著者は、ナントから大学病院動物施設 (UTE) ナントの畜産とケア、細胞と組織イメージング、イメージング ナント大学 (MicroPICell) の中核施設とフローサイトメトリー施設 (Cytocell) のスタッフに感謝します。彼らの専門家のテクニカル サポート。この仕事 INSERM、CNRS、ユニヴェルシテ ・ ド ・ ナント、Institut 国立デュがん (インカ #PLBio2014-155)、リーグのナシオナル contre le がん (AO 地域間 2017 年)、欧州コンソーシアム時代ネット Transcan2 によって資金が供給された (Immunoglio)。チームは財団注ぐラ凝った Medicale (DEQ20170839118) によって資金を供給します。LabEX 囲碁のコンテキストでこの作品を実現し、IHU セスタス プログラムでサポートされている、国家研究機関 Investissements d'Avenirを介してプログラム ANR-11-LABX-0016-01 と ANR-10-IBHU-005、それぞれ。IHU セスタス プロジェクトはナント メトロポールとペイ ・ ド ・ ラ ・ ロワール地域でもサポートされます。著者は、Chirine ラフィア ・が原稿を修正ヘルプを提供することをありがちましょう。

次プロシージャを含む動物科目制度ガイドライン (契約 #00186.02; ペイ ド ラ ロワール [フランス] の地域倫理委員会) によるとを行った。人間の PBMCs は情報に基づいた健康なドナー (エタブリセモン Français デュ歌ったナント, フランス) から集められた血から分離しました。すべての手順は、無菌条件の下で実行されます。
1. 非特異的細胞エフェクター T 細胞の拡張
<ol><li>準備し、フィーダー細胞 35 Gy を照射します。2 x 105 - 4 x 105エフェクター細胞の刺激の 3 つの明確な健康なドナーから 10 x 106 PBMCs と 1 x 10 の6 BLCLs を準備します。</li>
	<li>フィーダー細胞と 15 ml の 10% の熱不活化 FCS、2 ミリメートル L グルタミン、ペニシリン (100 IU/mL) とストレプトマイシン (0.1 μ g/mL) と 300 IU/mL 組換え IL-2 添加 RPMI のエフェクター細胞を再懸濁します。</li>
	<li>最終濃度 1 μ G/ml に PHA L を追加、慎重にミックス、および 150 μ L/ウェルの 96 穴 U 底プレート細胞懸濁液を配布します。</li>
	<li>37 ° C で、加湿雰囲気で 5% CO2で孵化させなさい。</li>
	<li>大細胞塊文化井戸のフォームまでプレートの日常点検 (~ 7 日)。</li>
	<li>1 x 106セル/mL の新鮮な培養液中で培養用フラスコにセルを転送します。</li>
	<li>(2 倍の週) を数えることで細胞数を決定し、新鮮な培地の 1 x 106セル/mL でそれらを維持します。 注: エフェクター免疫細胞は静止状態 (初期増幅刺激後通常 3 週間) で治療的投与の準備ができてする必要があります。純度とこれらのエフェクター細胞の反応性は、生体内注入 (例えば、生体外の試金と) 前にチェックしなければなりません。</li>
</ol>2. 術前のエフェクター細胞の準備
<ol><li>エフェクター細胞数を確認した後遠心分離 (300 x gで 5 分) で 50 mL のチューブでエフェクター細胞を収集します。 注: 任意の損失を補うために細胞 (例えば50 × 106) の超過分を準備します。</li>
	<li>慎重に上澄みを除去し、15 mL の滅菌 PBS と 300 × gで 5 分間遠心洗浄を実行するのに細胞を再懸濁します。</li>
	<li>慎重にそして完全に上澄みを除去し、1 mL の滅菌 PBS で細胞ペレットを再懸濁します。</li>
	<li>5 分間 300 × gで遠心分離を 1.5 mL マイクロ チューブの再懸濁のセルを転送します。</li>
	<li>慎重にそして完全にゆっくりとピペッティング上澄みを削除します。</li>
	<li>マウスごと滅菌 PBS の 8 μ L で細胞ペレットを再懸濁します。 注: これは重要なステップです。</li>
	<li>マイクロ ピペットを用いて細胞懸濁液の量を測定します。必要に応じて、滅菌 PBS (20 × 106線量あたり 15 μ L の PBS セル) を追加し、慎重に混ぜます。</li>
	<li>15 と 20 μ L (強制的 < 20 μ L) 間マウスあたり最終巻にあるマイクロ ピペットを使用して確認してください。</li>
	<li>定位注射まで氷の上細胞を保ちます。 注: 3 時間以上縦長はテストしませんでした。</li>
</ol>3. 定位注射
<ol><li>
機器のセットアップ
	<ol>
<li>組み立てるし、頭蓋内注射 (例えば、シリンジ サイズ、音量、注入の速度) の精度を確保するための製造元の指示に従って小動物定位脳手術フレームをキャリブレーションします。 注: 低速注入率は (すなわち2 〜 3 μ L/分) 推奨します。</li>
