JP2011513399A - 同種癌細胞による免疫療法 - Google Patents
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Abstract
【選択図】なし
Description
本出願は2008年3月3日出願の米国特許出願第61/033,425号の利益を主張し、引用によって組み込まれる。
米国政府は、米国保健社会福祉省からのNIHのコントラクトCA039201で提供されるように、本発明において特定の権利を有している。
C57BL/6J(B6)マウスはJackson Laboratory社又はCharles River Laboratories社から購入した。B6基礎環境を有するIgのμ鎖欠損マウスはJackson Laboratory社から購入した。
脾細胞及びリンパ節(LN)細胞の単一細胞懸濁液はgfp−OT−Iマウスから取得され、貯蔵された。それらは塩化アンモニウム溶解によって赤血球が枯渇された。gfp−OT−I細胞は、抗CD8αの磁気ミクロビーズを用いた能動的なカラム選択と、製造者の指示に従ったMACSカラム(Miltenyi Biotec社)とによって、選別された。分離されたOT−I細胞の純度は、フローサイトメトリー分析によって決定される場合、95%より高かった。精製された細胞上のVα2及びVβ5.1.2の発現は、フローサイトメトリーによって定量化された。B細胞の精製用に、CD19陽性細胞は抗CD19ミクロビーズ(Miltenyi Biotec社)で精製された。BCDMマウス中のB細胞を再構成するために、107の精製された細胞が、腫瘍細胞の移植前に2日間、尾静脈を通して養子移植された。
CD8陽性のCTL増殖を測定するために、マウスは106のgfp−OT−Iで養子移植され、1ないし4×106の非照射EG7−gp96−Ig細胞の腹腔内(i.p.)注入によって2日後に免疫化される。免疫処置に続いて、細胞は定期的な間隔で、腹膜腔、腸間膜の傍大動脈リンパ節(dLN)、及び末梢血から収集された。赤血球は塩化アンモニウム溶解によってサンプルから除去された。100万の細胞が4℃で10分間インキュベートされ、PBS中の抗CD16/32 mAbが0.5%のBSA(PBA)を含んで、FcR結合を遮断した。細胞はその後、指示された抗体とともに30分間インキュベートされた。サンプルはFACScan(Becton Dickinson社)上でCELL Questソフトウェア(BD Bioscience社)を用いて分析された。各組織ごとの指示された免疫細胞の全数は、各組織中の標的細胞及び全細胞数の割合で算出された。
非照射のEG7、LLC、又はLLC−ova細胞は、200μlのPBSでマウスの側腹部に皮下注入された。LLC−ova細胞の接種5日後(日数5)に、0.3mlのPBS量における106の精製されたgfp−OT−Iが尾静脈を通して注入された。2日後、マウスは、グラフに示されたスケジュールによる、0.5mlのPBS量での106の非照射のLLC−ova−gp96−Ig又はEG7−gp96−Ig細胞の腹腔内注入によって免疫化された。コントロールマウスはPBS、EG7、又はLLC−ovaで治療された。側腹部中の腫瘍の寸法は、少なくとも20日の間、週に2回、2次元で測定された。
有意性はt検定によって評価された。p<0.05の計算値は、統計的有意性を示すと見なされた。
熱ショック融合蛋白質gp96−Igの腫瘍細胞への形質移入によって、gp96でシャペロン化されたペプチドとともにgp96−Igの分泌が生じた。gp96−Igは、gp96の小胞体保留シグナル(KDEL)の、IgG1のFc部分との置換によって産生される、修飾タンパク質である。マウスでのgp96−Igを分泌する腫瘍細胞の注入によって、腫瘍特異性の免疫及び記憶の誘発と、同一であるが形質移入されない腫瘍での後の攻撃の防御とが生じる。分泌型のgp96−Igによって産生される腫瘍免疫は、EL4特異性の抗原といった腫瘍内在性抗原から得られるペプチドを含む、gp96でシャペロン化されたペプチドに対して、及び、EL4(EG7)又はLLC(LLC−ova)に形質移入される卵白アルブミンといった代替抗原に対して特異的である。卵白アルブミンの代替抗原は、卵白アルブミン特異性のOT−I TCR遺伝子導入型CD8陽性細胞の養子移植を介して、生体内でCD8陽性のCTL増殖を正確に決定する方法を提供する。
