JP2021510738A - 4−1bbと組み合わせたキメラ抗原受容体免疫治療製品の投与方法 - Google Patents
4−1bbと組み合わせたキメラ抗原受容体免疫治療製品の投与方法 Download PDFInfo
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Abstract
Description
本発明をよりたやすく理解するために、最初に用語の定義を以下に示す。以下の用語や他の用語は、明細書全体にわたって補足的に説明されている。
キメラ抗原受容体(CAR又はCAR-T)は、遺伝子改変された受容体である。この改変された受容体は、当技術分野における公知の技術により、容易にT細胞を含む免疫細胞に挿入することができ、当該細胞で発現することができる。CARを使用することにより、単一の受容体は、特定の抗原を認識し、当該抗原に結合した際に、免疫細胞を活性化して、当該抗原を有する細胞を攻撃して破壊するようにプログラムすることができる。当該抗原が腫瘍細胞上に存在する場合、CARを発現する免疫細胞は、腫瘍細胞を標的として殺すことができる。
本明細書には、びまん性大細胞型B細胞リンパ腫(DLBCL)非特異型、原発性縦隔大細胞型B細胞リンパ腫、高悪性度B細胞リンパ腫及び濾胞性リンパ腫由来DLBCLを含む、再発又は難治性の大細胞型B細胞リンパ腫の患者であって、2回以上の全身治療歴を有する患者の治療のための、CD19を標的とする遺伝子改変されたT細胞免疫治療製品が記載されている。ある態様では、CD19を標的とする免疫療法製品は自己由来である。ある態様では、CD19を標的とする免疫療法製品は同種異系由来である。ある態様では、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品は、アキシカブタジン シロルーセル(Axi-cel(登録商標)、YESCART(登録商標))である。
本明細書に記載された方法は、被験者におけるがんの治療、腫瘍サイズの縮小、腫瘍細胞の殺傷、腫瘍細胞の増殖防止、腫瘍の成長防止、患者からの腫瘍の排除、腫瘍の再発防止、腫瘍転移の防止、患者の寛解の誘導、又はその組合せに使用することができる。ある態様では、この方法は完全奏効を誘導する。別の態様では、この方法は部分奏効を誘導する。
Axi-cel(登録商標)投与後の薬力学及び薬物動態
YESCART(登録商標)(アキシカブタジン シロルーセル;Axi-cel(登録商標);KTE-C19)は、2回以上の全身治療歴を有する、成人の再発又は難治性(r/r)大細胞型B細胞リンパ腫の患者の治療のために米国食品医薬品局(FDA)が承認した、CD19を標的とする遺伝子改変された自家キメラ抗原受容体(CAR)T細胞治療製品である。承認された適応症には、びまん性大細胞型B細胞リンパ腫(DLBCL)非特異型、原発性縦隔大細胞型B細胞リンパ腫(PMBCL)、高悪性度B細胞リンパ腫及び濾胞性リンパ腫由来DLBCLが含まれる。
ある態様では、成人の難治性の大細胞型B細胞リンパ腫の患者の治療に適応されたCD19を標的とする遺伝子改変された自家T細胞免疫治療製品は、2回以上の全身治療の後に投与する。ある態様では、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の輸注バックは、キメラ抗原受容体(CAR)陽性T細胞の懸濁液を約68mL含有する。目標用量は、体重1kgあたり約1×106個〜約2×106個のCAR陽性生T細胞とすることができ、最大、2×108個のCAR陽性生T細胞とすることができる。ある態様では、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品は、Axi-cel(登録商標)(YESCART(登録商標)、アキシカブタジン シロルーセル)である。
CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の解凍と投与のタイミングを連携させる。ある態様では、事前に投与開始時間を確認し、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の解凍開始時間は、患者の準備が整ったときに投与できるように調整される。
ある態様では、本明細書に記載のCD19を標的とする遺伝子改変された自家T細胞免疫治療製品の投与方法は、以下の1以上の工程又は考慮すべき事項を含む。
・投与前及び回復期間中に、トシリズマブ及び緊急用機器が利用可能であることを確認する。
・白血球除去フィルターを使用しない。
・CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の投与は、中心静脈アクセスを推奨する。
・患者IDと、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の輸注バックの患者IDの一致を確認する。