		<li>感染症から微生物安全キャビネット (MSC) 楽器の無菌性を維持し、マウスを保護するための下で材料をインストールします。 注: 場所"等温ブロック」の 37 ° C の水浴中このシステムは、手術中にマウスの体温を制限します。手続き後のケアのために必要であるパッドを加熱は、連続温度監視中に使用する必要があります。</li>
	</ol>
</li>
	<li>
動物の術前準備
	<ol>
<li>ケタミン (10 mg/mL) とマウスの体重の 10 μ L/g でキシラジン (0.1 mg/mL) の腹腔内注入マウスを麻酔します。</li>
		<li>完全な麻酔と動物の鎮痛を確保するつま先ピンチ テストを実行します。 注: 任意の動きが非深い鎮痛の表示、操作を繰り返す前に、数分以上が必要な場合は。</li>
		<li>マウスは麻酔は正しく、(間に 2 つの耳、鼻まで) 手術部位から毛皮を削除するのにはさみを使用します。</li>
	</ol>
</li>
	<li>
術前セル準備
	<ol>
<li>任意のセルの凝集を防ぐために各注入前にピペットで細胞の (複数回) を慎重に再懸濁します。</li>
		<li>慎重に泡の吸引を避けるために 22 G 変らずに必要な細胞懸濁液容積 (15-20 μ L) を描画します。 注: 変らずにこのセルの読み込み手順は注入されたボリュームでの差異を最小化することが重要です。各コホートのエフェクター細胞学も数を確保するための手続任意のセルの凝集を防ぐために個別注射用セルを再読み込みします。</li>
		<li>その後、適応シリンジ ポンプに注射器を配置します。</li>
	</ol>
</li>
	<li>
手続きの注意
	<ol>
<li>ポビドン ヨードの 5% 溶液を少なくとも 3 に浸した綿棒で手術部位を消毒 x。</li>
		<li>マウスの目の角膜の乾燥防止のために潤滑の眼軟膏を配置します。</li>
		<li>暖かい等温ブロック上の定位脳手術フレームに麻酔下のマウスの位置は、手術中にマウスの温度を維持し、死亡率を制限する滅菌ラップで覆われて。 マウスの鼻と歯注: はプロシージャの間に十分な呼吸流量を確保するため、歯のバーの上適切に配置する必要があります。</li>
		<li>歯のバーの上にマウスが、一度頭を固定するマウスの耳の下でしっかりとイヤバーを締めます。 注: するまたは呼吸の妥協に鼓膜を損傷しないように注意してください。</li>
		<li>頭蓋骨を公開する後方前方から頭蓋の上部に沿って滅菌ハサミで 1-2 cm 正中矢状皮膚切開を確認します。</li>
		<li>矢状面と冠状縫合糸 (図 1に示すように) 注入前に定位のローカリゼーションのためのランドマークとして機能する (前) 交差点を識別します。</li>
		<li>このポイントより上, マイクロシリンジを配置します。</li>
		<li>変らず右横 2 mm と 0.5 mm 前の前方に移動します。</li>
		<li>あらかじめ定義された座標で滅菌ドリルで頭蓋骨に小さな穴を作り、ドリルを使用する。脳の任意の外傷性の損傷を避けるために表在性のままに注意してください。 注: このプロトコルでは、免疫細胞が確立された腫瘍 (腫瘍細胞の注入後 1 週間) 内で注入されました。皮膚がリニューアル オープン (瘢痕)、注射をする必要があります (穴は注入後 2 週間までまだ存在一般に) 腫瘍細胞移植に使用される同じ座標で行われます。座標は、脳実質13,14の腫瘍とエフェクター細胞を注入するために選ばれました。</li>
	</ol>
</li>
	<li>
免疫エフェクター細胞の注入
	<ol>
<li>慎重に穴に、変らずを挿入し、ゆっくり動いて、硬膜下 3 mm とエフェクター細胞を注入する前に 2.5 mm の最終的な深さにして後方 0.5 mm の針を転送します。</li>
		<li>2-3 μ L/分でエフェクター細胞の注入を実行し、射出時間に沿ってマウスを監視します。</li>
		<li>注入が完了すると、わずか 1 mm の針を撤回し、変らずを注入サイトから漏洩を防ぐため、変らず撤退完全にゆっくりと前に 1 つの追加分の場所に保管します。 注: 次の定位脳手術装置から動物の除去、今後実験用噴射装置がすぐにきれい。</li>
	</ol>
</li>
	<li>
手術後のケアとマウスのフォロー アップ
	<ol>
<li>定位脳手術フレームから動物を削除してすぐに切開部位のポビドン ヨード溶液の 5% を適用し、適切な外科的縫合糸で皮膚を閉じます。</li>
		<li>傷口に直接 2% リドカイン ゲルを適用し、手続き後の鎮痛のため皮下注射ブプレノルフィンの 0.15 μ g/g を管理します。</li>
		<li>場所戻ってマウスの適切な体温を維持し、低体温症を避けるために、加熱パッドの上のケージに麻酔下のマウスは 37 ° C に設定。 注: 別のハウジングは必要ではありません。</li>
		<li>それは完全に麻酔から回復するまでマウスを監視し、ハウジング ルームにそれを転送します。 注: までに、このプロトコルもサポートいくつかの予期せぬ合併症が発生したとして (注入されたマウスの < 5%)。</li>
		<li>毎日、マウスを監視し、(例えば、背を丸めて姿勢、減らされた移動性、虚脱、または重要な体重減少 [≥ 15%])、健康の減少兆候が観察されるときそれらを安楽死させます。</li>
	</ol>
</li>
</ol>

