JP2023520286A - Pd1ベースワクチン接種組成物およびその方法 - Google Patents
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Abstract
Description
本開示は、癌免疫療法、癌ワクチン、その組成物および方法の分野に属する。
特に、抗CTLA-4抗体を用いた中皮腫に対する最初のランダム化第3相試験は、その主要エンドポイントの全生存期間の改善を達成できなかった(5、6)。PD1およびPD-L1チェックポイント阻害抗体は、第1/2相試験で、進行型中皮腫の治療において、いくつかの有望な結果を示したが、全奏効率は、まだ、30%未満である(7、8)。既存の免疫療法の有効性を高めるために、我々は、中皮腫患者の能動ワクチン接種により抗腫瘍応答を誘発することが必要であると考えている。
特定の実施形態では、TAAはTWIST1である。
特定の実施形態では、癌はTWIST-1-発現癌である。
特定の実施形態では、癌は、中皮腫、AB1中皮腫、4T1乳癌、メラノーマ、結腸癌、前立腺癌、および胃癌からなる群より選択される。
特定の実施形態では、免疫チェックポイント阻害薬は、抗CTLA-4抗体である。
特定の実施形態では、ワクチンは、10日間~3週間の間隔で3回、筋肉内に投与される。
特定の実施形態では、抗CTLA-4抗体は、200μg~400mgの投与量で投与される。
特定の実施形態では、ワクチンは、PD1ベースTWIST1ワクチンの投与の24時間後および4日毎に3回、腹腔内に投与される。
特定の実施形態では、リンカーをさらに含む。
特定の実施形態では、組織プラスミノーゲンアクチベーター(tPa)をさらに含む。
本特許または出願ファイルは、少なくとも1つのカラー図面を含む。カラー図面を含む本特許または特許出願公開のコピーは、要請があれば、必要な手数料を支払うことにより、特許庁により提供される。
TWIST1の発現は、中皮腫進行と相関し、AB1中皮腫の浸潤および転移を促進する。我々は、最初に、ヒト中皮腫中のTWIST1発現の効果を、The Cancer Genome Atlas(TCGA)の中皮腫コホート(MESO)からの異なるステージの87人の患者間のその発現レベルを比較することにより調査した。より高いTWIST1発現は、初期ステージ腫瘍(TNM IまたはII)に比べて、進行ステージ中皮腫(TNM IIIおよびIV)の患者で見つかった(図1A)。加えて、患者が彼らの腫瘍中のTWIST1発現に基づいて2つの群に層別化された場合、強いTWIST1発現を有する患者は、有意に低減した全生存期間を示し(図1B)、TWIST1発現と中皮腫腫瘍形成の関連性を示唆した。
悪性中皮腫の治療のための新規および潜在的治療標的の解明は、この高悪性度腫瘍型に対する効果的治療の非存在下で、差し迫った必要性のまま残されている。以前の研究は、マウスモデルにおける乳癌および前立腺癌を制御するための抗原特異的T細胞応答を誘発する免疫療法の手法として、TWIST1を送達するための酵母およびポックスウイルスベクターの使用について記載した(26、27、33)。比較すると、本研究は、我々の知る限りでは、免疫コンピテント中皮腫癌モデルでのDNAワクチンによるTWIST1特異的T細胞の誘導を最初に示すものである。我々の結果は、sPD1-TWIST1ワクチン接種が、TWIST1特異的T細胞応答に依存する皮下および転移性中皮腫チャレンジの両方での腫瘍抑制を提供するために、中皮腫免疫療法のための治療的介入としての潜在力を有することを示す。重要なのは、我々は、CTLA-4免疫チェックポイント阻害と組み合わせたsPD1-TWIST1ワクチン接種が、免疫抑制TME中で、TWIST1特異的T細胞をさらに活性化および強化して、より良好な細胞傷害活性および長く続く記憶を付与し、マウス中の既発症AB1中皮腫および4T1乳癌に対して、永続性の腫瘍退縮および延命効果に繋がることを示すことである。最終的に、我々は、効果的T細胞は、マウスおよびヒトTWIST1配列間で高度に保存された、高度に免疫優性短鎖ペプチドを認識し、それにより、ヒトPD1-TWIST1ワクチンをさらに最適化し、その有効性を最大化し、潜在的副作用を最小化するための論理的根拠を提供することを明らかにした。
方法
マウス。全てのマウスは、HKU Laboratory Animal Unit(LAU)の標準操作手順に従って維持し、全ての手順は、HKUの教育および研究における生動物の使用に関する委員会(CULATR)により承認された(認可番号#4249-17)。6~8週齢雌BALB/cおよびSCIDマウスを使用した。
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Claims (17)
- 対象におけるTWIST1特異的T細胞応答を誘導する方法であって、PD1およびTWIST1を含む有効量のDNAワクチンを前記対象に投与することを含む、方法。
- 腫瘍関連抗原(「TAA」)に対する免疫寛容の克服に効果的である、請求項1に記載の方法。
- 前記TAAがTWIST1である、請求項2に記載の方法。
- 癌の浸潤および転移の制御に効果的である、請求項1に記載の方法。
- 前記癌がTWIST-1-発現癌である、請求項4に記載の方法。
- 前記癌が、中皮腫、AB1中皮腫、4T1乳癌、メラノーマ、結腸癌、前立腺癌、および胃癌からなる群より選択される、請求項5に記載の方法。
- 免疫チェックポイント阻害薬を前記対象に投与することをさらに含む、請求項1に記載の方法。
- 前記免疫チェックポイント阻害薬が抗CTLA-4抗体である、請求項7に記載の方法。
- DNAワクチン構築物の前記有効量が100μg~200mgである、請求項1に記載の方法。
- 前記ワクチンが、10日間~3週間の間隔で3回、筋肉内に投与される、請求項9に記載の方法。
- 前記抗CTLA-4抗体が、200μg~400mgの投与量で投与される、請求項8に記載の方法。
- 前記ワクチンが、PD1ベースTWIST1ワクチンの投与の24時間後および4日毎に3回、腹腔内に投与される、請求項11に記載の方法。
- 可溶性PD1およびTWIST1を含むDNAワクチン構築物。
- リンカーをさらに含む、請求項13に記載のDNAワクチン構築物。
- 組織プラスミノーゲンアクチベーター(tPA)をさらに含む、請求項14に記載のDNAワクチン構築物。
- (i)可溶性PD1;および(ii)TWIST1;ならびに許容可能な医薬担体、を含むDNAワクチン構築物を含む組成物。
- (i)可溶性PD1;および(ii)TWIST1;ならびに許容可能な医薬担体、を含むDNAワクチン構築物を含むキット。
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