・注入前にチューブを生理食塩水でプライミングする。
・重力で、又は蠕動ポンプを用い、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品のバックの内容物全体を30分以内に注入する。CD19を標的とする遺伝子改変された自家T細胞免疫治療製品は、解凍後、室温で最大3時間安定である。
・細胞の凝集を防ぐため、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の注入中に輸注バックを静かに攪拌する。
・輸注バッグの内容物全体が注入された後、全ての製品が確実に送達されるように、同じ注入速度により生理食塩水でチューブをすすぐ。
・CD19を標的とする遺伝子改変された自家T細胞免疫治療製品には、複製不能レトロウイルスベクターで遺伝子改変されたヒト血液細胞が含まれている。感染症の可能性を回避するために、取扱い及び廃棄は、一般的な注意事項とローカルバイオセーフティガイドラインに従う。
ある態様では、CD19を標的とする遺伝子改変された自家T細胞免疫治療製品の投与は、認定された医療施設で行われる。ある態様では、本明細書に記載の方法は、認定医療施設において、投与後少なくとも7日間、患者のCES及び神経毒性の徴候及び症状を監視することを含む。ある態様では、患者は、投与後少なくとも4週間、認定医療施設の近くにいるように指示される。
ある態様では、この方法は、有害反応の管理を含む。ある態様では、前記有害反応は、サイトカイン放出症候群(CRS)、神経毒性、過敏性反応、重篤な感染症、血球減少症及び低ガンマグロブリン血症からなる群から選択される。
4-1BB(CD137)タンパク質受容体は、特定のT細胞(CD8+だけではなくCD4+メモリーT細胞にも)及びナチュラルキラー(NK)細胞に見られる(Fisher, T.S., Kamperschroer, C., Oliphant, T. et al. Cancer Immunol Immunother (2012) 61: 1721. https://doi.org/10.1007/s00262-012-1237-1; Westwood JA, Potdevin Hunnam TCU, Pegram HJ, Hicks RJ, Darcy PK, Kershaw MH (2014) Routes of Delivery for CpG and Anti-CD137 for the Treatment of Orthotopic Kidney Tumors in Mice. PLoS ONE 9(5): e95847. https://doi.org/10.1371/journal.pone.0095847)。4-1BBは、TNFRSF9;腫瘍壊死因子受容体スーパーファミリー、メンバー9;ILA;4-1BB;CD137;CDw137;腫瘍壊死因子受容体スーパーファミリーメンバー9;CD137抗原とも称される。ウトミルマブを含む4-1BB結合分子は、米国特許第8,337,850号にさらに記載されており、参照によりその全体が本明細書に組み込まれる。
結合分子の「治療有効量」という用語は、意図された治療目的に有効な量を指す。例えば、がんの治療では、望ましい又は有益な効果の例には、がん細胞のさらなる増殖又は拡散の阻止、がん細胞の死、がんの再発の阻止、がんに関連する痛みの軽減又は哺乳動物の生存の改善が含まれる。4-1BB抗体の治療有効量は、通常、哺乳動物の体重1kgあたり、約0.001〜約500mg、より一般的には約0.01〜約200mgである。例えば、その量は、哺乳動物の体重1kgあたり、約0.3mg、約1mg、約3mg、約5mg、約10mg、約50mg、約100mg又は約200mgである場合がある。ある態様では、4-1BB抗体の治療有効量は哺乳動物の体重1kgあたり約0.01〜30mgである。別の態様では、4-1BB抗体の治療有効量は、哺乳動物の体重(kg)あたり約0.05〜30mgである。投与される正確な用量は、当業者がたやすく決定することができ、これは、治療する疾患の種類や重症度、結合分子、投与経路、投与時間、治療期間、追加の治療法、治療する患者の年齢、性別、体重、体調、健康状態及び病歴、並びに医療分野で周知の要因などの多くの要因に依存する。
アキシカブタジン シロルーセルとウトミルマブの併用療法は、がん患者を効果的に治療するために使用することができる。この実施例は、少なくとも2回の全身治療歴を有する難治性の大細胞型B細胞リンパ腫又は難治性のびまん性大細胞型B細胞リンパ腫(DLBCL)の被験者に対するウトミルマブと組み合わせたKTE-C19(アキシカブタジン シロルーセル)の安全性及び有効性を評価する多施設共同研究を示す。この治験は、第1相及び第2相と呼ばれる2つの異なる段階に分かれている。