<ol>
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D. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Innate+and+adaptive+immune+responses+of+the+central+nervous+system.">Innate and adaptive immune responses of the central nervous system.</a> Critical Reviews in Immunology. 26 (2), 149-188 (2006).</li><li>Louveau, A., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Structural+and+functional+features+of+central+nervous+system+lymphatic+vessels.">Structural and functional features of central nervous system lymphatic vessels.</a> Nature. 523 (7560), 337-341 (2015).</li><li>Menei, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Local+and+sustained+delivery+of+5-fluorouracil+from+biodegradable+microspheres+for+the+radiosensitization+of+glioblastoma:+a+pilot+study.">Local and sustained delivery of 5-fluorouracil from biodegradable microspheres for the radiosensitization of glioblastoma: a pilot study.</a> Cancer. 86 (2), 325-330 (1999).</li><li>Menei, P., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Stereotaxic+implantation+of+5-fluorouracil-releasing+microspheres+in+malignant+glioma.">Stereotaxic implantation of 5-fluorouracil-releasing microspheres in malignant glioma.</a> Cancer. 100 (2), 405-410 (2004).</li><li>Salot, S., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Large+scale+expansion+of+gamma+9+delta+2+T+lymphocytes:+Innacell+gamma+delta+cell+therapy+product.">Large scale expansion of gamma 9 delta 2 T lymphocytes: Innacell gamma delta cell therapy product.</a> Journal of Immunological Methods. 326 (1-2), 63-75 (2007).</li><li>Bennouna, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Phase-I+study+of+Innacell+gammadelta,+an+autologous+cell-therapy+product+highly+enriched+in+gamma9delta2+T+lymphocytes,+in+combination+with+IL-2,+in+patients+with+metastatic+renal+cell+carcinoma.">Phase-I study of Innacell gammadelta, an autologous cell-therapy product highly enriched in gamma9delta2 T lymphocytes, in combination with IL-2, in patients with metastatic renal cell carcinoma.</a> Cancer Immunology, Immunotherapy. 57 (11), 1599-1609 (2008).</li><li>Singh, S. K., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Identification+of+human+brain+tumour+initiating+cells.">Identification of human brain tumour initiating cells.</a> Nature. 432 (7015), 396-401 (2004).</li></ol>

著者が明らかに何もありません。

養子伝選択ネイティブまたは設計された免疫エフェクター細胞腫瘍浸潤の脳腫瘍、非変形細胞15、に対して反応性を制限することの世話などを効率的に治療するために有望なアプローチを表す 16,17,18。ただし、脳を含む中枢神経系は、血液脳関門の存在と古典的なリンパ排液システム<sup class="xref"...

