JPWO2006001122A1 - Rnaウイルスが導入された樹状細胞を含む抗癌剤 - Google Patents
Rnaウイルスが導入された樹状細胞を含む抗癌剤 Download PDFInfo
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Abstract
Description
Alemany R. et al., Replicative adenoviruses for cancer therapy. Nat Biotechnol., 2000, 18:723-727 Curiel, D.T., The development of conditionally replicative adenoviruses for cancer therapy., Clin Cancer Res., 2000, 6:3395-9 Kirn, D., Virotherapy for cancer: Current status, hurdles, and future directions., Cancer Gene Therapy, 2002, 9:959-960 Mineta T. et al., Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med , 1995, 1:938-943
〔1〕ゲノム複製能を持つRNAウイルスが導入された樹状細胞を含む抗癌剤、
〔2〕RNAウイルスが外来蛋白質をコードしない、〔1〕に記載の抗癌剤、
〔3〕RNAウイルスが感染性ウイルス粒子を形成しない複製欠損ウイルスである、〔1〕または〔2〕に記載の抗癌剤、
〔4〕RNAウイルスが可溶性FGF受容体またはIFN-βをコードする、〔1〕または〔3〕に記載の抗癌剤、
〔5〕RNAウイルスが感染性または非感染性ウイルス粒子である、〔1〕から〔4〕のいずれかに記載の抗癌剤、
〔6〕RNAウイルスがゲノムRNA−蛋白複合体である、〔1〕から〔4〕のいずれかに記載の抗癌剤、
〔7〕ゲノム複製能を持つRNAウイルスを樹状細胞に導入する工程を含む、抗癌剤の製造方法、
〔8〕ゲノム複製能を持つRNAウイルスが導入された樹状細胞を投与する工程を含む癌の抑制方法、に関する。
ラッサウィルスなどのアレナウイルス科(Arenaviridae)
インフルエンザウイルスなどのオルソミクソウイルス科(Orthomyxoviridae)
SARSウイルスなどのコロナウイルス科(Coronaviridae)
風疹ウイルスなどのトガウイルス科(Togaviridae)
ムンプスウイルス、麻疹ウイルス、センダイウイルス、RSウイルスなどのパラミクソウイルス科(Paramyxoviridae)
ポリオウイルス、コクサッキーウイルス、エコーウイルスなどのピコルナウイルス科(Picornaviridae)
マールブルグウイルス、エボラウイルスなどのフィロウイルス科(Filoviridae)
黄熱病ウイルス、デング熱ウイルス、C型肝炎ウイルス、G型肝炎ウイルスなどのフラビウイルス科(Flaviviridae)
ブンヤウイルス科(Bunyaviridae)
狂犬病ウイルスなどのラブドウイルス科(Rhabdoviridae)
レオウイルス科(Reoviridae)
1)コロナウイルス
Enjuanes L, Sola I, Alonso S, Escors D, Zuniga S.
Coronavirus reverse genetics and development of vectors for gene expression.
Curr Top Microbiol Immunol. 2005;287:161-97. Review.
2)トガウイルス
Yamanaka R, Zullo SA, Ramsey J, Onodera M, Tanaka R, Blaese M, Xanthopoulos KG.
Induction of therapeutic antitumor antiangiogenesis by intratumoral injection of genetically engineered endostatin-producing Semliki Forest virus.
Cancer Gene Ther. 2001 Oct;8(10):796-802.
Datwyler DA, Eppenberger HM, Koller D, Bailey JE, Magyar JP.
Efficient gene delivery into adult cardiomyocytes by recombinant Sindbis virus.
J Mol Med. 1999 Dec;77(12):859-64.
3)ピコルナウイルス
Lee SG, Kim DY, Hyun BH, Bae YS.
Novel design architecture for genetic stability of recombinant poliovirus: the manipulation of G/C contents and their distribution patterns increases the genetic stability of inserts in a poliovirus-based RPS-Vax vector system.
J Virol. 2002 Feb;76(4):1649-62.
Mueller S, Wimmer E.
Expression of foreign proteins by poliovirus polyprotein fusion: analysis of genetic stability reveals rapid deletions and formation of cardioviruslike open reading frames.
J Virol. 1998 Jan;72(1):20-31.
4)フラビウイルス
Yun SI, Kim SY, Rice CM, Lee YM.
Development and application of a reverse genetics system for Japanese encephalitis virus.
J Virol. 2003 Jun;77(11):6450-65.
Arroyo J, Guirakhoo F, Fenner S, Zhang ZX, Monath TP, Chambers TJ.
Molecular basis for attenuation of neurovirulence of a yellow fever Virus/Japanese encephalitis virus chimera vaccine (ChimeriVax-JE).
J Virol. 2001 Jan;75(2):934-42.
5)レオウイルス
Roner MR, Joklik WK.
Reovirus reverse genetics: Incorporation of the CAT gene into the reovirus genome.
Proc Natl Acad Sci U S A. 2001 Jul 3;98(14):8036-41. Epub 2001 Jun 26.