多くのワクチン接種のストラテジーは、分泌型のgp96−Igを含み、腫瘍及び腫瘍抗原に対しマウス内で防御免疫を樹立できるが、治療用のワクチン接種による既存の樹立腫瘍を拒絶することは更に困難である。CD8の増殖の抗原非特異性の抑制を観察するために、我々はワクチン接種の異なるスケジュールがどのように腫瘍の拒絶及び/又は腫瘍の増殖に影響を与えるかを分析した。
Th1抗腫瘍応答が、野生型マウスと比較してB細胞欠損マウス(BCDM)で増加することが、いくつかのグループによって報告されてきた。従って、我々はgp96媒介型のCTL増殖及び抗腫瘍免疫におけるB細胞の役割を研究した。腹膜腔はCD5陰性CD19陽性のB細胞で、及びCD5陽性CD19陽性のB1B細胞で埋められ、後者はIgMを産生し、活性時にアイソタイプスイッチを受けない。EG7−gp96−Igでの腹腔内免疫処置で、CD5陰性CD19陽性の集団は免疫処置後の日数4で約5倍に増加するが、CD5陽性のB1B細胞は中程度に増加する。gp96媒介型のOT−Iの増殖は免疫処置後の日数4及び5で最大になる。それは、ワクチン接種部位である腹膜腔でのDC細胞及びNK細胞の漸増及び活性に先行される。B細胞欠損マウスにおいては、DC、特にNK細胞の漸増は3の別個の実験で増加し、漸増した細胞は腹膜腔中でより長く残った。その際は有意性に到達しなかったが、再現性があった。野生型B細胞のBCDMへの養子移植は、DC細胞及びNK細胞の漸増の増加を消滅させた。その知見は、B細胞が生得性の免疫細胞のgp96誘発型の漸増に影響を与えることを示唆し、B細胞が更にCD8陽性のCTL増殖を制御又は抑制することに関与しうることを示唆する。
上に示したように、野生型マウスにおいて樹立されたEG7の増殖制御は最小限で毎日のgp96免疫処置を要求する。同様に、LLCの進行は頻回の免疫処置で遅延できる。EG7及びEL4細胞はBCDM中で拒絶され、腫瘍を樹立しないが、しかしながら、LLC及びLLC−ovaは野生型マウスよりも遅い速度で増殖するもののBCDMに樹立できる。LLC−ovaはBCDMで、及び野生型マウスで7日間、側腹部に皮下で樹立された。OT−Iは静脈内に養子移植され、2日後に、LLC−ova−gp96−Igは単一用量で腹腔内投与され、腫瘍の増殖がモニタリングされた。BCDMにおいては、単一の免疫処置によって、3のラットにおける、樹立される7日間のLLC−ova腫瘍の完全な拒絶と、2のラットにおける有意な腫瘍の縮小とを生じた。無治療においては、LLC−ovaは野生型マウスよりも遅い速度であるとはいえ、BCDMで進行的に増殖し続けた。BCDMのB細胞の再構成は野生型マウスに見られるのと同様のワクチン接種の効果、すなわち進行の遅延を与えた。
同種の肺癌細胞株AD100はgp96−Ig及びHLA−A1を形質移入される。細胞のうち少なくとも70%が、100万の細胞から24時間ごとに60ngより多くのgp96−Igを発現する。組換え型癌細胞は非照射され、その後、進行性、再発性、又は転移性のNSCLC(ステージIIIB/IV)に罹患する患者に皮内注入された。HLAの適合は要求されない。毒性についての懸念が生じない場合は、患者は17週にわたり毎週又は2週に1回、5×107の同種癌細胞でワクチン接種される。代替的に、全部で4.5×108の同種癌細胞は(a)18週にわたる9の注入、(b)18週にわたる18の注入、あるいは(c)18週にわたる36の注入によって送達してもよい。