糸球体基底膜 (WHO グレード IV 星状細胞腫) は、成人では最も頻繁に、積極的な脳腫瘍の症例です。積極的な治療法は手術とラジオ化学療法を組み合わせた、GBM 変わりません非常に予後不良 (14.6 カ月と 2 年死亡 > 73% の生存期間中央値)1に関連付けられています。これは、いくつかの効率的な治療の進歩が2の最後の 10 年を検証されている証拠します。効果的な治療戦略3,4、5のデザイン候補の中で免疫療法6現在検討するいると高度侵襲とラジオ/化学療法抵抗性の腫瘍を削除セルは、迅速かつ致命的な腫瘍再発7への重要な貢献の疑いがあります。様々 な潜在的な免疫学的ターゲットが識別されたとの提案された免疫療法や自然を含むまたは変更した αβ GBM の腫瘍抗原など応力誘起分子8,9、ϒδ T リンパ球 10。選択した糸球体基底膜反応免疫細胞エフェクターを管理する可能性は、残存腫瘍のサイトに直接エフェクター リンパ球の上昇量を提供するユニークな機会を表します。この戦略をサポートするため、我々 は最近脳腫瘍 GBM 患者9,11の開発を忠実に同所性同種ヒト糸球体基底膜移植を運ぶ免疫不全マウスに基づくモデルに要約を示しています。さらに、これらのモデルに対して転送された同種の人間 Vϒ9Vδ2T のリンパ球の強い抗腫瘍活性効率を示すため使用されました。
このプロトコルでは、糸球体基底膜、同種リンパ球の養子の転送に基づくなどの脳腫瘍の定位放射線免疫療法を達成するため重要な実験手順について説明します。記事ショー: (i) 治療同種免疫エフェクター T リンパ球, リンパ球 Vϒ9Vδ2T 人間; などの増幅(ii) これらのエフェクター T のリンパ球の注射用の準備(iii) 内腫瘍近傍の脳定位放射線管理のための手順。この記事は、定位注射後これらの細胞のエフェクターの行動に洞察力を提供します。
ここで紹介する治療法は、それぞれの脳腫瘍免疫不全マウスの線量あたり20 x 106エフェクター細胞の注入に基づいています。初期の in vitro拡張ステップは、免疫細胞の大量生産に必要です。したがって、非特異的細胞拡張フィトヘマグルチニン (PHA L) を使用して実行され、同種フィーダー細胞を照射: 健常者とエプスタイン バール ウイルス EBV 変換 B リンパ芽球細胞から末梢血単核球 (PBMCs)EBV を含む培養 1 μ G/ml シクロスポリン A の存在下で、マーモセット B95 8 細胞ラインから上清中の体外感染による PBMCs 由来株 (BLCLs)
抗糸球体基底膜の免疫細胞が比較され、生体外の試金9から選択。これらのエフェクター細胞がアクティブになります、標準プロトコルを使用して (例えば、人間 Vγ9Vδ2 T リンパ球9またはヒト抗ヘルペス ウイルス T リンパ球12) 性質に従って最低純度として日常的に、> 80% で増幅フローサイトメトリー解析をチェックします。下記のとおりセル拡張プロシージャは、様々 な人間のリンパ球のサブセットに適用されます。

<table><tbody><tr><td>PBMCs</td><td></td><td></td><td>from 3 different healthy donors</td></tr><tr><td>BLCLs</td><td></td><td></td><td>from 3 different donors</td></tr><tr><td>Roswell Park Memorial Institute medium (RPMI)</td><td>Gibco</td><td>31870-025</td><td></td></tr><tr><td>FCS</td><td>Dutscher</td><td>S1810-500</td><td></td></tr><tr><td>L-glutamine</td><td>Gibco</td><td>25030-024</td><td></td></tr><tr><td>penicillin/streptomycin</td><td>Gibco</td><td>15140-122</td><td></td></tr><tr><td>IL-2</td><td>Novartis</td><td>proleukin</td><td></td></tr><tr><td>PHA-L</td><td>Sigma</td><td>L4144</td><td></td></tr><tr><td>Stereotaxic frame</td><td>Stoelting Co.</td><td>51600</td><td></td></tr><tr><td>Mouse adaptator for stereotaxic frame&amp;nbsp;&amp;nbsp;</td><td>Stoelting Co.</td><td>51624</td><td></td></tr><tr><td>microsyringe pump injector&amp;nbsp;</td><td>WPI</td><td>UMP3-4</td><td></td></tr><tr><td>NanoFil Syringe</td><td>WPI</td><td>NF34BV-2</td><td></td></tr><tr><td>NSG mice</td><td>Charles River</td><td>NSGSSFE07S</td><td></td></tr><tr><td>Ketamine</td><td>Merial</td><td>Imalg&amp;egrave;ne 1000</td><td></td></tr><tr><td>Xylazine</td><td>Bayer</td><td>Rompur 2%</td><td></td></tr><tr><td>Scissors</td><td>WPI</td><td>201758</td><td></td></tr><tr><td>Forceps</td><td>WPI</td><td>501215</td><td></td></tr><tr><td>OmniDrill 115/230V</td><td>WPI</td><td>503598</td><td></td></tr><tr><td>Vicryl 4-0</td><td>Ethicon</td><td>VCP397H</td><td></td></tr><tr><td>Xylocaine</td><td>Astrazeneca</td><td>3634461</td><td></td></tr></tbody></table>

stereotactic adoptive transfer of cytotoxic immune cells in murine models of orthotopic human glioblastoma multiforme xenografts