その他のRNAウイルスの増殖方法および組み換えウイルスの製造方法については、ウイルス学実験学 各論、改訂二版(国立予防衛生研究所学友会編、丸善、1982 を参照のこと。
(実験1)
健常者より単球をネガティブセレクションで濃縮 (enrichment) した。単球の濃縮のためのネガティブセレクションは、RosetteSepTM-human monocyte enrichment cocktail (Stem Cell Technology Inc.) を用いた。すなわち、tetrameric antibody(抗体2分子が結合している抗体で、一方は赤血球を認識する抗glycophorin A抗体、他方が単核球の表面抗原を認識する抗体でできている)を用い、除去したい細胞を赤血球に結合させ、Ficoll PaqueTM Plus (Pharmacia Biotech Inc.) で除去することにより実施した。このネガティブセレクションにより、CD2、CD3、CD8、CD19、CD56、CD66bを発現している細胞が除去され、残った細胞を単球濃縮細胞として、次のDCの分化誘導に用いた。この時のCD14+細胞は65-80%であった。単球濃縮細胞に GM-CSF (500 U/ml)とIL-4 (250 U/ml) を添加し、endotoxin free RPMI + 10%FCSで培養後、DCの作成を行った。3-4日目に半分の培養上清を同じ組成の新しい培養液で培養液交換を行った。副刺激分子(Costimulatory molecule)、ならびにCD11c、HLA-class II (DR, DP, DQ)、およびCD1aの発現が陽性であることを確認し、その他のlineage marker(CD3、CD56、CD19、CD15およびCD14)を表出していないことも確認した(図1および非提示データ)。この細胞を用いて、ウイルスの導入効率を検討した。この時点で、生細胞の90-98%がDCマーカー (CD11c、HLA-class II(DR,DP,DQ)) を発現していた。
なお、本実施例におけるセレクションは上記キットを用いたが、抗体でコートされた磁気ビーズを用いても、同様のセレクションを実施することが可能である。血球分離等をもちいて単核球を採取するなど、細胞を大量に調製する場合は、ビーズを用いることが好ましい。
実験1より得られたDC (分化誘導後7日目) に、緑色蛍光蛋白質 (GFP) を発現するセンダイウイルス (SeV-GFP)(伝播型、WO00/70070)をMOIをふって感染させ、経時的に細胞数の変化、GFPの発現、costimulatory moleculesの発現程度について検討した。その結果、MOIについては、MOI 20以上で%GFPは最大となった(図2〜5)。GFPの平均蛍光強度 (mean fluorescence intensity; MFI) については、MOI 100まで上げることにより更に上昇させることが可能である (非提示データ)。また、8日目までGFPのMFIは上昇した。costimulatory molecules (CD80およびCD86) については、全体的にMOI 20以上で最大となった。細胞数の減少については、MOIで1〜20の間はあまり変化ないが、MOI 50ではやや減少する傾向が見られたが有意差はなかった(図6)。
MOI 20でDCにSeV-GFPを感染させ、経時的にFACSを用いて、GFPの発現を検討した。その結果、2週以後は発現が低下する(細胞数も減少)ものの、2箇月までは発現細胞を確認できた(図7)。以下の実施例で示すように、RNAウイルスの感染でDCは活性化される。従って、RNAウイルスを用いたDCへの遺伝子導入は臨床応用として、ワクチンへの応用が可能である。投与はインビボでもエクスビボでも可能であるが、例えばエクスビボ投与によりRNAウイルスを感染させたDCを頻回投与することにより、長期にわたって体内における遺伝子発現を持続させることが可能である。
活性化と感染効率を検討した。活性化の有無でウイルスの感染効率が変化するかどうか検討を行った。7日間培養後のDCに2日間LPS (1 micro-g/ml) で刺激した後、SeV-GFPをMOI 30で感染、2日後にFACSでGFPを解析した。逆にSeV-GFP感染2日後にLPS刺激(2日間)を同じ条件で施行した。(図8および9)
結果;ヒトでは、LPSで活性化した後に、%GFPにおいて60%近くの陽性を認めた。これに対してマウスDCでは陽性率は極めて低かった (非提示データ)。しかしヒトにおいてもMFIは非常に低く、活性化した後のDCには遺伝子導入効率の極端な低下を認めた。これに対して、SeVを導入後にLPSで刺激しても、遺伝子導入効率は変化しなかった。この結果は、RNAウイルスを導入したDCを得るには、未成熟DC、すなわち活性化を受けていないDCを使用することが好ましいことを示している。
感染に必要な接触時間の検討を行った(図10)。その結果、約30分以下で遺伝子導入が可能であることが判明した。
他のウイルスベクターでの報告でCD34細胞に遺伝子導入し、DC分化誘導で遺伝子導入DC作製に成功した報告がある (J. Immunol. Meth. 2002; 153-165)。SeV-GFPでも同様の方法を試みた。ヒト臍帯血より、CD34マイクロビーズを用いて、CD34陽性幹細胞を分離(CD34 >90%)し、MOI 0、10、100で感染させた後、良く洗浄した。その細胞をRPMI + 10%FCSにSCF (50 ng/ml)、GM-CSF (500 U/ml)、TNF-alpha (50 ng/ml) を添加し、3日間培養後、SCF (50 ng/ml)、GM-CSF (500 U/ml)、IL-4 (250 U/ml)、TNF-alpha (50ng/ml) を添加したメディウムで継代 (半量のメディウムを3〜4日に交換) したものをウイルス感染より13日目にGFPの発現を検討した。その結果、遺伝子導入効率は65〜70%に達し、他のベクター以上にGFPの発現効率の良いDCが作製された。感染後のDCは副刺激分子の発現の解析より、感染させていないものと比べて活性化を受けているものが回収された。(図11および12)
以上の実施例から、RNAウイルスはレンチウイルス、レトロウイルスに比較して、導入効率は格段に優れており、アデノウイルスに劣らない導入効率を極めて簡便に迅速に得ることができることが実証された。また、他のベクターでは活性化マーカーは変動しないが、RNAウイルスの感染によりDCを活性化を誘導できることが判明した。
(実験1)
DCにSeV-GFPをMOI 30-50で感染させ、1日後にLPSで刺激(2日間)し、その後、costimulatory moleculesの発現を検討した。コントロールとして、LPS刺激のみ、SeV-GFP感染のみ、およびLPS刺激もSeV-GFP感染もなし、の条件について比較検討した。
結果;得られた結果から、SeV感染のみでもDCの活性化が起こることが示された。
LPSと匹敵するもの;CD80(+)HLA-DR(-)CD83(-)
