JP2019516712A - 癌を処置するためのグルタミン酸調節剤と免疫療法の併用 - Google Patents
癌を処置するためのグルタミン酸調節剤と免疫療法の併用 Download PDFInfo
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Abstract
Description
本願は、2016年5月20日に出願された米国仮出願番号第62/339,433号の利益を主張する。
本発明は、癌の処置におけるグルタミン酸調節剤および免疫療法の抗癌剤の使用に関する。
(a)免疫療法抗癌剤;および
(b)本発明の方法においてグルタミン酸調節剤と併せて免疫療法抗癌剤を投与することについての説明書
を含むキットが提供される。一の態様において、免疫療法抗癌剤は、ニボルマブ、ペンブロリズマブ、ピディルズマブ(pidilzumab)、デュルバルマブ、アテゾリズマブ、アベルマブ、イピリムマブおよびトレメリムマブから選択される。
(a)グルタミン酸調節剤;および
(b)本発明の方法において免疫療法抗癌剤と併せてグルタミン酸調節剤を投与することについての説明書
を含むキットが提供される。一の態様において、グルタミン酸調節剤は、リルゾールまたはそのプロドラッグである。
以下の詳細な説明は、当業者が本発明を実施するのを助けるために提供される。当業者は、本開示の趣旨または範囲から逸脱せずに、本明細書に記載の実施態様に改変および変更を加えることができる。別段の定義がない限り、本明細書で使用される全ての技術用語および科学用語は、本開示が属する技術分野の当業者によって一般に理解されるのと同じ意味を有する。本明細書で使用される用語は、特定の実施態様を説明するためだけのものであって、限定することを意図するものではない。
を有する。当業者は、他のグルタミン酸調節剤から類似または変種プロドラッグが調製され得ることを認識する。このような薬剤は、本発明の組合せの一部として有用であり得る。
この実施例において、免疫治療剤である抗PD−1と併せたグルタミン酸調節剤であるBHV−4157の組合せの効果は、Zeng, J., et al., Int J Radiat Oncol Biol Phys., 2013 June 1; 86(2):343-349に実質的に記載されている神経膠腫モデル(その一部を以下に再現する)においていずれか単独のものと比較した。
GL261−Luc細胞は、5%COおよび5%O2に維持した湿式インキュベーター(Gibco)において、ダルベッコ変法イーグル培地(DMEM)+10%ウシ胎仔血清+1%ペニシリンストレプトマイシン中にて37℃で増殖させる。
4〜6週齢または6〜8週齢の雌性C57BL/6Jマウス(Harlan)を、Sonabend AM, Velicu S, Ulasov IV, et al. A safety and efficacy study of local delivery of interleukin12 transgene by PPC polymer in a model of experimental glioma. Anticancer Drugs. 2008;19:133-142に記載の同所性神経膠腫実験に使用する。同系神経膠腫を確立するために、130,000個のGL261−Luc細胞を1分間にわたって左線条体に1μLの体積で定位的に以下の座標に注射する:前方1mm、ブレグマから側方1mm、および皮質表面から深さ3mm。移植から7日目、21日目および35日目にルシフェラーゼイメージングにより腫瘍負荷をモニターし、各群の平均腫瘍放射輝度がほぼ同等になるようにマウスを腫瘍放射輝度に基づいて無作為に処置アームに割り当てる。動物が予め決定された神経脱落の兆候(歩行不能(failure to ambulate)、体重減少>20%体重、嗜眠、猫背の姿勢)を示した時に、該動物を安楽死させる。腫瘍の発生率は100%である。生存実験において、各アームは、マウス6〜10匹を有する。全ての実験は少なくとも3回繰り返される。