膠 (GBM)、成人では、最も頻繁に、積極的な脳腫瘍の症例は、予後不良な一般的に関連付けられている、最後の 10 年間で不足している効率的な治療法が提案されています。新しい治療戦略を設計するための有望な候補者、間細胞免疫療法は高度侵襲を排除する対象となっているし、化学療法放射線腫瘍細胞、可能性がありますこの癌の迅速かつ致命的な再発に関与します。したがって、腫瘍近傍の人間の Vϒ9Vδ2 の T リンパ球など、同種の糸球体基底膜反応免疫細胞エフェクター administration(s) 効率を提供するユニークな機会を表しますが、非常に直接の治療薬に集中して、脳の悪性腫瘍のサイト。同所性同種人間原発性脳腫瘍を運ぶ免疫不全マウスにおける準備と同種の人間のリンパ球の脳定位固定装置の管理のためのプロトコルを紹介します。本研究は、可能性と intrabrain 腫瘍ベッド内で同種の人間のリンパ球の定位注射に依存するこれらの細胞免疫療法の抗腫瘍効果の前臨床証拠の概念を提供します。

本研究では、脳内定位注射腫瘍ベッド内で直接実行に基づく腫瘍を持つマウスの細胞免疫エフェクター細胞の養子の転送の戦略について説明します。
大規模な注入量に関連付けられている脳損傷のすべてのリスクを最小限に抑える、エフェクター細胞懸濁液 (20 x 106 15 20 μ L の PBS セル) を集中する必要があります?...

Watch this Scientific Journal Video about Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts at JoVE.com

Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts

同所性同種人間神経膠腫異種移植片のマウスモデルの細胞傷害性免疫細胞の定位の養子転送

同所性同種人間原発性脳腫瘍を運ぶ免疫不全マウスにおける準備と同種の人間のリンパ球の脳定位固定装置の管理のためのプロトコルを紹介します。本研究は、実現可能性と intrabrain 配信細胞免疫療法の抗腫瘍効果の概念実証を提供します。

Glioblastoma multiforme (GBM), the most frequent and aggressive primary brain cancer in adults, is generally associated with a poor prognosis, and scarce ...

stereotactic-adoptive-transfer-cytotoxic-immune-cells-murine-models

Research

JoVE Journal

Immunology and Infection

7.8K ビュー.  CRCINA. 同所性同種人間原発性脳腫瘍を運ぶ免疫不全マウスにおける準備と同種の人間のリンパ球の脳定位固定装置の管理のためのプロトコルを紹介します。本研究は、実現可能性と intrabrain 配信細胞免疫療法の抗腫瘍効果の概念実証を提供します。

ビデオ: Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts

A Simple Guide Screw Method for Intracranial Xenograft Studies in Mice

The grafting of human tumor cells into the brain of immunosuppressed mice is an established method for the study of brain cancers including glioblastoma (glioma) and medulloblastoma. The widely used stereotactic approach only allows for the injection of a single animal at a time, is labor intensive and requires highly specialized equipment. The guide screw method, initially developed by Lal et al.,1 was developed to eliminate cumbersome stereotactic procedures. We now describe a modified guide screw approach that is rapid and exceptionally safe; both of which are critical ethical considerations. Notably, our procedure now incorporates an infusion pump that allows up to 10 animals to be simultaneously injected with tumor cells.
To demonstrate the utility of this procedure, we established human U87MG glioma cells as intracranial xenografts in mice, which were then treated with AMG102; a fully human antibody directed to HGF/scatter factor currently undergoing clinical evaluation2-5. Systemic injection of AMG102 significantly prolonged the survival of all mice with intracranial U87MG xenografts and resulted in a number of complete cures. 
This study demonstrates that the guide screw method is an inexpensive, highly reproducible approach for establishing intracranial xenografts. Furthermore, it provides a relevant physiological model for validating novel therapeutic strategies for the treatment of brain cancers.

In order to evaluate novel therapeutic paradigms for the treatment of glioma, physiological relevant models are essential. We utilize an implantable guide screw procedure for establishment of intracranial xenograft models that is more rapid and safer than stereotactic approaches.

マウスにおける頭蓋内異種移植研究のための簡単​​なガイドスクリュー方式

The grafting of human tumor cells into the brain of immunosuppressed mice is an established method for the study of brain cancers including glioblastoma ...

医学

Combination Radiotherapy in an Orthotopic Mouse Brain Tumor Model

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the understanding of the mechanics of tumor invasion, and direct intracerebral inoculation of tumor provides the opportunity of observing the invasive process in a physiologically appropriate environment2. As far as human brain tumors are concerned, the orthotopic models currently available are established either by stereotaxic injection of cell suspensions or implantation of a solid piece of tumor through a complicated craniotomy procedure3. In our technique we harvest cells from tissue culture to create a cell suspension used to implant directly into the brain. The duration of the surgery is approximately 30 minutes, and as the mouse needs to be in a constant surgical plane, an injectable anesthetic is used. The mouse is placed in a stereotaxic jig made by Stoetling (figure 1). After the surgical area is cleaned and prepared, an incision is made; and the bregma is located to determine the location of the craniotomy. The location of the craniotomy is 2 mm to the right and 1 mm rostral to the bregma. The depth is 3 mm from the surface of the skull, and cells are injected at a rate of 2 &mu;l every 2 minutes. The skin is sutured with 5-0 PDS, and the mouse is allowed to wake up on a heating pad. From our experience, depending on the cell line, treatment can take place from 7-10 days after surgery. Drug delivery is dependent on the drug composition. For radiation treatment the mice are anesthetized, and put into a custom made jig. Lead covers the mouse's body and exposes only the brain of the mouse. The study of tumorigenesis and the evaluation of new therapies for GBM require accurate and reproducible brain tumor animal models. Thus we use this orthotopic brain model to study the interaction of the microenvironment of the brain and the tumor, to test the effectiveness of different therapeutic agents with and without radiation.