・スクリーニング
・登録/白血球アフェレーシス
・ブリッジング療法(該当する場合)
・前処置の化学療法
・併用治療(KTE-C19及びウトミルマブ)
・治療後の評価
・長期間の追跡
ある局面では、選択基準は以下のとおり:
・組織学的に証明された大細胞型B細胞リンパ腫は(Swerdlow et al, 2016)で定義された以下の型を含む:
・ABC/GCB型以外のDLBCL
・MYC及びBCL2及び/又はBCL6の再構成を有するか有さないHGBCL
・FL由来DLBCL
・T細胞/組織球豊富型大細胞型B細胞リンパ腫
・慢性炎症を伴うDLBCL
・皮膚原発DLBCL、下肢型
・EBウイルス(EBV)陽性DLBCL
・以下の1以上で定義される化学療法不応性疾患
・2次以上の治療に抵抗性である
・直近の治療レジメンに対する最良の応答がPDである
・直近の治療の少なくとも2サイクル後の最良の応答がSDで、その期間が直近の投与から6月以内
又は
・ASCT後の難治性
・ASCT後12月以内の疾患の進行又は再発(生検による再発の証明が必要)
・ASCT後にサルベージ療法が行われる場合、直近の治療に反応しなかったか、その後再発
・ルガーノ分類(Cheson et al. 2014)による少なくとも1つの確認可能な病変。以前に放射線が照射された病変は、放射線療法の終了後に進行と記録されている場合にのみ確認可能と見なす
・被験者は、最低限の適切な事前の以下の治療を受けていること:
・抗CD20モノクローナル抗体(医師が腫瘍はCD20陰性と判断した場合を除く)、及び
・アントラサイクリンが含まれる化学療法
・リンパ腫の中枢神経系(CNS)病変の証拠、疑い、及び/又は病歴の不在
・アフェレーシスの予定日は、直近の全身治療から少なくとも2週、又は5半減期のいずれか短い期間、経過している必要がある
・以前の治療による毒性は安定し、グレード1以下まで回復している必要がある(脱毛症などの臨床的に重要でない毒性を除く)
・18歳以上
・米国東海岸がん臨床試験グループ(ECOG)パフォーマンスステータスが0又は1
・好中球絶対数(ANC);1000/μL以上
・血小板数;75,000/μL以上
・リンパ球絶対数;100/μL以上
・以下に定義される十分な腎機能、肝機能、肺機能及び心臓機能:
・クレアチニン クリアランス(Crockcroft Gault式による推定値);60mL/分以上
・血清アラニンアミノトランスフェラーゼ/アスパラギン酸アミノトランスフェラーゼALT/AST;正常上限値(ULN)の2.5倍以下
・総ビリルビン;1.5mg/dL以下、Gilbert症候群の被験者を除く
・心駆出率;50%以上で、被験者がアントラサイクリン系の治療を受けていないか、心臓イベント又はパフォーマンスステータスの変化を経験していない場合、180日以内に心膜液貯留がないこと
・臨床的に重要な胸水がないこと
・酸素吸入を行わない場合の安静時酸素飽和度92%より高い
・妊娠の可能性がある女性は、血清又は尿による妊娠検査で陰性であること(不妊手術を受けた女性又は閉経後少なくとも2年経過した女性は、妊娠の可能性があるとは見なされない)。
・組織学的に確認されたDLBCL
・少なくとも2系統の全身療法の後、疾患が難治性であること
・測定可能な基礎疾患
・スクリーニング時に生検を得ていること(保存又は最近のスクリーニング)
・推定余命が3月以上
・18歳以上
・米国東海岸がん臨床試験グループ(ECOG)パフォーマンスステータスが0又は1
・患者の骨髄機能は、
・好中球絶対数(ANC);1.5×109/L以上
・血小板数;100×109/L以上
・ヘモグロビン;8g/dL以上
であることを含み、適切であること
・患者の肝機能は、
・総ビリルビン;正常上限値(ULN)の1.5倍以下、
・アスパラギン酸アミノトランスフェラーゼ(AST)及びアラニンアミノトランスフェラーゼ(ALT);ULNの2.5倍以下
であることを含み、適切であること
・患者は、Crockcroft Gault式で算出されたクレアチニン クリアランスが60mL/分以上である、適切な腎機能を有していなければならない。
・組織学的に証明されたPMBCL
・リヒター症候群の発症歴
・キメラ抗原受容体(CAR) T細胞(CAR T細胞)治療又は他の遺伝子改変されたT細胞治療を含む薬剤によらない抗がん治療歴
・アミノグリコシドに起因する重篤な即時型過敏症の経験
・制御されていない、又は管理のために抗菌剤の静脈投与を必要とする、真菌、細菌、ウイルス又は他の感染の存在又は疑い。但し、積極的な治療に応答し、かつ、スポンサーのメディカルモニターと相談した後であれば、単純なUTI及び合併症のない細菌性咽頭炎は許可
・HIV感染歴若しくは急性又は慢性活動性B又はC型肝炎の感染歴。肝炎感染歴を有する被験者は、現行の米国感染症学会(IDSA)のガイドライン又は該当する国のガイドラインによる標準的な血清及び遺伝子検査において、感染が除去されている必要がある