LPSより強いもの;CD86(+)CCR7(-)
LPSより弱いもの;CD40(-)
(+)はLPS+SeVで相乗効果のあるものを表す。(図13−15)
MOI 30でDCにSeV-GFPを感染(感染後3日目、感染後1日目に、あるグループはLPSで刺激)させ、実験1と同様の群について、食細胞能力を検討した(1 micro-m PCV-RED latex-microspheres を使用。棒グラフは4℃で陽性となるバックグランドを差し引いたもの)。
結果;活性化マーカーでも見たように、SeVで感染したものは、活性化のため、貪食能の低下が見られた。特に、GFPの発現が高いもの程、貪食能が低かった。従って、例えばDCで腫瘍抗原を提示させるために腫瘍のlysateを使用する場合は、RNAウイルスをDCに導入する前にlysateとDCを共培養することが好ましい。(図16−17)
RNAウイルスによる樹状細胞の活性化に伴う樹状細胞サイトカイン産生能を検討するために、7日間の培養で得られた単球由来樹状細胞 (MoDC) を12穴のプレートで48時間(8x105/2ml/well:メディウムはX-vivo15TM+2%自己血清+ GM-CSF (500 U/ml)+IL-4 (250 U/ml))、以下の群の条件で培養した上清中のTNF-alpha、IL-1beta、IL-6、IL-8の値をLuminexTM systemで測定した。SeVの感染はMOI 30で2日間培養した。
Unstimulated群:メディウムのみの群
Allantoic fluid群:SeVの浮遊液である鶏卵しょう尿液(SeVは含まない)60 micro-L添加した群
UV-SeV-GFP群:SeV-GFP溶液を紫外線照射し、replication能力を除去した溶液60 micro-L添加した群
SeV-GFP:SeV-GFP溶液を60 micro-L添加した群(replication-competent SeV)
結果:UV照射をしない複製可能なSeV(replication-competent SeV)でGFPを遺伝子導入した樹状細胞のみTNF-alpha、IL-1beta、IL-6を産生、IL-8の産生を増大した(図18)。この時の、樹状細胞上のCD40、CD80、CD83、CD86、HLA-DRの発現上昇はreplication-competent SeVのみで誘導された(図19および20)。このことは、SeVを樹状細胞に遺伝子導入するのみで、免疫応答時に重要な炎症性サイトカイン(proinflammatory cytokine)の樹状細胞による産生を惹起することができることを意味している。また、UV処理したSeVではサイトカイン産生を誘導できなかったことから、樹状細胞遺伝子導入時における樹状細胞の膜上のレセプターとSeVの接触による樹状細胞の活性化というよりも、SeVの感染後におこるウイルスゲノムRNAの増幅過程が、樹状細胞の活性化に重要であることも示唆している。
RNAウイルスによる樹状細胞の活性化に伴う樹状細胞抗原提示能を検討するために、上記と同様の実験群について、それらのDCを3000 radの放射線を照射した後、T細胞の活性化能力について検討した。(doseをふったDCと純化(CD3+>95%)のアロあるいはsyngenic T細胞と3日間共培養した)。SeV-GFPに対する反応の指標として、syngenic T細胞を用いた。
結果;DC比とT細胞の量が少なく差が比較的顕著でないが、SeV感染単独で、LPSに匹敵するアロT細胞刺激性を持っていることが示された(図21)。なお、DCは放射線照射しないで用いることも可能である。
RNAウイルスによる樹状細胞の活性化に伴う樹状細胞抗原提示能を、現在もっとも樹状細胞成熟化能力が強力とされているサイトカインカクテル刺激による抗原提示能と比較した。7日間の培養で得られたヒト単球由来樹状細胞 (MoDC) を12ウエルのプレートで48時間培養した{1 x 106/2 ml/well:メディウムはX-vivo15TM+2%自己血清+ GM-CSF (500 U/ml)+IL-4 (250 U/ml)、以下の群の条件で培養}。なおRNAウイルスとして、F遺伝子を欠失し、温度感受性の変異MおよびHN蛋白質(M遺伝子: G69E, T116A, A183S、HN遺伝子: A262T, G264R, K461G)遺伝子を搭載し、且つ、持続感染型変異を有する変異PおよびL蛋白質(P遺伝子:L511F、 L遺伝子:N1197S, K1795E)遺伝子を搭載するセンダイウイルス(SeV-dFMtsHNtsPLmut-GFP (SeV/TS dFとも略称する))も比較として用いた(WO2003/025570; Inoue M, et al. J Virol 2003;77:3238-3246; Inoue M, et al. Mol. Ther. 2003; 7(5):S37)。このウイルスは、感染した細胞において感染性ウイルス粒子を形成する能力を失っている。
・SeV(-)群:メディウムのみの群
・SeV-dFMtsHNtsPLmut-GFP群:SeV-dFMtsHNtsPLmut-GFP(GFPを搭載したF遺伝子欠損, M/HN/P/L変異型SeV)をMOI 50で添加した群
・SeV-GFP群:SeV-GFP(GFPを搭載した伝播型SeV)溶液ををMOI 50で添加した群
・サイトカインカクテル群:サイトカインカクテル群(IL-1β 50 ng/ml、IL-6 500 ng/ml、INF-α 2500 U/ml、TNF-α 100 ng/ml、PGE2 20μM)を添加した群
48時間後に得られたMoDCに30 Gy照射した後、そのMoDC(4 x 104/ウエルから6.25 x 102/ウエル)とアロの末梢血由来T細胞(1 x 105/ウエル){アロの末梢血より、RosetteSepTM-human T cell enrichment kit (StemCell Technologies, Vancouver, Canada)を用いて得られた96%以上の純度のT細胞}を4日間培養した後、各ウエルに1μCiの[3H]-thymidineを添加し、8時間後の[3H]-thymidineの取り込み量をBeta Plate System (Pahrmacia LKB Biothechnology, Uppsala, Sweden) でカウントした。メディウムはX-vivo15TM+2%自己血清を使用した。示された図のX軸はウエルあたりの培養MoDC数/ウエルあたりのT細胞数(=1 x 105)、Y軸は[3H]-thymidine取り込み量(cpm)を示す(図22)。
結果:刺激していない樹状細胞と比較し、SeV-GFPを感染させた樹状細胞はアロのT細胞を有意に増殖させ、その能力は、ポシティブコントロールで、現在もっとも樹状細胞成熟化能力が強力とされているサイトカインカクテル刺激と同等以上であった。この抗原提示能力の程度はF欠損型HN温度感受性SeV(SeV-dFMtsHNtsPLmut-GFP)を感染させた樹状細胞でもほぼ同等であった(図22)。