ハムスター抗マウスPD−1モノクローナル抗体産生ハイブリドーマG4は、Hirano F, Kaneko K, Tamura H, et al. Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res. 2005;65:1089-1096に記載されているように抗体を産生するために使用される。
4〜6週齢の雌性C57BL/6Jマウスの左線条体に各々130,000個のGL261細胞を頭蓋内移植した。マウスは、Johns Hopkins University Animal FacilityのInstitutional Animal Care and Use Committeeプロトコルに従って収容および維持した。腫瘍負荷を評価するために7日目、21日目および35日目にマウスを生物発光IVIS(登録商標)イメージング(Perkin Elmer)によって画像化し、以下のように、1アーム当たり10匹のマウスの群に無作為に割り当てた:
1. 対照
2. 抗PD−1
3. トリグリルゾール15mg/kg
4. トリグリルゾール30mg/kg
5. トリグリルゾール45mg/kg
6. 抗PD−1+トリグリルゾール15mg/kg
7. 抗PD−1+トリグリルゾール30mg/kg
8. 抗PD−1+トリグリルゾール45mg/kg
典型的には、本発明による併用療法、すなわち、免疫療法抗癌剤およびグルタミン酸調節剤は、少なくとも2.0、より典型的には少なくとも2.3(60日目に測定した、MSR60)のマウス生存比をもたらす。
以下は、Merck & Co., Inc.(Whitehouse Station, NJ, USA)から入手可能なキートルーダ(KEYTRUDA)(登録商標)(ペンブロリズマブ)との併用療法において本発明のグルタミン酸調節剤をどのように使用できるかの例を例示する。追加情報については、静脈内使用のための、静脈内用キートルーダ(KEYTRUDA)(ペンブロリズマブ)注射のための、注射用キートルーダ(KEYTRUDA)(ペンブロリズマブ)の重要事項説明書(HIGHLIGHTS OF PRESCRIBING INFORMATION)(uspi−mk3475−iv−1703r007)(「キートルーダ(KETRUDA)添付文書」)を参照のこと。
KEYNOTE−006: イピリムマブ処置を受けていない黒色腫患者における対照試験。
ペンブロリズマブの安全性および効力は、イピリムマブで処置されたことがない患者における進行メラノーマの処置についての多施設の対照III相試験KEYNOTE−006で研究された。患者は、2週間おき(n=279)または3週間おき(n=277)にペンブロリズマブ10mg/kgを受けるか、または3週間おき(n=278)にイピリムマブ3mg/kgを受けるように無作為化した(1:1:1)。BRAF V600E変異体黒色腫の患者は、以前にBRAF阻害剤治療を受けていることを必要としなかった。疾患進行または許容できない毒性があるまで患者をペンブロリズマブで処置した。疾患進行の初期証拠を有する臨床的に安定な患者は、疾患進行が確認されるまで処置を続けることが許された。腫瘍状態の評価は、12週間目、次いで、6週間おきに48週間目まで、その後、12週間おきに行われた。834人の患者のうち、60%が男性であり、44%が65歳以上であり(年齢の中央値は62歳であった[範囲18〜89])、98%が白人であった。患者の65%がステージM1cであり、9%が脳転移の病歴があり、66%が以前に治療を受けておらず、34%が以前に1回治療を受けていた。31%が1のECOG活動指標(Performance Status)を有しており、69%が0のECOG活動指標(Performance Status)を有しており、32%が上昇したLDHを有していた。BRAF変異は、302人(36%)の患者で報告された。BRAF変異腫瘍を有する患者のうち、139(46%)が以前にBRAF阻害剤で処置されていた。主要効力評価基準は、無増悪生存期間(PFS;固形腫瘍における奏効評価基準[RECIST]、バージョン1.1を用いた放射線学的および腫瘍学総合評価[IRO]レビューによって評価される)および全生存期間(OS)であった。二次的効力評価基準は、全奏効割合(ORR)および奏効期間であった。表2は、イピリムマブによる治療を受けていない患者における重要な効力基準を要約している。