・留置ライン又はドレーンの存在(例.経皮的腎瘻チューブ、留置型フォーリーカテーテル、胆管ドレーン、又は胸膜/腹膜/心膜カテーテル)。Port-a-Cath又はヒックマンカテーテルなどの専用の中心静脈カテーテルは許可
・脳脊髄液中に悪性細胞を有する被験者、脳転移のある被験者又は臨床で中枢神経系(CNS)リンパ腫と判定されたことのある被験者
・てんかん性発作、脳血管虚血/出血、認知症、小脳疾患又はCNSの病変を伴う自己免疫疾患などのCNS障害の病歴又は存在
・心房又は心室リンパ腫を有する被験者
・登録後12月以内の、心筋梗塞、心血管形成術若しくはステント術、不安定狭心症又は他の臨床的に重要な心臓病歴
・腫瘍塊に基づく緊急治療の必要性(例.血管圧迫、腸閉塞又は貫壁性の胃の病変)
・原発性免疫不全症候群
・2年以内の、最終的に臓器損傷をもたらすか、又は、全身性の免疫抑制治療/全身性の疾患修飾治療を必要とする自己免疫疾患(例.クローン病、関節リウマチ、全身性エリテマトーデス)の既往歴。安定量の甲状腺補充ホルモンが投与されている自己免疫関連甲状腺機能低下症の患者、及び安定量のインスリン療法で1型糖尿病が制御されている患者は、この試験の被験者となる可能性がある
・登録後6月以内の症候性深部静脈血栓症又は肺塞栓症の病歴
・治療の安全性又は有効性の評価に干渉する可能性が高い病状
・この治療で使用される薬剤に対する重度の即時型過敏反応の既往歴
・前処置の化学療法開始予定日から6週以内の生ワクチン接種
・前処置の化学療法に潜在する胎児又は乳児に対する危険な影響ゆえに、出産の可能性又は授乳中の女性。不妊手術を受けた女性又は閉経後少なくとも2年経過した女性は、妊娠の可能性があるとは見なされない
・治療に同意した時からウトミルマブ投与後90日まで、及び前処置の化学療法の終了後少なくとも6月に避妊の実施を希望しない被験者(男女とも)
・非メラノーマ性の上皮内がん(例.子宮頸部、膀胱、乳房)又は治療計画がなく監視療法を行っている低悪性度(Gleasonスコア6以下)の前立腺がん以外の悪性腫瘍の既往歴(但し、3年以上無病の場合を除く)
・登録予定日から6週以内の自家幹細胞移植
・同種幹細胞移植(SCT)を含む臓器移植歴
・この治療でアキシカブタジン シロルーセル(KTE-C19)が投与され、再治療の対象となる被験者を除く、CD19標的治療歴
・登録前2週以内の標準的又は実験的な抗がん治療(細胞減少療法及び放射線療法、免疫療法又はエリスロポエチンを除くサイトカイン療法)歴
・PD-L1阻害剤、PD-1阻害剤、抗CTLA4、抗CD137(4-1BB)、抗OX40又は他の免疫チェックポイント阻害剤若しくは活性化剤による治療歴
・ウトミルマブの初回投与前、6週又は薬物の半減期5回分のどちらか短い期間内の全身性の免疫刺激剤(インターフェロン及びIL-2を含むがこれらに限定されるものではない)による治療歴
・特発性肺線維症、組織化肺炎(例.閉塞性細気管支炎)、薬剤性肺炎、特発性肺炎の病歴、又はスクリーニング時の胸部CTスキャンによる活動性肺炎。放射線分野での放射線肺炎(線維症)の既往を除く
・治験責任医師の判断による、フォローアップ訪問を含むプロトコルで必要な全ての訪問又は手順を完了する可能性が低い、又は参加の要件を遵守する可能性が低い被験者。
・臨床による症候性の中枢神経系(CNS)リンパ腫
・同種SCTを含む臓器移植歴
・4-1BBアゴニストによる治療歴
・登録前2週以内の標準的又は実験的な抗がん治療(細胞減少療法及び放射線療法、免疫療法又はエリスロポエチンを除くサイトカイン療法)歴
・登録から3週以内の自家幹細胞移植
・この治療でKTE-C19が投与され、再治療の対象となる被験者を除く、CD19標的治療歴
・キメラ抗原受容体(CAR) T細胞(CAR T細胞)治療を含む薬剤によらない抗がん治療の使用
・2年以内の全身性の免疫抑制治療を必要とする自己免疫疾患の既往歴
・初回投与前3年以内の他の悪性腫瘍((i) 適切に治療された基底細胞若しくは扁平上皮皮膚がん、(ii) 乳房若しくは子宮頸部の上皮内癌、又は(iii) 治療(例.手術、放射線若しくは内分泌療法)の予定がなく監視療法を行っている低悪性度(Gleasonスコア6以下)の前立腺がんを除く)の診断。
KTE-C19に対する耐性をさらに評価する。薬物動態、薬力学、腫瘍及び免疫バイオマーカー、並びに製品の特性の評価を含む治療評価計画は、実施例1に記載された難治性の大細胞型B細胞リンパ腫又は難治性のDLBCLの被験者における、4-1BB(CD137)アゴニスト抗体であるウトミルマブと組み合わせたAxi-cel(登録商標)の安全性、有効性及び作用機序を評価する多施設共同研究をサポートする。この評価計画は、抗CD19 CAR T細胞表面のCD137の急速なアップレギュレーションが、アゴニストによる活性化に対する応答を引き起こし、増殖と臨床活性の増加につながるかどうかを、トランスレーショナル分析で決定する。腫瘍微小環境(TME)での耐性の作用機序及び神経学的毒性(CSF)の機序も調査できる。