Aに記載の方法でヒト末梢血(HLA-A 0201の健常ドナー)より、CD14+細胞を濃縮し、x-vivo 15TM (Cambrex社製) + 2% autologous serumをメディウムとして、GM-CSF (500U/ml)、IL-4 (250U/ml) を添加(3〜4日に一度、半量のメディウムを交換)、未熟樹状細胞を作製した。作製した未熟樹状細胞を次の3群に分け、更に48時間GM-CSF (500U/ml)、IL-4 (250U/ml) の存在下に培養した。
1群 何も加えない
2群 SeV-GFPの感染 (MOI 30)
3群 サイトカインのカクテル (IL-1β 50ng/ml、IL-6 500ng/ml、IFN-α 2500U/ml、TNF-α 100ng/ml、PGE2 20 micro-M) による刺激
その後、樹状細胞を回収して、MART-1ペプチド (EAAGIGILTV (配列番号:1)) をパルス(50 micro-g/ml;3時間)して、樹状細胞を採取したのと同じ健常人末梢血のT細胞をネガティブセレクションで濃縮 (CD3+>97%) して、ペプチドパルスした上記3群の樹状細胞と7日間培養した(X-vivo 15TM + 2%autologous serum)。(3-4日毎、あるいはメディウムの黄変時に半量のメディウムを交換した。最初の刺激時はIL-2なしでT細胞と樹状細胞を混合培養し、3日目からIL-2を100 U/ml添加開始した。)これを2回繰り替えし、それぞれの混合培養から、細胞を回収し、CTL assayのエフェクター細胞として使用した。
ターゲット細胞は、T2細胞(HLA-A2+の人から得られたT細胞-B細胞ハイブリドーマでTAP欠損細胞株)を使用した。この細胞は、TAP(class Iへのトランスポーター)がないため、細胞質内の蛋白の分解により産生されたペプチドをClass Iに誘導できないことから、ペプチドを外来から添加するとそのペプチドがClass Iにload されて、Class Iの発現が起こる。このターゲットを変異MART-1ペプチド (ELAGIGILTV (配列番号:2))(上記の刺激で使用したペプチドに対してT細胞レセプター認識部は変化なく、HLA-A2の結合を強めたもの)をパルスしたもの、Infuluenzaのペプチド (Flu; third partyとしてのペプチド; GILGFVFTL (配列番号:3)) をパルスしたものを作製し、Crで細胞をラベルし、上記3群のエフェクターT細胞とこの2種類のtargetを20:1、10:1、5:1、2.5:1 で4時間混合培養してCTL活性を調べた。
以下に実験の組み合わせをまとめた。
──────────────────────────────────
エフェクター細胞 ターゲット細胞 図のシンボル
1群のエフェクターT細胞 変異MART1ペプチド + T2細胞 実線の黒四角
2群のエフェクターT細胞 変異MART1ペプチド + T2細胞 実線の黒三角
3群のエフェクターT細胞 変異MART1ペプチド + T2細胞 実線の黒逆三角
1群のエフェクターT細胞 Fluペプチド + T2細胞 点線の黒菱形
2群のエフェクターT細胞 Fluペプチド + T2細胞 点線の黒丸
3群のエフェクターT細胞 Fluペプチド + T2細胞 点線の白四角
──────────────────────────────────
結果;上記3群のDCで活性化をしていないDC(MART1ペプチド+)でT細胞を刺激しても、MART-1特異的CTLは誘導できないが、ポジティブコントロールとして、サイトカインで活性化(現在腫瘍免疫の樹状細胞療法で最も強く活性化できる方法)した樹状細胞で、T細胞を刺激するとMART-1特異的CTLが誘導できた(ターゲットにパルスする変異MART-1ペプチドに替えて、刺激に用いたMART-1ペプチドを用いても同様の結果が得られた)。SeVを導入した樹状細胞を使用した場合、ポジティブコントロールと同程度のCTL活性が得られた(図23)。つまり、CTLアッセイで判定した場合、SeVを感染させるだけで樹状細胞は活性化され、サイトカインで活性化した樹状細胞と同じレベルにin vitroでCTLを誘導できることが示された。T細胞賦活化としてSeVを使用すれば、標的遺伝子の導入とともに活性化が起こせるので、サイトカインなどの活性化因子を添加する必要がなくなり、コスト節減、時間節減、細胞のviabilityの保持に寄与する。
本実施例は、RNAウイルスのインビボおよびエクスビボ投与による腫瘍の治療方法の一例を示す。
(実験1)
腫瘍モデルとして、MHC Class Iを非常に低いレベルでしか発現せず免疫原性に乏しいB16メラノーマの移植モデルを採用した。腫瘍モデルマウスには、C57BL/6マウス(6〜8週齢、メス)(日本チャールズ・リバー)を用い、樹状細胞はC57BL/6マウス(8週齢、メス)(日本チャールズ・リバー)より採取した。樹状細胞は、C57BL/6 マウスの大腿骨より骨髄を採取し、SpinSepTM, murine hematopoetic progenitor enrichmentcocktail (抗CD5抗体, 抗CD45R抗体, 抗CD11b抗体, 抗Gr-1抗体,抗TER119抗体, 抗7/4抗体、StemCell technology) を使用し、T cell を除去した後、IL-4およびGM-CSFを添加し1週間培養して得た。1 x 105/100 micro-L のB16メラノーマ細胞をday 0にマウスの腹部皮下 (s.c.) 接種した。Day 10、17、および24に、活性化刺激を加えない樹状細胞、LPSで活性化させた樹状細胞 (LPS DC)、あるいはSeV-GFPまたはマウス インターフェロンβを発現するSeV-IFNβを導入して活性化させた樹状細胞 (それぞれSeV GFP DCまたはSeV IFNβ DC) を腫瘍周囲に投与した。このとき、樹状細胞に腫瘍抗原(B16のfreeze and thawによる腫瘍ライセート)をパルスしてから投与する実験も行った。これらとは別に、腫瘍接種後10日目 (day 10) にSeV-IFNβを直接、腫瘍内注入 (intratumoral injection) して抗腫瘍効果を調べる実験も行った。
樹状細胞へのSeVの導入では、上記のように1週間培養した樹状細胞にSeV-IFNβをMOI 40で感染させ、8時間培養した。腫瘍抗原をパルスする場合は、上記のように1週間培養した樹状細胞を回収し、腫瘍抗原となるtumor lysateをパルス (DC : tumor lysate= 1 : 3) し、18時間培養した後、SeV-IFNβをMOI 40で感染させ、8時間培養した。その後、これらの樹状細胞を回収し、5x105 から 10x105 細胞数をマウスの腫瘍周囲に投与した。
[(試料のcpm - 自発放出のcpm) / (最大放出のcpm - 自発放出のcpm)] x 100