・ 客観的奏効率(ORR)
・ 有害事象の種類、重篤度および頻度
・ 生存期間(OS)、1年目および2年目での画期的な生存率
・ 応答している患者の奏効期間
・ 進行性疾患への時間(PFS)
・ 処置が失敗するまでの時間
・ 次の治療または死までの時間(TTNTD)
・ 新しい転移が存在しないこと
・ 相関科学:以下のカテゴリーにおける腫瘍の微小環境および末梢血の変化:
・ TILおよびPD−L1発現
・ 免疫細胞の表現型および遺伝子発現
・ 血管新生マーカー
・ 代謝エフェクター分子
・ エキソソーム形成。
以下は、Bristol-Myers Squibb Company(Princeton, NJ USA)から入手可能なオプジーボ(OPDIVO)(登録商標)(ニボルマブ)との併用療法において本発明のグルタミン酸調節剤をどのように使用できるかの例を例示する。追加情報については、静脈内使用のための、オプジーボ(OPDIVO)(ニボルマブ)注射の重要事項説明書(1506US1700258−01−01)(「オプジーボ(OPDIVO)添付文書」)を参照のこと。
進行性(切除不能または転移性)黒色腫の処置のためのニボルマブ3mg/kgの安全性および効力は、第3相無作為化二重盲検試験(CA209066)で評価された。該試験には、確認された未治療のステージIIIまたはIVのBRAF野生型黒色腫および0または1のECOG活動指標(performance-status)スコアを有する成人患者(18歳以上)が含まれていた。活動性自己免疫疾患、眼球黒色腫、または活動性脳および軟膜髄膜転移を有する患者は、該試験から除外した。合計418人の患者が、2週間おきにニボルマブ(n=210)3mg/kgを60分間にわたる静脈内投与または3週間おきにダカルバジン(n=208)1000mg/m2を受けるように無作為化された。無作為化は、腫瘍PD−L1状態およびM期(M0/M1a/M1b対M1c)によって層別化された。処置は、臨床的有用性が観られる限り、または処置がもはや許容されなくなるまで、継続された。疾患進行後の処置は、研究者によって決定されるとおり、臨床的有用性を有するか、または試験薬物に対して実質的な有害作用を有しなかった患者に対して許可された。固形腫瘍効果判定基準(Response Evaluation Criteria in Solid Tumours)(RECIST)バージョン1.1に従った腫瘍評価は、無作為化の9週間後に行われ、最初の1年間は6週間おきに続け、その後、12週間おきに続けられた。主要効力評価基準は、全生存期間(OS)であった。重要な二次的効力評価基準は、研究者評価PFSおよび客観的奏効率(ORR)であった。ベースライン特性は、2つのグループ間でバランスがとれていた。年齢の中央値は65歳であり(範囲:18〜87)、59%が男性であり、99.5%が白人であった。ほとんどの患者は、0(64%)または1(34%)のECOG活動スコアを有していた。患者の61%が試験参加時にM1c期疾患を有していた。患者の74%が皮膚黒色腫を有しており、11%が粘膜黒色腫を有しており;患者の35%がPD−L1陽性黒色腫(>5%腫瘍細胞膜発現)を有していた。患者の16%が以前にアジュバント療法を受けており;最も一般的なアジュバント処置はインターフェロン(9%)であった。患者の4%が脳転移歴を有しており、患者の37%が試験参加時にULNよりも高いベースラインLDHレベルを有していた。効力の結果は、表3に示される。
以下は、Bristol-Myers Squibb Company(Princeton, NJ USA)から入手可能なヤーボイ(YERVOY)(登録商標)(イピリムマブ)との併用療法において本発明のグルタミン酸調節剤をどのように使用できるかの例を例示する。追加情報については、静脈内使用のための、ヤーボイ(YERVOY)(イピリムマブ)注射の重要事項説明書(1506US1700258−01−01)(「ヤーボイ(YERVOY)添付書類」)を参照のこと。