投与前(前処置期)、及びT細胞の投与後であって、第7〜14日又はその前後の血中で製品が増殖するピークとほぼ一致する時に、腫瘍のコア針生検を行う。投与前後の生検のスケジュールを図8に示す。コア針生検のFFPEは、60mLの中性緩衝ホルマリン(FFPEの固定液)を含む120mLの瓶、1.5mLクライオバイアル(FFT)及び適切なラベルを用いて作成する。固定剤にコア針生検材料(3〜4コア)を入れ、FFPEに加工する。残りのコア(1〜2)は、液体窒素(LN2)又はドライアイス/エタノールスラリー中で急速冷凍するために、直ちに1.5mLクライオバイアルに入れる。検体を−80℃で保管する。図9に、コア針生検の検体処理スキームをまとめる。
IHC−免疫浸潤
・CD19 CAR検出(in situハイブリダイゼーション法、FISH及びISH)
・CD25及びCD107α(CARの活性化及び脱顆粒の証拠)
・Ki-67(腫瘍内でのCAR増殖の証拠)
・PD-1(CAR疲弊の証拠)
IHC−腫瘍
・CD19(CAR標的抗原)
・CD22(CD19陰性病変の有病率)
・PD-L1/2(チェックポイントを介した耐性)
・カスパーゼ3(CARによる腫瘍細胞殺傷の証拠)
追加のIHC分析/目標
・CAR T細胞/腫瘍細胞の近接性の評価
・CAR製品検出の開発
・相関イメージングリソースパートナーの開発
微小残存病変(MRD)
Adaptive Biotechnology社のClonoSIGHT(登録商標)技術を高感度でMRDを検出するために用いる。腫瘍特異的免疫グロブリン遺伝子の同定及び測定のためのAdaptive社のハイスループットシークエンシングプラットフォームを使用した診断時及び治療中の循環腫瘍DNA(ctDNA)の評価は、治療前の検体で行われ、その後、縦断的な監視が行われる。疾患の遺伝マーカーの評価は10−6の感度があり、患者の末梢血を利用して行われる。この方法は、CRが決定された場合、CTイメージングと分子疾患のクリアランスと比較して、疾患の優れた監視を実証する可能性がある。登録の期間(校正)、OR評価時に開始された吸引、3月ごとに1年間、18月、24月に収集されたadaptiveの検体は、完全奏効(CR)と判断された被験者のMRDをサポートするために用いられる。
Adaptive Biotechnology社のImmunoSEQ(登録商標)技術は、一連の難治性大細胞型B細胞リンパ腫又はDLBCLの生検(投与前、投与後及び再発時)で、B細胞受容体(BCR)の多様性を特徴付けるために使用される。BCRの多様性の評価は、治療中の悪性クローンを特定又は確認するために使用でき、二次性悪性腫瘍ではなく、元の腫瘍の再発を確認するためにも使用できる。また、末梢血リンパ球のBCRのシークエンシングは、正常なB細胞レパートリーの回復を確認するために使用される。
この実施例では、抗CD19 CAR T細胞に対するウトミルマブの影響を研究した。ウトミルマブの存在下又は不存在下で、CAR T細胞を刺激又は活性化するツール抗体と共に前記細胞をインキュベートした。サイトカイン、ケモカイン及びエフェクター分子(分析物)の産生又はその濃度による潜在的な影響を評価した。抗CD19 CAR T細胞は、健康な被験者(A、B、C、D及びE)の末梢血単核球から得た。R10培地中の抗CD19 CAR T細胞(1×106細胞/mL)を、37℃、5%CO2中で一晩インキュベートした。96ウェルプレートを、ツール抗体(0.33μg/mL)、ウトミルマブ(3倍希釈による0〜100μg/mLの滴定濃度)又は4-1BBに結合しないコントロール抗体(3倍希釈による0〜100μg/mLの滴定濃度)で、4℃で一晩かけてコーティングした。コーティングされたプレートを、R10培地で2回洗浄し、1×105の抗CD19 CAR T細胞を加えた。各ウェルの総最終容量を、R10培地で200μLに調整した。37℃、5%CO2中で一晩インキュベートした後、上清を回収し、MILLIPLEX MAP Human CD8+ T Cell Magnetic Bead Panel Premixed 17 Plex - Immunology Multiplex Assayを用いて分析した。ピーク倍率の変化を、ウトミルマブの存在下での分析物の出力を、対応する濃度のコントロール抗体の存在下での出力で割ることによって計算した。各分析物の滴定濃度にわたるピーク倍率の差を表8に示す。
本明細書は、ポリペプチドの配列を含む。便宜のため、以下の表9に、各配列をその対応する説明及び配列番号と関連付ける。
Claims (47)
