後(図29AおよびBに示すデータ)、または、3回目の追加免疫から8および15日後(図29Cのデータ)のいずれかの日の屠殺時に得た。血清をELISAによって抗体について検定し、結果を希釈率対光学密度として(図29AおよびB)、または、最適希釈率1/400での光学密度として(図29C)表した。
進行性前立腺癌の患者3例は、事前の低用量のCY(300mg/m2)、および、NCM(1ml−100単位、IL−2当量)と併用した非共役のALF&LLHペプチド(各100μg)、および、連日のINDO(25mg、1日3回)、および、9回の追加的なNCMの注射(1ml)を受けた。15日目に、NCMの追加免疫およびペプチドが与えられた。別の患者(#4)は、この投薬計画においてOVA共役ペプチドを受けた。NCM(0.1ml)、ALFもしくはLLH(10μg)による遅延型過敏性反応(DTH)を、cm単位の紅斑および継続時間について24時間後に読み取った、皮内皮膚試験によって測定した。結果は表VIに提示される。
米国特許番号
4,439,196
4,447,233
4,447,224
4,475,196
4,486,194
4,487,603
4,738,927
4,925,678
4,959,217
4,992,367
5,100,664
5,167,616
5,169,383
5,503,841
5,225,182
5,632,983
5,643,565
5,698,194
5,800,810
6,060,068
米国特許出願公開
US 2004/0136952 A1
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Claims (14)
- 癌を患う患者における少なくとも一つの外因性腫瘍抗原に対する免疫応答を誘発することにより進行性前立腺癌を治療するための組成物であって、
サイトカインIL−1、IL−2、IL−6、IL−8、IFN−γ、およびTNF−αを含む有効量のサイトカイン混合物を含有し、
該組成物は、さらに少なくとも一つの該外因性腫瘍抗原を含む投薬計画における投与のためにあり、
該サイトカインは少なくとも一つの該外因性腫瘍抗原のアジュバントとして作用し、および、患者における少なくとも一つの該外因性腫瘍抗原に対する免疫応答を刺激し、
前記少なくとも一つの外因性腫瘍抗原は、少なくとも一つのペプチドであり、
該免疫応答は、患者における進行性前立腺癌の症状および影響を緩和または解消するのに有効であり、
前記患者は、以前に外科手術、放射線治療、化学治療またはこれらの組み合わせを受けている、そして、
前記患者は、腫瘍再発、及びPSA抗原レベルの増加を有する、前記組成物。 - 前記サイトカイン混合物が、IL−12、GM−CSF、およびG−CSFをさらに含有する、請求項1に記載の組成物。
- 前記投薬計画は、該組成物および少なくとも一つの該外因性腫瘍抗原を同時に投与することを含む、請求項1または2に記載の組成物。
- 少なくとも一つの有効量の該外因性腫瘍抗原をさらに含有する、請求項1〜3のいずれかに記載の組成物。
- 少なくとも一つの該外因性腫瘍抗原は、一種以上の前立腺特異的膜抗原(PSMA)ペプチドを含む、請求項1〜4のいずれかに記載の組成物。
- 前記症状および影響は、骨痛を含む、請求項1〜5のいずれかに記載の組成物。
- 前記患者における疾患の症状および影響を緩和または解消することは、PSA抗原レベルを安定化させることを含む、請求項1〜6のいずれかに記載の組成物。
- 前記患者は、以前に外科手術を受けており、ここで、外科手術は、前立腺切除術および/または精巣摘出術を含む、請求項1〜7のいずれかに記載の組成物。
- 前記患者は、HLA−A2陽性である、請求項1〜8のいずれかに記載の組成物。
- 前記投薬計画は、さらに、非ステロイド抗炎症薬(NSAID)およびシクロフォスファミドを投与することを含む、請求項1〜9のいずれかに記載の組成物。
- 前記NSAIDは、インドメタシンである、請求項10に記載の組成物。
- 前記組成物が、滅菌注射溶液として処方される、請求項1〜11のいずれかに記載の組成物。
- 前記組成物が、前記患者へ局所外リンパ注射により投与される、請求項1〜12のいずれかに記載の組成物。
- 前記投薬計画は、さらに、前記組成物および少なくとも一つの該外因性腫瘍抗原を1回よりも多く投与することを含む、請求項1〜13のいずれかに記載の組成物。
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JP2013189480A (ja) | 2013-09-26 |
CA2694428A1 (en) | 2008-01-31 |
JP2017155059A (ja) | 2017-09-07 |
MX2009000934A (es) | 2009-07-29 |
EP2056861A2 (en) | 2009-05-13 |
US9492519B2 (en) | 2016-11-15 |
EP2056861A4 (en) | 2012-04-25 |
EP2684569A1 (en) | 2014-01-15 |
JP2009544724A (ja) | 2009-12-17 |
WO2008014220A3 (en) | 2008-05-02 |
AU2007276835A1 (en) | 2008-01-31 |
US9492517B2 (en) | 2016-11-15 |
WO2008014220A2 (en) | 2008-01-31 |
CA2694428C (en) | 2018-06-12 |
AU2007276835B2 (en) | 2013-03-28 |
US20070025958A1 (en) | 2007-02-01 |
JP2016029100A (ja) | 2016-03-03 |
US20140030217A1 (en) | 2014-01-30 |
US20100047205A1 (en) | 2010-02-25 |
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