樹立腫瘍が抗腫瘍免疫を抑制することが十分に理解されよう。腫瘍特異性のT細胞は樹立腫瘍の存在下でアネルギー性となる。その研究で用いられたB細胞リンパ腫に対するアネルギーは抗原特異性であり、MHCで限定され、MHC合致型で骨髄由来の抗原提示細胞の存在に依存した。他の研究においては、抗原非特異性で骨髄性のサプレッサー細胞及び制御性T細胞は抗腫瘍免疫の抑制に結びつけられた。生体内でのCTL応答の抑制が抗原と別個の経路を通して樹立腫瘍によって得られうることを、我々の研究は示す。gp96−ovaのワクチン接種に応じたOT−Iの増殖は、腫瘍による卵白アルブミンの発現と別個に、樹立腫瘍によって抑制される。この型の抑制は制御性T細胞によって、あるいは骨髄性サプレッサー細胞又はM2マクロファージといった、他のサプレッサー細胞によって得られうる。この仮説によると、抑制活性はgp96ワクチン接種により腫瘍を有するマウスに誘発された腹膜細胞の移植によって、腫瘍のないマウスに移植可能である。
Claims (14)
- ヒト対象を免疫処置する方法であって、当該方法が、
(a)修飾されたgp96熱ショックタンパク質を分泌する同種癌細胞の免疫原性組成物を前記ヒト対象に投与するステップであって、前記修飾が小胞体(ER)用の保留シグナルを含む、天然型gp96のドメインを少なくとも除去するステップと、
(b)修飾されたgp96熱ショックタンパク質を分泌する同種癌細胞の別の免疫原性組成物を前記ヒト対象に投与するステップであって、前記修飾が小胞体用の保留シグナルを含む、天然型gp96のドメインを少なくとも除去するステップと、
を具え、前記免疫原性組成物を投与するステップと、前記別の免疫原性組成物を投与するステップとの間が2週間未満であることを特徴とする方法。 - 請求項1に記載の方法において、前記免疫原性組成物を投与するステップと、前記別の免疫原性組成物を投与するステップとの間が1週間以下であることを特徴とする方法。
- 請求項1に記載の方法において、各々が前記修飾されたgp96熱ショックタンパク質を分泌する同種癌細胞からなる少なくとも9の免疫原性組成物が、前記ヒト対象に少なくとも毎週投与されることを特徴とする方法。
- 請求項1ないし3のうちのいずれか1項に記載の方法において、ER保留シグナルを含むドメインをIgG1又はIgG2の1以上の重鎖定常領域で少なくとも置換することによって、前記天然型gp96が修飾されることを特徴とする方法。
- 請求項1ないし3のうちのいずれか1項に記載の方法において、ER保留シグナルを含むドメインをIgG1又はIgG2のFcドメインで少なくとも置換することによって、前記天然型gp96が修飾されることを特徴とする方法。
- 請求項1ないし5のうちのいずれか1項に記載の方法において、前記癌細胞がHLA−A1又はHLA−A2を発現することを特徴とする方法。
- 請求項1ないし6のうちのいずれか1項に記載の方法において、少なくとも、前記修飾されたgp96熱ショックタンパク質がウシパピローマウイルスからの1以上の制御シグナルからなるベクターによってコード化されることを特徴とする方法。
- 請求項1ないし7のうちのいずれか1項に記載の方法において、前記癌細胞が細胞腫に由来することを特徴とする方法。
- 請求項1ないし7のうちのいずれか1項に記載の方法において、前記癌細胞が肺癌に由来することを特徴とする方法。
- 請求項1ないし3のうちのいずれか1項に記載の方法において、AD100が、
ER保留シグナルを含むドメインをIgG1又はIgG2のFcドメインで少なくとも置換することによって修飾される天然型gp96(gp96−Ig)と、
HLA−A1又はHLA−A2と、
をコード化し、かつ、ウシパピローマウイルスからの1以上の制御シグナルからなる1又は2の発現ベクタを形質移入することを特徴とする方法。 - 請求項1ないし10のうちのいずれか1項に記載の方法が、前記免疫原性組成物の初回投与前及び/又は投与中に、対象のB細胞を枯渇させるステップを更に具えることを特徴とする方法。