The purpose of this article is to describe the use of an orthotopic glioblastoma model for chemoradiation studies. This article will go though cell processing, implanting, and radiotherapy of the mouse using an intracranial model.

同所性マウス脳腫瘍モデルのコンビネーション放射線治療

Glioblastoma multiforme (GBM) are the most common and aggressive adult primary brain tumors1. In recent years there has been substantial progress in the ...

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality treatment consisting of surgical resection, post-operative radiation therapy and temozolomide chemotherapy 1. New therapeutic approaches are clearly needed to improve patient survival and quality of life. The development of more effective treatment strategies would be aided by animal models of GBM that recapitulate human disease yet allow serial imaging to monitor tumor growth and treatment response. In this paper, we describe our technique for the precise stereotactic implantation of bio-imageable GBM cancer cells into the brains of nude mice resulting in tumor xenografts that recapitulate key clinical features of GBM 2. This method yields tumors that are reproducible and are located in precise anatomic locations while allowing in vivo bioluminescent imaging to serially monitor intracranial xenograft growth and response to treatments 3-5. This method is also well-tolerated by the animals with low perioperative morbidity and mortality.

Stereotactic Intracranial Implantation and In vivo Bioluminescent Imaging of Tumor Xenografts in a Mouse Model System of Glioblastoma Multiforme

We describe an integrated method for the precise, stereotactic implantation of human glioblastoma multiforme cells into the brains of nude mice and subsequent serial in vivo imaging to monitor growth and response to treatment of the resultant xenografts.

定位頭蓋内注入と<emインビボ&gt;</em多形性膠芽腫のマウスモデル系における腫瘍異種移植片の&gt;生物発光イメージング

Glioblastoma multiforme (GBM) is a high-grade primary brain cancer with a median survival of only 14.6 months in humans despite standard tri-modality ...

Primary Orthotopic Glioma Xenografts Recapitulate Infiltrative Growth and Isocitrate Dehydrogenase I Mutation

Malignant gliomas constitute a heterogeneous group of highly infiltrative glial neoplasms with distinct clinical and molecular features. Primary orthotopic xenografts recapitulate the histopathological and molecular features of malignant glioma subtypes in preclinical animal models. To model WHO grades III and IV malignant gliomas in transplantation assays, human tumor cells are xenografted into an orthotopic site, the brain, of immunocompromised mice. In contrast to secondary xenografts that utilize cultured tumor cells, human glioma cells are dissociated from resected specimens and transplanted without prior passage in tissue culture to generate primary xenografts. The procedure in this report details tumor sample preparation, intracranial transplantation into immunocompromised mice, monitoring for tumor engraftment and tumor harvesting for subsequent passage into recipient animals or analysis. Tumor cell preparation requires 2 hr and surgical procedure requires 20 min/animal.

Malignant gliomas constitute a heterogeneous group of highly infiltrative glial neoplasms with distinct clinical and molecular features. Primary orthotopic xenografts recapitulate the histopathological and molecular features of malignant glioma subtypes in preclinical animal models.

原発性異形性神経膠腫は浸潤性の増殖とイソクエンテインゲナーゼI突然変異

Malignant gliomas constitute a heterogeneous group of highly infiltrative glial neoplasms with distinct clinical and molecular features. Primary ...

Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care

Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care.

The lymphodepletive and immunomodulatory effects of chemotherapy and radiation standard of care can be leveraged to enhance the antitumor efficacy of T cell immunotherapy. We outline a method for generating EGFRvIII-specific chimeric antigen receptor (CAR) T cells and administering them in the context of glioblastoma standard of care.

ケアの膠芽腫の標準のコンテキストにおける養子療法のためのCAR T細胞の生成

Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo ...