第3相二重盲検試験に、以前に下記のうち1つ以上を含む処置計画で処置された進行性(切除不能または転移性)黒色腫を有する患者が登録された:IL−2、ダカルバジン、テモゾロミド、フォテムスチンまたはカルボプラチン。患者は、3:1:1の比率で、イピリムマブ3mg/kg+治験用gp100ペプチドワクチン(gp100)、イピリムマブ3mg/kg単剤療法、またはgp100単独を受けるように、無作為化された。すべ点患者は、HLA−A2*0201タイプであった;このHLAタイプは、gp100の免疫提示を支持する。患者は、それらのベースラインBRAF変異状態にかかわらず登録された。患者は、許容されるように、3週間おきにイピリムマブを4回投与された(導入療法)。導入期間の完了前に明らかな腫瘍負荷の増加を示した患者は、十分な活動指標を示し場合には、許容されるように、導入療法を続けた。イピリムマブに対する腫瘍応答の評価は、導入療法の完了から約12週間後に行われた。初期臨床応答後(PRまたはCR)または最初の腫瘍評価から3か月以上経ってからのSD(修正WHO基準による)後にPDを発症した患者に、イピリムマブによるさらなる処置(再処置)が与えられた。主要なエンドポイントはイピリムマブ+gp100グループ対gp100グループにおけるOSであった。重要な二次的エンドポイントは、イピリムマブ+gp100グループ対イピリムマブ単剤療法グループ、およびイピリムマブ単剤療法グループ対gp100グループにおけるOSであった。合計676人の患者が以下のように無作為化された:イピリムマブ単剤療法グループに137人、イピリムマブ+gp100グループに403人、およびgp100単独グループに136人。大多数が導入の間に全4回の投与を受けた。32人の患者が再処置を受けた:イピリムマブ単剤療法グループに人において8人、イピリムマブ+gp100グループにおいて23人、gp100グループにおいて1人。追跡調査期間は、55か月間までであった。ベースライン特性は、グループ間で十分にバランスがとれていた。年齢の中央値は57歳であった。患者の大多数(71〜73%)がM1c期疾患を有しており、患者の37〜40%がベースラインで乳酸デヒドロゲナーゼ(LDH)の上昇を有していた。合計77人の患者が以前に処置された脳転移の病歴を有していた。イピリムマブを含有する処置計画は、OSにおいてgp100対照グループに対して統計学的に有意な利点を示した。イピリムマブ単剤療法とgp100との間のOSの比較のためのハザード比(HR)は0.66(95%CI:0.51、0.87;p=0.0026)であった。17サブグループ分析により、観察されたOS利点は、ほとんどのサブグループの患者内で一致していた(M[転移]期、以前のインターロイキン2、ベースラインLDH、年齢、性別、および以前の治療のタイプおよび数)。しかしながら、50歳を超える女性に関しては、イピリムマブ処置のOS利点を支持するデータは限られていた。したがって、50歳を超える女性に対するイピリムマブの効力は不明である。サブグループ分析は少数の患者しか含まないので、これらのデータから決定的な結論を引き出すことはできない。1年目および2年目のOSの中央値および推定値を表4に示す。
以下は、Merck & Co., Inc.(Whitehouse Station, NJ, USA)から入手可能なキートルーダ(KEYTRUDA)(登録商標)(ペンブロリズマブ)との併用療法において本発明のグルタミン酸調節剤をどのように使用できるかの例を例示する。追加情報については、静脈内使用のための、静脈内用キートルーダ(KEYTRUDA)(ペンブロリズマブ)注射のための、注射用キートルーダ(KEYTRUDA)(ペンブロリズマブ)の重要事項説明書(HIGHLIGHTS OF PRESCRIBING INFORMATION)(uspi−mk3475−iv−1703r007)(「キートルーダ(KETRUDA)添付文書」)を参照のこと。