ここで、最大放出は1% triton X と共にインキュベートしたターゲット細胞、自発放出は培養液のみでインキュベートしたターゲット細胞を用いた。
メラノーマ細胞株 B16F1(ATCC CRL-6323)1×105個を、C57BL/6マウス(6〜8週齢、雌)の腹側皮下へ接種した(n = 4)。接種後5日(day 5)および12日(day 12)に、特別な治療遺伝子を有さないSeV(GFP発現SeV;SeV-GFP)、ヒト可溶型FGF受容体を発現するセンダイウイルス(SeV-sFGFR)、またはヒトPDGFRα可溶型を発現するSeV-hsPDGFRα、各1×108PFUを腫瘍内注射し、以降、腫瘍サイズを経時的に測定した。その結果、いずれのSeV投与群においても、SeV非投与群に比べて腫瘍サイズが有意に縮小した(図27)。このように、SeVのインビボ投与は、治療遺伝子を持たないものであっても抗腫瘍効果を発揮することができた。可溶型FGF受容体を発現するSeVを投与した場合は、SeV-GFP投与群よりも強い腫瘍増殖抑制効果が確認され、可溶型PDGFRαを発現するSeVを投与した場合の抗腫瘍効果は最も顕著で、腫瘍サイズはほどんど増加しなかった。
メラノーマ細胞株 B16F1(ATCC CRL-6323)1×105個を、C57BL/6マウス(6週齢、雌)の腹側皮下へ接種した(n = 4)。それとは別に、C57BL/6マウス(6〜8週齢、雌)の骨髄細胞を採取し、SpinSepTM (STEM CELL TECHNOLOGIES, INC)によるCD45R、CD5、CD11b、TER119、Gr-1、7-4のネガティブセレクションにて抽出した細胞をGM-CSF 250IU/ml、IL-4 250IU/ml存在下に7日間培養し、マウス骨髄細胞由来の樹状細胞を得た。その樹状細胞に、治療遺伝子を有さないセンダイウイルス(GFP発現SeV;SeV-GFP)をMOI 60、あるいはヒト可溶型PDGFα受容体を発現するセンダイウイルス(SeV-hsPDGFRα)、腫瘍抗原TRP2を発現するセンダイウイルス(SeV-TRP2)、または腫瘍抗原gp100を発現するセンダイウイルス(SeV-gp100)をそれぞれMOI 20ずつで感染させ、遺伝子導入を行った。
Claims (8)
- ゲノム複製能を持つRNAウイルスが導入された樹状細胞を含む抗癌剤。
- RNAウイルスが外来蛋白質をコードしない、請求項1に記載の抗癌剤。
- RNAウイルスが感染性ウイルス粒子を形成しないウイルスである、請求項1に記載の抗癌剤。
- RNAウイルスが可溶性FGF受容体またはIFN-βをコードする、請求項1に記載の抗癌剤。
- RNAウイルスが感染性または非感染性ウイルス粒子である、請求項1から4のいずれかに記載の抗癌剤。
- RNAウイルスがゲノムRNA−蛋白複合体である、請求項1から4のいずれかに記載の抗癌剤。
- ゲノム複製能を持つRNAウイルスを樹状細胞に導入する工程を含む、抗癌剤の製造方法。
- ゲノム複製能を持つRNAウイルスが導入された樹状細胞を投与する工程を含む癌の抑制方法。
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Families Citing this family (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE69638196D1 (de) * | 1995-11-01 | 2010-07-22 | Dnavec Research Inc | Rekombinantes sendai-virus |
US20030166252A1 (en) * | 1999-05-18 | 2003-09-04 | Kaio Kitazato | Paramyxovirus-derived RNP |
US20020002143A1 (en) * | 2000-03-30 | 2002-01-03 | Munehide Kano | AIDS virus vaccines using sendai virus vector |
US20060104950A1 (en) * | 2002-10-24 | 2006-05-18 | Shinji Okano | Methods of Tranducing genes into T cells |
KR101279748B1 (ko) * | 2003-11-04 | 2013-07-04 | 가부시키가이샤 디나벡크 겐큐쇼 | 유전자 도입된 수상세포의 제조방법 |
EP1712243A4 (en) * | 2004-01-13 | 2007-04-11 | Dnavec Research Inc | GENE THERAPY FOR TUMOR USING A NEGATIVE CHAIN RNA VIRAL VECTOR ENCODING AN IMMUNOSTIMULATORY CYTOKINE |
AU2005206410A1 (en) * | 2004-01-22 | 2005-08-04 | Dnavec Research Inc. | Method of producing minus strand RNA virus vector with the use of hybrid promoter containing cytomegalovirus enhancer and avian beta-actin promoter |
WO2005097988A1 (ja) * | 2004-03-23 | 2005-10-20 | Dnavec Research Inc. | 組織の維持および/または修復に関連する骨髄関連細胞 |
CA2571849A1 (en) * | 2004-06-24 | 2006-01-05 | Dnavec Research Inc. | Anticancer agent containing dendritic cell having rna virus transferred thereinto |
EP1916298B1 (en) * | 2005-06-14 | 2011-12-28 | Dnavec Corporation | Methods for producing monoclonal antibodies |
CN101405389A (zh) * | 2006-01-17 | 2009-04-08 | 生物载体株式会社 | 新型蛋白质表达系统 |
US20090053790A1 (en) * | 2006-01-31 | 2009-02-26 | Ishihara Sangyo Kaisha, Ltd. | Polypeptide Having Affinity for Envelope Virus Constituent and Use Thereof in Transferring Substance Into Cell |
KR20140146224A (ko) | 2006-04-14 | 2014-12-24 | 어드밴스드 셀 테크놀로지, 인코포레이티드 | 혈관 콜로니 형성 세포 |