- CD19を標的とする遺伝子改変されたT細胞免疫治療製品及び4-1BB(CD137)アゴニストの投与を含む、治療を必要とする患者のB細胞リンパ腫又は白血病を治療する方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品は、自家又は同種免疫治療製品である、請求項1に記載の方法。
- 前記T細胞は、ex vivoで遺伝子改変された、請求項1又は2に記載の方法。
- 前記T細胞は、ウイルス、レトロウイルス又はレンチウイルスの形質導入によって遺伝子改変された、請求項1〜3のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品は、CD28及びCD3ζ共刺激ドメインが結合した抗CD19単鎖可変領域フラグメント(scFv)を含むキメラ抗原受容体(CAR)を発現するように遺伝子改変された、請求項1〜4のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品は、アキシカブタジン シロルーセルである、請求項1〜5のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、抗原結合分子又はその断片である、請求項1〜6のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、配列番号1で示されるVH領域のアミノ酸配列中の3つのCDR、及び配列番号3で示されるVL領域のアミノ酸配列中の3つのCDRを含む、単離された抗体又はその抗原結合部位である、請求項1〜7のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、(a) 配列番号5で示されるアミノ酸配列を有するH-CDR1;(b) 配列番号6で示されるアミノ酸配列を有するH-CDR2;(c) 配列番号7で示されるアミノ酸配列を有するH-CDR3;(d) 配列番号8で示されるアミノ酸配列を有するL-CDR1;(e) 配列番号9で示されるアミノ酸配列を有するL-CDR2;及び(f) 配列番号10で示されるアミノ酸配列を有するL-CDR3を含む、単離された抗体又はその抗原結合部位である、請求項1〜8のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、完全ヒトモノクローナル抗体である、請求項1〜9のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、配列番号1で示されるVH領域のアミノ酸配列及び配列番号3で示されるVL領域のアミノ酸配列を含む、請求項1〜10のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、配列番号2で示される重鎖のアミノ酸配列(場合により、C末端のリジン残基は存在しない)及び配列番号4で示される軽鎖のアミノ酸配列を含む、請求項1〜11のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストはウトミルマブである、請求項1〜12のいずれか一項に記載の方法。
- 前記B細胞リンパ腫又は白血病が、急性リンパ性白血病(ALL)、AIDS関連リンパ腫、ALK陽性大細胞型B細胞リンパ腫、バーキットリンパ腫、慢性リンパ性白血病(CLL)、古典的ホジキンリンパ腫、びまん性大細胞型B細胞リンパ腫(DLBCL)、原発性縦隔大細胞型B細胞リンパ腫(PMBCL)、濾胞性リンパ腫、血管内大細胞型B細胞リンパ腫、HHV8関連多中心性キャスルマン病起因大細胞型B細胞リンパ腫、リンパ腫様肉芽腫症、リンパ形質細胞性リンパ腫、マントル細胞リンパ腫(MCL)、辺縁帯B細胞リンパ腫(MZL)、粘膜関連リンパ組織リンパ腫(MALT)、節性辺縁帯B細胞リンパ腫(NMZL)、結節性リンパ球優位型ホジキンリンパ腫、非ホジキンリンパ腫、形質芽球性リンパ腫、中枢神経系原発悪性リンパ腫、原発性滲出性リンパ腫、脾辺縁帯リンパ腫(SMZL)、ワルデンシュトレームマクログロブリン血症、再発又は難治性の大細胞型B細胞リンパ腫、びまん性大細胞型B細胞リンパ腫(DLBCL)非特異型、高悪性度B細胞リンパ腫及び濾胞性リンパ腫由来DLBCLからなる群から選択される、請求項1〜13のいずれか一項に記載の方法。
- 前記B細胞リンパ腫は、再発又は難治性の大細胞型B細胞リンパ腫,びまん性大細胞型B細胞リンパ腫(DLBCL)非特異型、原発性縦隔大細胞型B細胞リンパ腫(PMBCL)、高悪性度B細胞リンパ腫及び濾胞性リンパ腫由来DLBCLからなる群から選択される、請求項1〜14のいずれか一項に記載の方法。