ペンブロリズマブの安全性および効力は、以前に白金含有化学療法で処置された患者における進行NSCLCの処置についての多施設の非盲目対照試験KEYNOTE−010において研究された。患者は、≧1%のTPSをもってPDL1 IHC 22C3 pharmDxTM Kitに基づいてPD−L1発現を有した。EGFR活性化変異またはALK転座を有する患者は、また、ペンブロリズマブの投与前にこれらの変異に対する承認された治療中に疾患進行を有した。患者は、疾患進行または許容できない毒性があるまで3週間おきに2mg/kg(n=344)もしくは10mg/kg(n=346)の用量でペンブロリズマブを受けるか、または3週間おきに75mg/m2の用量でドセタキセル(n=343)を受けるように無作為化された(1:1:1)。該試験では自己免疫疾患を有する患者;免疫抑制を必要とする病状を有する患者;または過去26週間以内に30Gyを超える胸部照射を受けた患者は除外された。腫瘍状態の評価は、9週間おきに行われた。この母集団のベースライン特性は、以下を含んだ:年齢の中央値63歳(65歳以上42%);男性61%;白人72%およびアジア人21%、ならびにECOG活動指標0および1を有する人それぞれ34%および66%。疾患特性は、扁平(21%)および非扁平(70%);M1(91%);安定した脳転移(15%)および変異の発生率EGFR(8%)またはALK(1%)であった。以前の治療は、included白金ダブレット計画(100%)を含んでいた;患者は、1(69%)または2以上(29%)の治療ラインを受けた。主要効力評価基準は、RECIST 1.1を用いて盲検独立中央判定(BICR)によって評価されるOSおよびPFSであった。二次的効力評価基準は、ORRおよび奏効期間であった。表5に、全集団(TPS≧1%)およびTPS≧50%を有する患者に対する重要な効力基準をまとめている。
Claims (44)
- 癌の処置を必要とする患者における癌の処置方法であって、該患者に治療有効量のグルタミン酸調節剤および免疫療法抗癌剤を投与することを含む、方法。
- グルタミン酸調節剤が、(i)イオンチャネル型グルタミン酸受容体;(ii)代謝型グルタミン酸受容体;または(iii)グルタミン酸輸送体の調節、制御、減弱または増強を促進する薬剤である、請求項1記載の方法。
- グルタミン酸調節剤が、グルタミン酸放出を阻害する薬剤である、請求項1記載の方法。
- グルタミン酸調節剤が、グルタミン酸またはグルタミンの代謝を調節、調整、減弱または増強する薬剤である、請求項1記載の方法。
- イオンチャネル型グルタミン酸受容体が、N−メチル−D−アスパラギン酸(「NMDA」)、α−アミノ−3−ヒドロキシ−5−メチル−4−イソオキサゾールプロピオン酸(「AMPA」)およびカイニン酸(kainite)から選択される、請求項2記載の方法。
- 代謝型グルタミン酸受容体が、mGluR1およびmGluR5から選択される1型受容体;mGluR2およびmGluR3から選択されるII型受容体;またはmGluR4、mGluR6、mGluR7およびmGluR8から選択されるIII型受容体のうち1つ以上である、請求項2記載の方法。
- グルタミン酸輸送体が、グリアまたはニューロンにおいて発現する、請求項2記載の方法。
- グルタミン酸調節剤が、リルゾール、メマンチン、n−アセチルシステイン、アマンタジン、トピラマート、プレガバリン、ラモトリギン、ケタミン、s−ケタミン、AZD8108、AZD6765(ラニセミン)、BHV−4157(トリグリルゾール(trigriluzole))、デキストロメトルファン、AV−101、CERC−301、GLY−13、およびそれらの薬学的に許容される塩、プロドラッグまたは類似体から選択される、請求項1記載の方法。
- グルタミン酸調節剤が、下記式:
- 免疫療法抗癌剤が、抗体、ペプチド、タンパク質、小分子、アジュバント、サイトカイン、腫瘍溶解性ウイルス、ワクチン、二特異的分子および細胞治療薬から選択される、請求項1記載の方法。
- 免疫療法抗癌剤が、チェックポイント阻害剤である、請求項10記載の方法。