免疫・感染学

Translational Orthotopic Models of Glioblastoma Multiforme

Genetically engineered mouse (GEM) models for human glioblastoma multiforme (GBM) are critical to understanding the development and progression of brain tumors. Unlike xenograft tumors, in GEMs, tumors arise in the native microenvironment in an immunocompetent mouse. However, the use of GBM GEMs in preclinical treatment studies is challenging due to long tumor latencies, heterogeneity in neoplasm frequency, and the timing of advanced grade tumor development. Mice induced via intracranial orthotopic injection are more tractable for preclinical studies, and retain features of the GEM tumors. We generated an orthotopic brain tumor model derived from a GEM model with Rb, Kras, and p53 aberrations (TRP), which develops GBM tumors&#160;displaying linear foci of necrosis by neoplastic cells, and dense vascularization analogous to human GBM. Cells derived from GEM GBM tumors are injected intracranially into wild-type, strain-matched recipient mice and reproduce grade IV tumors, therefore bypassing the long tumor latency period in GEM mice and allowing for the creation of large and reproducible cohorts for preclinical studies. The highly proliferative, invasive, and vascular features of the TRP GEM model for GBM are recapitulated in the orthotopic tumors, and histopathology markers reflect human GBM subgroups. Tumor growth is monitored by serial MRI scans. Due to the invasive nature of the intracranial tumors in immunocompetent models, carefully following the injection procedure outlined here is essential to prevent extracranial tumor growth.

Here, we describe a preclinical orthotopic mouse model for GBM, established by intracranial injection of cells derived from genetically engineered mouse model tumors. This model displays the disease hallmarks of human GBM. For translational studies, the mouse brain tumor is tracked by in vivo MRI and histopathology.

多形性膠芽腫の並進同所性モデル

Genetically engineered mouse (GEM) models for human glioblastoma multiforme (GBM) are critical to understanding the development and progression of brain ...

がん研究

Creating Anatomically Accurate and Reproducible Intracranial Xenografts of Human Brain Tumors

Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live animal &#8211;&#160;particularly in sites with unique physiological and architectural qualities such as the brain. In vitro and ectopic models cannot account for features such as vasculature, blood brain barrier, metabolism, drug delivery and toxicity, and a host of other relevant factors. Orthotopic models have their limitations too, but with proper technique tumor cells of interest can be accurately engrafted into tissue that most closely mimics conditions in the human brain. By employing methods that deliver precisely measured volumes to accurately defined locations at a consistent rate and pressure, mouse models of human brain tumors with predictable growth rates can be reproducibly created and are suitable for reliable analysis of various interventions. The protocol described here focuses on the technical details of designing and preparing for an intracranial injection, performing the surgery, and ensuring successful and reproducible tumor growth and provides starting points for a variety of conditions that can be customized for a range of different brain tumor models.

The brain is a unique site with qualities that are not well represented by in vitro or ectopic analyses. Orthotopic mouse models with reproducible location and growth characteristics can be reliably created with intracranial injections using a stereotaxic fixation instrument and a low pressure syringe pump.

解剖学的に正確な作成と人間の脳の腫瘍の再現性頭蓋内異種移植片

Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live ...

An Immunocompetent Murine Model for Laser Interstitial Thermal Therapy of Glioblastoma

Glioblastoma (GB), the most aggressive form of primary brain cancer, accounts for approximately half of all high-grade primary brain tumors in adults and has no cure. Laser interstitial thermal therapy (LITT) is a Food and Drug Administration (FDA)-approved treatment for GB and is used in patients who may not be candidates for conventional surgical resection. While the clinical efficacy of LITT has been established, research beyond clinical case studies and case series is limited and hindered by the lack of an established animal model. This protocol uses C57BL/6 mice and syngeneic CT2A glioma cancer cell line to closely recapitulate human GB&#160;while also using a 1064 nm Neodymium-doped Yttrium Aluminum Garnet (Nd:YAG) laser, such as is used in one of the two FDA-approved LITT systems, providing excellent pre-clinical relevance. The successful establishment of this LITT murine model will provide a valuable platform for investigating the unique features of LITT ablation and its effects on the tumor microenvironment, potentially leading to improved therapeutic strategies.

Glioblastoma is a devastating form of primary brain cancer, and laser interstitial thermal therapy is emerging as a promising alternative to conventional surgical resection for inoperable glioblastoma. This protocol describes an optimized pre-clinical mouse model that can be used to study treatment effects or adjuvant and combinatorial treatments.

Glioblastoma (GB), the most aggressive form of primary brain cancer, accounts for approximately half of all high-grade primary brain tumors in adults and ...

Intranasal Delivery of Therapeutic Stem Cells to Glioblastoma in a Mouse Model

The intrinsic tropism towards brain malignancies renders stem cells as promising carriers of therapeutic agents against malignant tumors. The delivery of therapeutic stem cells via the intranasal route is a recently discovered alternative strategy, with strong potential for clinical translation, due to its non-invasive nature compared to intracranial implantation or delivery via systemic routes. The lack of blood brain barrier further strengthens the therapeutic potential of stem cells undergoing intranasal brain entry. This article summarizes the essential techniques utilized in our studies and outlines the basic principles of intranasal strategy for stem cell delivery using a mouse model of intracranial glioma xenografts. We demonstrate the optimized procedures that generate consistent and reproducible results with specific predetermined experimental parameters and offer guidelines for streamlined work flow that ensure efficient execution and reliable experimental outcome. The article is designed to serve as a baseline for further experimental customization based on hypothesis, stem cell types, or tumor specifics.