WO2008065752A1 (fr) * | 2006-11-30 | 2008-06-05 | National University Corporation Hokkaido University | Agent immunothérapeutique contenant un arndi en tant que principe actif |
EP2952583A1 (en) | 2007-03-12 | 2015-12-09 | Oncolytics Biotech Inc. | Reoviruses having modified sequences |
JPWO2008136438A1 (ja) * | 2007-04-27 | 2010-07-29 | 国立大学法人九州大学 | 遺伝子治療用ウイルスベクター |
JP5227317B2 (ja) * | 2007-05-17 | 2013-07-03 | ディナベック株式会社 | 樹状細胞の製造方法 |
US8719420B2 (en) * | 2008-05-13 | 2014-05-06 | At&T Mobility Ii Llc | Administration of access lists for femtocell service |
US8691212B2 (en) * | 2008-09-16 | 2014-04-08 | Genomldea Inc. | Therapeutic/prophylactic agent for prostate cancer |
KR101527260B1 (ko) | 2008-11-14 | 2015-06-08 | 디나벡크 가부시키가이샤 | 수상세포의 제조방법 |
US20100266642A1 (en) * | 2009-02-20 | 2010-10-21 | Bind Biosciences, Inc. | Modified cells for targeted cell trafficking and uses thereof |
EP2236520A1 (en) * | 2009-03-31 | 2010-10-06 | Leukocare Ag | Stabilizing composition for immobilized biomolecules |
JP6013187B2 (ja) * | 2009-12-04 | 2016-10-25 | ステム セル アンド リジェネレイティブ メディスン インターナショナル, インコーポレイテッド | ヒト胚性幹細胞由来血管芽細胞からナチュラルキラー細胞および樹状細胞を生成する方法 |
DE102010018961B4 (de) * | 2010-04-23 | 2012-09-20 | Eberhard-Karls-Universität Tübingen Universitätsklinikum | Genetisch modifiziertes Paramyxovirus zur Behandlung von Tumorerkrankungen |
KR101365208B1 (ko) * | 2011-12-06 | 2014-02-20 | 가톨릭대학교 산학협력단 | 바이러스를 이용하여 제조된 심근염 치료용 면역관용 수지상 세포 및 이의 제조 방법 |
CA2896053A1 (en) | 2012-12-21 | 2014-06-26 | Ocata Therapeutics, Inc. | Methods for production of platelets from pluripotent stem cells and compositions thereof |
CA2991212A1 (en) | 2015-07-02 | 2017-01-05 | PrimeVax Immuno-Oncology, Inc. | Compositions and methods for combination therapy with dengue virus and dendritic cells |
US10765727B2 (en) | 2015-09-26 | 2020-09-08 | PrimeVax Immuno-Oncology, Inc. | Compositions and methods for producing dendritic cells |
WO2017223330A1 (en) * | 2016-06-22 | 2017-12-28 | Icahn School Of Medicine At Mount Sinai | Viral delivery of rna utilizing self-cleaving ribozymes and crispr-based applications thereof |
CN110139671A (zh) | 2016-11-16 | 2019-08-16 | 普莱瓦克斯免疫肿瘤学公司 | 用于治疗癌症的组合免疫疗法 |
CN117417886B (zh) * | 2023-10-20 | 2024-05-14 | 广东壹加再生医学研究院有限公司 | 一种负载肿瘤抗原的树突状细胞激活的t淋巴细胞的培养方法 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000070070A1 (fr) * | 1999-05-18 | 2000-11-23 | Dnavec Research Inc. | Vecteur de virus paramyxoviridae defectueux dans un gene enveloppe |
JP2001503385A (ja) * | 1996-08-13 | 2001-03-13 | カイロン コーポレイション | ポリヌクレオチド送達のための組成物および方法 |
JP2002272465A (ja) * | 2000-05-18 | 2002-09-24 | Dnavec Research Inc | 外来遺伝子導入用パラミクソウイルスベクター |
JP2005532286A (ja) * | 2002-04-04 | 2005-10-27 | サノフィ−アベンティス | 新規な1,2,3−置換インドリジン誘導体類、FGFsの阻害剤、それらの製造方法およびそれらを含む医薬組成物 |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5124148A (en) * | 1988-04-27 | 1992-06-23 | United Cancer Research Institute | Method for treating viral diseases with attenuated virus |