- チェックポイント阻害剤が、PD−1、PD−L1およびCTLA−4から選択されるチェックポイント受容体の阻害剤である、請求項11記載の方法。
- PD−1の阻害剤が、ニボルマブ、ペンブロリズマブおよびピディルズマブ(pidilzumab)から選択される抗PD−1抗体である、請求項12記載の方法。
- PD−L1の阻害剤が、BMS−936559、デュルバルマブ、アテゾリズマブ、アベルマブおよびMDX−1105から選択される抗PD−L1抗体である、請求項12記載の方法。
- PD−L1の阻害剤がペプチドである、請求項12記載の方法。
- CTLA−4の阻害剤が、イピリムマブおよびトレメリムマブから選択される抗CTLA−4抗体である、請求項12記載の方法。
- グルタミン酸調節剤および免疫療法抗癌剤が、少なくとも2.0の60日目のマウス生存比(MSR60)を提供する能力を有する、請求項1記載の方法。
- 免疫療法抗癌剤で処置されている患者においてグルタミン酸を調節する方法であって、免疫療法抗癌剤による処置に近い時期に、患者におけるグルタミン酸受容体またはグルタミン酸輸送体とグルタミン酸調節剤とを接触させることを含む、方法。
- グルタミン酸調節剤がリルゾールである、請求項18記載の方法。
- リルゾールが、静脈内に、筋肉内に、非経口的に、舌下に、経鼻的に、または経口的に投与される、請求項19記載の方法。
- リルゾールが、プロドラッグの形態で投与される、請求項20記載の方法。
- プロドラッグが、下記式:
- グルタミン酸受容体またはグルタミン酸輸送体とグルタミン酸調節剤との接触が、免疫療法抗癌剤による処置の前、同時または後に行われる、請求項18記載の方法。
- 近い時期が、免疫療法抗癌剤による処置の1週間以内である、請求項18記載の方法。
- 免疫療法抗癌剤で処置されている癌を患っている患者を感作させる方法であって、免疫療法抗癌剤による処置と近い時期に、該患者に、治療有効量のグルタミン酸調節剤を投与することを含む、方法。
- 感作が、抗腫瘍効果の増強を促進する、請求項25記載の方法。
- 抗腫瘍効果の増強が、患者の客観的奏効率の増加または奏効期間の増大によって測定される、請求項26記載の方法。
- 抗腫瘍効果の増強が、患者の全生存期間の増大を促進する、請求項27記載の方法。
- 患者が、免疫療法抗癌剤の初回投与後、少なくとも約10か月間、少なくとも約11か月間、少なくとも約12か月間、少なくとも約13か月間、少なくとも約14か月間、少なくとも約15か月間、少なくとも約16か月間、少なくとも約17か月間、少なくとも約18か月間、少なくとも約19か月間、少なくとも約20か月間、少なくとも約21か月間、少なくとも約22か月間、少なくとも約23か月間、少なくとも約2年間、少なくとも約3年間、少なくとも約4年間、または少なくとも約5年間の全生存期間を示す、請求項28記載の方法。
- 全生存期間が、治療有効量の免疫療法抗癌剤により処置されたがグルタミン酸調節剤によって処置されなかった患者の全生存期間の少なくとも約1.1倍、少なくとも約1.2倍、少なくとも約1.3倍、少なくとも約1.4倍、少なくとも約1.5倍、少なくとも約2.0倍、少なくとも約3.0倍、または少なくとも約3.0倍である、請求項28記載の方法。
- 免疫療法抗癌剤で処置されている癌を患っている患者における応答を改善する方法であって、該改善を必要としている患者に、有効量の免疫療法抗癌剤およびリルゾールまたはそのプロドラッグを投与することを含む、方法。
- 免疫療法抗癌剤がチェックポイント阻害剤である、請求項31記載の方法。
- チェックポイント阻害剤が、PD−1、PD−L1およびCTLA−4から選択されるチェックポイント受容体の阻害剤である、請求項32記載の方法。
- 患者が、さらに、抗LAG3抗体、抗CD137抗体、抗KIR抗体、抗TGFp抗体、抗IL−10抗体、抗B7−H4抗体、抗Fasリガンド抗体、抗CXCR4抗体、抗メソテリン抗体、抗CD20抗体、抗CD27抗体、抗GITR抗体、抗OX40抗体、またはそれらの組合せから選択される抗体で処置される、請求項31記載の方法。