- 前記B細胞リンパ腫は、難治性のびまん性大細胞型B細胞リンパ腫である、請求項1〜15のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品及び前記4-1BB(CD137)アゴニストは、2回以上の全身治療歴を有する患者に投与される、請求項1〜16のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品は、体重1kgあたり約1×106個〜約2×106個のCAR陽性生T細胞の用量で、最大用量が約1×108個のCAR陽性生T細胞まで、前記患者の静脈内に投与される、請求項1〜17のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品の投与は、単回である、請求項1〜18のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品の投与は、複数回である、請求項1〜19のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、静脈内に投与される、請求項1〜20のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、約1mg〜約200mgの用量で投与される、請求項1〜21のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、約1mg、約10mg、約30mg、約100mg又は約200mgの用量で投与される、請求項22に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品及び前記4-1BB(CD137)アゴニストは、同時に投与される、請求項1〜23のいずれか一項に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品は、前記4-1BB(CD137)アゴニストの前に投与される、請求項1〜23のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストの初回用量は、前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品投与の翌日に投与される、請求項25に記載の方法。
- 前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品は、前記4-1BB(CD137)アゴニストの後に投与される、請求項1〜24のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストの投与は、完全寛解を示すまで続ける、非奏効/進行となるまで続ける、又は約1年間続ける、請求項1〜27のいずれか一項に記載の方法。
- 前記4-1BB(CD137)アゴニストは、約4週間ごとに投与される、請求項1〜28のいずれか一項に記載の方法。
- 前記患者は、前記CD19を標的とする遺伝子改変されたT細胞免疫治療製品及び前記4-1BB(CD137)アゴニストの投与の前に、前処置の化学療法が行われる、請求項1〜29のいずれか一項に記載の方法。
- 前記患者の有害反応の徴候及び症状を投与後に観察することをさらに含む、請求項1〜30のいずれか一項に記載の方法。
- 前記有害反応は、サイトカイン放出症候群(CRS)、神経毒性、過敏性反応、重篤な感染症、血球減少症及び低ガンマグロブリン血症からなる群から選択される、請求項31に記載の方法。
- 前記患者の末梢血単核球(PBMC)の表現型及び活性化のマーカーの変化を投与後に観察することをさらに含む、請求項1〜32のいずれか一項に記載の方法。
- 前記患者のPBMCの表現型及び活性化のマーカーは、汎T細胞マーカー、細胞傷害性T細胞マーカー、分化T細胞マーカー、分化マーカー、IL−2受容体、活性化マーカー、PD1、4-1BB、ヘルパーT細胞マーカー、顆粒球マーカー、B細胞マーカー、単球/マクロファージマーカー、NK細胞マーカー及び/又はアキシカブタジン シロルーセル識別を含む、請求項33に記載の方法。
- 前記患者のPBMCの表現型及び活性化のマーカーは、CD3、CD4、CD8、CD45RA、CCR7、CD122、CD27、CD28、CD95、CD57、CD107α、CD279、CD25、CD69、CD137、CD66b、CD19、CD14、CD56及び/又はCD19 CARに対する抗体を含むパネルで観察される、請求項33又は34に記載の方法。
- 前記マーカーは、フローサイトメトリーで確認される、請求項33〜35のいずれか一項に記載の方法。
- 前記患者の血清のケモカイン、サイトカイン及び/又は免疫エフェクターのレベルを投与後に観察することをさらに含む、請求項1〜36のいずれか一項に記載の方法。