US6077519A (en) * | 1993-01-29 | 2000-06-20 | University Of Pittsburgh | Methods for isolation and use of T cell epitopes eluted from viable cells in vaccines for treating cancer patients |
PT1314431E (pt) * | 1993-04-30 | 2008-10-24 | Wellstat Biologics Corp | Composições purificadas de vírus da doença de newcastle |
US6300090B1 (en) * | 1994-07-29 | 2001-10-09 | The Rockefeller University | Methods of use of viral vectors to deliver antigen to dendritic cells |
EP0864645B9 (en) * | 1995-10-31 | 2006-03-22 | Dnavec Research Inc. | Negative-strand rna virus vector having autonomously replicating activity |
DE69638196D1 (de) * | 1995-11-01 | 2010-07-22 | Dnavec Research Inc | Rekombinantes sendai-virus |
US6734014B1 (en) * | 1996-02-08 | 2004-05-11 | The United States Of America As Represented By The Department Of Health And Human Services | Methods and compositions for transforming dendritic cells and activating T cells |
WO1998053048A1 (en) * | 1997-05-21 | 1998-11-26 | The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Methods and compositions for making dendritic cells from expanded populations of monocytes and for activating t cells |
JP2000253876A (ja) | 1999-03-08 | 2000-09-19 | Dnavec Research Inc | センダイウイルスベクターを用いたワクチンおよびワクチンタンパク質 |
US20030022376A1 (en) * | 1999-05-18 | 2003-01-30 | Kaio Kitazato | Paramyxovirus-derived RNP |
US20030166252A1 (en) * | 1999-05-18 | 2003-09-04 | Kaio Kitazato | Paramyxovirus-derived RNP |
US20020169306A1 (en) * | 1999-05-18 | 2002-11-14 | Kaio Kitazato | Envelope gene-deficient paramyxovirus vector |
EP1179594B1 (en) | 1999-05-18 | 2008-06-25 | Dnavec Research Inc. | Ribonucleoprotein complex in paramyxovirus |
US7226786B2 (en) * | 1999-05-18 | 2007-06-05 | Dnavec Research Inc. | Envelope gene-deficient Paramyxovirus vector |
US20020123479A1 (en) * | 1999-12-08 | 2002-09-05 | Song Elizabeth S. | Immunostimulation mediated by gene-modified dendritic cells |
US6472208B1 (en) * | 1999-12-13 | 2002-10-29 | Héma-Québec | Method of producing human IFN-α using sendai virus-infected hematopoietic stem cells |
US20020002143A1 (en) * | 2000-03-30 | 2002-01-03 | Munehide Kano | AIDS virus vaccines using sendai virus vector |
CA2322057A1 (en) * | 2000-05-18 | 2001-11-18 | Dnavec Research Inc. | Paramyxovirus vectors used for transfer of foreign genes |
AU2002305452A1 (en) * | 2001-05-08 | 2002-11-18 | Emory University | Regulating immine responses using dendritic cells |
WO2003004616A2 (en) | 2001-07-05 | 2003-01-16 | Phylogix, Inc. | Dendritic cell isolation methods |
BRPI0212545B8 (pt) | 2001-09-06 | 2021-05-25 | Northwest Biotherapeutics Inc | método ex vivo ou in vitro para produzir uma população de célula dendrítica madura e método para produzir células t |
CN1633599A (zh) * | 2001-09-18 | 2005-06-29 | 株式会社载体研究所 | 检查和制造降低了粒子形成能力的(-)链rna载体的方法 |
EP1438399A4 (en) * | 2001-09-28 | 2005-09-14 | Univ North Carolina | PARAMYXOVIRUSES AS GENE TRANSFER VECTORS TO PULMONARY CELLS |
CN1596311A (zh) * | 2001-09-28 | 2005-03-16 | 株式会社载体研究所 | 编码表位结合型β2m且感染哺乳动物细胞的病毒载体及其应用 |
WO2003102183A1 (fr) | 2002-06-03 | 2003-12-11 | Dnavec Research Inc. | Vecteurs de paramyxovirus codant pour un anticorps et son utilisation |