- 患者が、さらに、放射線療法、化学療法、ワクチン、サイトカイン、チロシンキナーゼ阻害剤、抗VEGF阻害剤、IDO阻害剤、IDO1阻害剤、TGF−β阻害剤、またはそれらの組合せで処置される、請求項31記載の方法。
- 癌が、黒色腫癌(melanoma cancer)、腎癌、前立腺癌、乳癌、結腸癌、肺癌、骨癌、膵癌、皮膚癌、頭頚部癌、皮膚もしくは眼内悪性黒色腫、子宮癌、卵巣癌、直腸癌、肛門部分の癌、胃癌、精巣癌、子宮癌、卵管癌、子宮内膜癌、子宮頚癌、膣癌、外陰癌、ホジキン病、非ホジキンリンパ腫、食道癌、小腸癌、内分泌系癌、甲状腺癌、副甲状腺癌、副腎癌、軟部組織肉腫、尿道癌、陰茎癌、慢性もしくは急性白血病(急性骨髄性白血病、慢性骨髄性白血病、急性リンパ芽球性白血病、慢性リンパ球性白血病を包含する)、幼児期固形腫瘍、リンパ球性リンパ腫、膀胱癌、腎臓もしくは尿管の癌、腎盂腎癌、中枢神経系(CNS)新生物、原発性CNSリンパ腫、腫瘍血管新生、脊髄軸腫瘍、脳幹神経膠腫、下垂体腺腫、カポジ肉腫、類表皮癌、扁平上皮癌、T細胞リンパ腫、環境誘発癌(アスベストによって誘発される癌を包含する)、およびそれらの組合せから選択される、請求項31記載の方法。
- 改善された応答が、全生存期間、クオリティ・オブ・ライフ、全奏効割合、奏効期間、無増悪生存期間、患者報告アウトカム、微小残存病変または免疫応答の1つ以上である、請求項31記載の方法。
- 癌の処置を必要とする患者に請求項1〜37のいずれか1項に記載のグルタミン酸調節剤と併せて免疫療法抗癌剤を投与することによる癌処置のための医薬組成物であって、有効量のグルタミン酸調節剤および薬学的に許容される担体を含む、医薬組成物。
- 請求項1〜37いずれか1項記載の癌処置のための医薬組成物を調整するためのグルタミン酸調節剤の使用。
- 癌を患っている患者の処置のためのキットであって、
(a)免疫療法抗癌剤;および
(b)請求項1〜37いずれか1項記載の方法においてグルタミン酸調節剤と併せて免疫療法抗癌剤を投与することについての説明書
を含む、キット。 - 癌を患っている患者の処置のためのキットであって、
(a)グルタミン酸調節剤;および
(b)請求項1〜37いずれか1項記載の方法において免疫療法抗癌剤と併せてグルタミン酸調節剤を投与することについての説明書
を含む、キット。 - グルタミン酸調節剤がリルゾールまたはそのプロドラッグである、請求項41記載のキット。
- プロドラッグが、下記式:
- 免疫療法抗癌剤が、ニボルマブ、ペンブロリズマブ、ピディルズマブ(pidilzumab)、デュルバルマブ、アテゾリズマブ、アベルマブ、イピリムマブおよびトレメリムマブから選択される、請求項40記載のキット。
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JP2019516711A (ja) * | 2016-05-20 | 2019-06-20 | バイオヘイブン・ファーマシューティカル・ホールディング・カンパニー・リミテッドBiohaven Pharmaceutical Holding Company Ltd. | 癌を処置するためのリルゾール、リルゾールプロドラッグまたはリルゾール類似体と免疫療法との併用 |
JP7169195B2 (ja) | 2016-05-20 | 2022-11-10 | バイオヘイブン・ファーマシューティカル・ホールディング・カンパニー・リミテッド | 癌を処置するためのリルゾール、リルゾールプロドラッグまたはリルゾール類似体と免疫療法との併用 |
KR20220015796A (ko) * | 2020-07-31 | 2022-02-08 | 서울대학교병원 | 다중약물 화학요법에 있어서 항암제의 유효 용량 정보의 제공 방법 |
KR102441650B1 (ko) | 2020-07-31 | 2022-09-08 | 서울대학교병원 | 다중약물 화학요법에 있어서 항암제의 유효 용량 정보의 제공 방법 |
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