Stem cells are promising therapeutic carriers to treat brain tumors due to their intrinsic tumor tropism. Non-invasive intranasal stem cell delivery bypasses the blood brain barrier and demonstrates strong potential for clinical translation. This article summarizes the basic principles of intranasal stem cell delivery in a mouse model of glioma.

マウスモデルにおける膠芽細胞腫に対する治療用幹細胞の鼻腔内送達

The intrinsic tropism towards brain malignancies renders stem cells as promising carriers of therapeutic agents against malignant tumors. The delivery of ...

Image-Guided Resection of Glioblastoma and Intracranial Implantation of Therapeutic Stem Cell-seeded Scaffolds

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in part to the inability of the current treatment, consisting of surgical resection followed by radiation and chemotherapy, to eliminate invasive tumor foci. Treatment of these foci may be improved with tumoricidal human mesenchymal stem cells (MSCs). MSCs exhibit potent tumor tropism and can be engineered to express therapeutic proteins that kill tumor cells. Advancements in preclinical models indicate that surgical resection induces premature MSC loss and reduces therapeutic efficacy. Efficacy of MSC treatment can be improved by seeding MSCs on a biodegradable poly(lactic acid) (PLA) scaffold. MSC delivery into the surgical resection cavity on a PLA scaffold restores cell retention, persistence, and tumor killing. To study the effects of MSC-seeded PLA implantation on GBM, an accurate preclinical model is needed. Here we provide a preclinical surgical protocol for image-guided tumor resection of GBM in immune-deficient mice followed by MSC-seeded scaffold implantation. MSCs are engineered with lentiviral constructs to constitutively express and secrete therapeutic TNF&#945;-related apoptosis-inducing ligand (TRAIL) as well as green fluorescent protein (GFP) to allow fluorescent tracking. Similarly, the U87 tumor cells are engineered to express mCherry and firefly luciferase, providing dual fluorescent/luminescent tracking. While currently used for investigating stem cell mediated delivery of therapeutics, this protocol could be modified to investigate the impact of surgical resection on other GBM interventions.

Tumor-seeking therapeutic mesenchymal stem cells (MSCs) show promise as a treatment for invasive glioblastoma. Optimal transplantation involves delivery of MSCs into the tumor resection cavity on scaffolds. Here, preclinical techniques to study MSC treatment of glioblastoma are provided including: image-guided tumor resection; implantation of MSC-seeded scaffolds; and postoperative therapy tracking.

膠芽腫の治療の幹細胞シード足場の頭蓋内注入画像誘導切除

Glioblastoma (GBM), the most common and aggressive primary brain cancer, carries a life expectancy of 12-15 months. The short life expectancy is due in ...

同所性同種人間神経膠腫異種移植片のマウスモデルの細胞傷害性免疫細胞の定位の養子転送

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この動画の章

マウスにおける頭蓋内異種移植研究のための簡単なガイドスクリュー方式

同所性マウス脳腫瘍モデルのコンビネーション放射線治療

定位頭蓋内注入と

原発性異形性神経膠腫は浸潤性の増殖とイソクエンテインゲナーゼI突然変異

ケアの膠芽腫の標準のコンテキストにおける養子療法のためのCAR T細胞の生成

多形性膠芽腫の並進同所性モデル

解剖学的に正確な作成と人間の脳の腫瘍の再現性頭蓋内異種移植片

An Immunocompetent Murine Model for Laser Interstitial Thermal Therapy of Glioblastoma

マウスモデルにおける膠芽細胞腫に対する治療用幹細胞の鼻腔内送達

膠芽腫の治療の幹細胞シード足場の頭蓋内注入画像誘導切除

同所性同種人間神経膠腫異種移植片のマウスモデルの細胞傷害性免疫細胞の定位の養子転送

要約

さらに動画を探す

この動画の章

マウスにおける頭蓋内異種移植研究のための簡単​​なガイドスクリュー方式

同所性マウス脳腫瘍モデルのコンビネーション放射線治療

定位頭蓋内注入と

原発性異形性神経膠腫は浸潤性の増殖とイソクエンテインゲナーゼI突然変異

ケアの膠芽腫の標準のコンテキストにおける養子療法のためのCAR T細胞の生成

多形性膠芽腫の並進同所性モデル

解剖学的に正確な作成と人間の脳の腫瘍の再現性頭蓋内異種移植片

An Immunocompetent Murine Model for Laser Interstitial Thermal Therapy of Glioblastoma

マウスモデルにおける膠芽細胞腫に対する治療用幹細胞の鼻腔内送達

膠芽腫の治療の幹細胞シード足場の頭蓋内注入画像誘導切除

マウスにおける頭蓋内異種移植研究のための簡単なガイドスクリュー方式