- 前記患者の血清のIL-15、IL-7、IL-2、IL-6、IL1α、IL-1β、IL-17α、TNFα、TNFβ、GM-CSF、CRP、SAA、IL-13、IL-4、IL-5、IL-10、IFNγ、IL-12p40、IL-12p70、IL-16、IL-8、MCP-1、MCP-4、MIP-1α、MIP-1β、IP-10、TARC、エオタキシン、エオタキシン-3、MDC、グランザイムA、グランザイムB、sFASL、パーフォリン、FGF−2、sICAM−1を観察する、請求項37に記載の方法。
- 前記ケモカイン、サイトカイン及び/又は免疫エフェクターのレベルは、複合的な分析法で確認される、請求項37に記載の方法。
- 前記患者の応答を、退縮[完全奏効(CR)若しくは部分奏効(PR)]治療不応[進行(PD)]、再発、又は進行若しくは完全退縮の証拠のない持続[PRの継続若しくは安定(SD)]と投与後に分析することをさらに含む、請求項1〜39のいずれか一項に記載の方法。
- 前記投与後の患者の応答の分析は、汎T細胞マーカー、細胞傷害性T細胞マーカー、分化T細胞マーカー、分化マーカー、IL−2受容体、活性化マーカー、PD1、4-1BB、ヘルパーT細胞マーカー、顆粒球マーカー、B細胞マーカー、単球/マクロファージマーカー、NK細胞マーカー及び/又はアキシカブタジン シロルーセル識別を含む患者のPBMCの表現型及び活性化のマーカーの分析を含む、請求項40に記載の方法。
- 前記患者のPBMCの表現型及び活性化のマーカーは、CD3、CD4、CD8、CD45RA、CCR7、CD122、CD27、CD28、CD95、CD57、CD107α、CD279、CD25、CD69、CD137、CD66b、CD19、CD14、CD56及び/又はCD19 CARに対する抗体を含むパネルで観察される、請求項41に記載の方法。
- 前記患者の血清のIL-15、IL-7、IL-2、IL-6、IL1α、IL-1β、IL-17α、TNFα、TNFβ、GM-CSF、CRP、SAA、IL-13、IL-4、IL-5、IL-10、IFNγ、IL-12p40、IL-12p70、IL-16、IL-8、MCP-1、MCP-4、MIP-1α、MIP-1β、IP-10、TARC、エオタキシン、エオタキシン-3、MDC、グランザイムA、グランザイムB、sFASL、パーフォリン、FGF−2、sICAM−1、sVCAM−1、VEGF、VEGF−C、VEGF−D、PLGF、IL1Rα、IL1Rβ及び/又はフェリチンを観察する、請求項40〜42のいずれか一項に記載の方法。
- 治療を必要とする患者のB細胞リンパ腫又は白血病を治療する方法であって、
(a) 前記患者にCD19を標的とする遺伝子改変されたT細胞免疫治療製品を投与し;
(b) 前記患者に4-1BB(CD137)アゴニストを投与し;かつ
(c) 前記患者の有害反応の徴候及び症状を投与後に観察する
ことを含む、方法。 - 治療を必要とする患者の難治性のびまん性大細胞型B細胞リンパ腫を治療する方法であって、
(a) 前記患者にCD19を標的とする遺伝子改変されたT細胞免疫治療製品を投与し;
(b) 前記患者に4-1BB(CD137)アゴニストを投与し:かつ
(c) 前記患者の末梢血単核球(PBMC)の表現型及び活性化のマーカーの変化を投与後に観察する
ことを含む、方法。 - 治療を必要とする患者の難治性のびまん性大細胞型B細胞リンパ腫を治療する方法であって、
(a) 前記患者にCD19を標的とする遺伝子改変されたT細胞免疫治療製品を投与し;
(b) 前記患者に4-1BB(CD137)アゴニストを投与し;かつ
(c) 前記患者の血清のケモカイン、サイトカイン及び/又は免疫エフェクターのレベルを投与後に観察する
ことを含む、方法。 - 治療を必要とする患者の難治性のびまん性大細胞型B細胞リンパ腫を治療する方法であって、
(a) 前記患者にCD19を標的とする遺伝子改変されたT細胞免疫治療製品を投与し;
(b) 前記患者に4-1BB(CD137)アゴニストを投与し;かつ
(c) 前記患者の応答を、退縮[完全奏効(CR)若しくは部分奏効(PR)]治療不応[進行(PD)]、再発、又は進行若しくは完全退縮の証拠のない持続[PRの継続若しくは安定(SD)]と投与後に分析する
ことを含む、方法。
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EP3740285A1 (en) | 2020-11-25 |
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TW201932593A (zh) | 2019-08-16 |
MX2020007543A (es) | 2020-09-09 |
BR112020014446A2 (pt) | 2020-12-29 |
SG11202006416TA (en) | 2020-08-28 |
CN111867680A (zh) | 2020-10-30 |
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