AU2002951082A0 (en) | 2002-08-30 | 2002-09-12 | The Corporation Of The Trustees Of The Order Of The Sisters Of Mercy In Queensland | Therapeutic cellular agents |
US20060104950A1 (en) * | 2002-10-24 | 2006-05-18 | Shinji Okano | Methods of Tranducing genes into T cells |
AU2003296439B2 (en) * | 2002-12-10 | 2009-05-07 | Argos Therapeutics, Inc. | In situ maturation of dendritic cells |
KR101279748B1 (ko) * | 2003-11-04 | 2013-07-04 | 가부시키가이샤 디나벡크 겐큐쇼 | 유전자 도입된 수상세포의 제조방법 |
EP1712243A4 (en) * | 2004-01-13 | 2007-04-11 | Dnavec Research Inc | GENE THERAPY FOR TUMOR USING A NEGATIVE CHAIN RNA VIRAL VECTOR ENCODING AN IMMUNOSTIMULATORY CYTOKINE |
AU2005206410A1 (en) * | 2004-01-22 | 2005-08-04 | Dnavec Research Inc. | Method of producing minus strand RNA virus vector with the use of hybrid promoter containing cytomegalovirus enhancer and avian beta-actin promoter |
CN1934257A (zh) * | 2004-01-22 | 2007-03-21 | 株式会社载体研究所 | 病毒载体的制备方法 |
CA2560046A1 (en) * | 2004-03-16 | 2005-09-22 | Dnavec Research Inc. | Methods for suppressing tumor proliferation |
WO2005097988A1 (ja) * | 2004-03-23 | 2005-10-20 | Dnavec Research Inc. | 組織の維持および/または修復に関連する骨髄関連細胞 |
CA2571849A1 (en) * | 2004-06-24 | 2006-01-05 | Dnavec Research Inc. | Anticancer agent containing dendritic cell having rna virus transferred thereinto |
KR20080031167A (ko) * | 2005-04-20 | 2008-04-08 | 디나벡크 가부시키가이샤 | 알츠하이머병 치료용의 고도로 안전한 비강투여용 유전자백신 |
CA2654033A1 (en) * | 2006-05-31 | 2007-12-06 | Dnavec Corporation | Therapeutic agent for alzheimer's disease |
JP5227317B2 (ja) * | 2007-05-17 | 2013-07-03 | ディナベック株式会社 | 樹状細胞の製造方法 |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001503385A (ja) * | 1996-08-13 | 2001-03-13 | カイロン コーポレイション | ポリヌクレオチド送達のための組成物および方法 |
WO2000070070A1 (fr) * | 1999-05-18 | 2000-11-23 | Dnavec Research Inc. | Vecteur de virus paramyxoviridae defectueux dans un gene enveloppe |
JP2002272465A (ja) * | 2000-05-18 | 2002-09-24 | Dnavec Research Inc | 外来遺伝子導入用パラミクソウイルスベクター |
JP2005532286A (ja) * | 2002-04-04 | 2005-10-27 | サノフィ−アベンティス | 新規な1,2,3−置換インドリジン誘導体類、FGFsの阻害剤、それらの製造方法およびそれらを含む医薬組成物 |
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AU2005257107A1 (en) | 2006-01-05 |
CN101006172B (zh) | 2012-09-05 |
EP1775343A1 (en) | 2007-04-18 |
US20080014183A1 (en) | 2008-01-17 |
EP1775342A4 (en) | 2007-11-07 |
JPWO2006001120A1 (ja) | 2008-04-17 |
EP1775343A8 (en) | 2007-09-26 |
JP2013151523A (ja) | 2013-08-08 |
CN101006171A (zh) | 2007-07-25 |
US20080031855A1 (en) | 2008-02-07 |
WO2006001122A1 (ja) | 2006-01-05 |
EP1775342A1 (en) | 2007-04-18 |
HK1106794A1 (en) | 2008-03-20 |
KR20070032022A (ko) | 2007-03-20 |
KR20070028573A (ko) | 2007-03-12 |
CN101006172A (zh) | 2007-07-25 |
AU2005257105A1 (en) | 2006-01-05 |
US8889118B2 (en) | 2014-11-18 |
CA2571844A1 (en) | 2006-01-05 |
CA2571849A1 (en) | 2006-01-05 |
EP1775342A8 (en) | 2007-06-20 |
JP5296983B2 (ja) | 2013-09-25 |
KR101270839B1 (ko) | 2013-06-05 |
EP1775343A4 (en) | 2007-11-14 |
WO2006001120A1 (ja) | 2006-01-05 |
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