- 請求項1ないし10のうちのいずれか1項に記載の方法が、前記免疫原性組成物の少なくとも1の投与前及び/又は投与中に、対象のB細胞を枯渇させるステップを更に具えることを特徴とする方法。
- 修飾されたgp96熱ショックタンパク質を分泌する同種癌細胞を用いてヒト対象の免疫処置又はワクチン接種を改良する方法であって、天然型gp96の修飾が小胞体(ER)用の保留シグナルを含むドメインを少なくとも除去し、前記改良が、
前記同種癌細胞を頻回投与するステップであって、同種癌細胞が2週間未満の時間を置いて対象に投与されるステップか、
前記同種癌細胞の少なくとも1の投与前及び又は投与中に前記対象中のB細胞を枯渇させるステップか、あるいは、
前記同種癌細胞を頻回投与するステップ、及び前記対象中のB細胞を枯渇させるステップの双方、
を具えることを特徴とする方法。 - 修飾されたgp96熱ショックタンパク質を分泌する同種癌細胞を含む免疫原性組成物の使用であって、天然型gp96の修飾がヒト対象の免疫療法のために、小胞体(ER)用の保留シグナルを含むドメインを少なくとも除去し、少なくとも2の免疫原性組成物は同種癌細胞が2週間未満の時間を置いて対象に投与されるか、前記同種癌細胞の少なくとも1の投与前及び又は投与中に前記対象中のB細胞を枯渇させるか、あるいはその双方であることを特徴とする使用。
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JP2018509888A (ja) * | 2015-02-06 | 2018-04-12 | ヒート バイオロジクス,インコーポレイテッド | ワクチンおよび共刺激分子を共発現するベクター |
WO2018199318A1 (ja) * | 2017-04-28 | 2018-11-01 | 国立大学法人高知大学 | 抗gpc-1抗体 |
JPWO2018199318A1 (ja) * | 2017-04-28 | 2020-03-12 | 国立大学法人高知大学 | 抗gpc−1抗体 |
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EP2257301A4 (en) | 2013-01-16 |
EP2752193A1 (en) | 2014-07-09 |
IL207958A (en) | 2015-09-24 |
CA2717854C (en) | 2019-02-19 |
EP2257301A2 (en) | 2010-12-08 |
ES2460899T3 (es) | 2014-05-14 |
AU2009223838A1 (en) | 2009-09-17 |
JP2014208690A (ja) | 2014-11-06 |
EP2257301B1 (en) | 2014-01-22 |
EP2752193B1 (en) | 2017-01-11 |
CN102014937A (zh) | 2011-04-13 |
US8475785B2 (en) | 2013-07-02 |
DK2257301T3 (da) | 2014-04-28 |
WO2009114085A2 (en) | 2009-09-17 |
WO2009114085A3 (en) | 2009-12-03 |
CA2717854A1 (en) | 2009-09-17 |
US20110250229A1 (en) | 2011-10-13 |
US20130302376A1 (en) | 2013-11-14 |
AU2009223838B2 (en) | 2012-07-26 |
IL207958A0 (en) | 2010-12-30 |
KR20110009095A (ko) | 2011-01-27 |
US9238064B2 (en) | 2016-01-19 |
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