JPWO2020097403A5 - - Google Patents

Description

の化合物、またはその薬学的に許容される塩であり、
式中、
XおよびYの一方は、-C(O)-であり、XおよびYの他方は、-C(O)-または-CH ₂ -であり；
（1）R ¹ 、R ² 、R ³ 、およびR ⁴ の各々は、独立して、ハロ、1～4個の炭素原子のアルキル、またはアルコキシもしくは1～4個の炭素原子であるか、または
（2）R ¹ 、R ³ 、R ⁴ 、およびR ⁵ の1つは、-NHR ^a であり、R ¹ 、R ² 、R ³ 、およびR ⁴ の残りは、水素であり、ここで、R ^a は、水素または1～8個の炭素原子のアルキルであり；
R ⁵ は、水素または1～8個の炭素原子のアルキル、ベンジル、またはハロであり；
但し、XおよびYが-C(O)-であり、かつ（i）R ¹ 、R ² 、R ³ 、およびR ⁴ の各々がフルオロであるか、または（ii）R ¹ 、R ² 、R ³ 、およびR ⁴ の1つがアミノである場合は、R ⁵ は水素以外である、
本発明1001～1067のいずれかの方法。
[本発明1069]
前記化合物が、以下の構造：

の化合物、またはその薬学的に許容される塩であり、
式中、XおよびYの一方は、-C(O)-であり、XおよびYの他方は、-C(O)-または-CH ₂ -であり、R ⁵ は、水素または低級アルキルである、
本発明1001～1068のいずれかの方法。
[本発明1070]
前記化合物が、以下の構造：

を有する3-(4-アミノ-1-オキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)ピペリジン-2,6-ジオン、またはその鏡像異性体もしくは鏡像異性体の混合物、またはその薬学的に許容される塩、溶媒和物、水和物、共結晶体、包接化合物、もしくは多形体であるかまたはそれを含む、本発明1001～1069のいずれかの方法。
[本発明1071]
前記化合物が、3-(4-アミノ-1-オキソ-1,3-ジヒドロ-2H-イソインドール-2-イル)ピペリジン-2,6-ジオンである、本発明1001～1070のいずれかの方法。
[本発明1072]
前記化合物が、以下の構造：

を有する3-(5-アミノ-2-メチル-4-オキソ-4H-キナゾリン-3-イル)-ピペリジン-2,6-ジオンであるかまたはそれを含む化合物、またはその鏡像異性体もしくは鏡像異性体の混合物、またはその薬学的に許容される塩、溶媒和物、水和物、共結晶体、包接化合物、もしくは多形体である、本発明1001～1067のいずれかの方法。
[本発明1073]
前記化合物が、3-(5-アミノ-2-メチル-4-オキソ-4H-キナゾリン-3-イル)-ピペリジン-2,6-ジオンである、本発明1001～1067および1072のいずれかの方法。
[本発明1074]
前記免疫調節化合物が、1日当たり1 mg～50 mgまたは約1 mg～50 mg、1日当たり1 mg～25 mgまたは約1 mg～25 mg、1日当たり1 mg～10 mgまたは約1 mg～10 mg、1日当たり1 mg～5 mgまたは約1 mg～5 mg、1日当たり5 mg～50 mgまたは約5 mg～50 mg、1日当たり5 mg～25 mgまたは約5 mg～25 mg、1日当たり5 mg～10 mgまたは約5 mg～10 mgの有効量で投与され、任意で、該投与が、サイクリングレジメンにおける継続期間にわたって毎日である、本発明1020～1073のいずれかの方法。
[本発明1075]
前記化合物が、以下の構造：

の化合物、またはその薬学的に許容される塩、溶媒和物、もしくは立体異性体であり、
式中、
Zは、C=OまたはCH ₂ であり；
R ¹¹ は、-Z ¹ -R ¹³ であり；
R ¹² は、Hまたは(C ₁ -C ₆ )アルキルであり；
Z ¹ は、6～10員環のアリール、ヘテロアリール、または複素環であり、その各々が、1つまたは複数のハロゲン；または結合で置換されていてもよく；
R ¹³ は、
-(CH ₂ ) _n -アリール、-O-(CH ₂ ) _n -アリール、または-(CH ₂ ) _n -O-アリール（式中、アリールは、1つまたは複数の以下で置換されていてもよい：(C ₁ -C ₆ )アルキル；1つもしくは複数のハロゲンで置換されていてもよいそれ自体；(C ₁ -C ₆ )アルコキシ、1つもしくは複数のハロゲンで置換されているそれ自体；オキソ；アミノ；カルボキシル；シアノ；ヒドロキシル；ハロゲン；重水素；1つもしくは複数の(C ₁ -C ₆ )アルキル、(C ₁ -C ₆ )アルコキシ、もしくはハロゲンで置換されていてもよい、6～10員環のアリールもしくはヘテロアリール；-CONH ₂ ；または-COO-(C ₁ -C ₆ )アルキル（式中、アルキルは、1つもしくは複数のハロゲンで置換されていてもよい））；
-(CH ₂ ) _n -複素環、-O-(CH ₂ ) _n -複素環、または-(CH ₂ ) _n -O-複素環（式中、複素環は、1つまたは複数の以下で置換されていてもよい：(C ₁ -C ₆ )アルキル、1つもしくは複数のハロゲンで置換されていてもよいそれ自体；(C ₁ -C ₆ )アルコキシ、1つもしくは複数のハロゲンで置換されているそれ自体；オキソ；アミノ；カルボキシル；シアノ；ヒドロキシル；ハロゲン；重水素；1つもしくは複数の(C ₁ -C ₆ )アルキル、(C ₁ -C ₆ )アルコキシ、もしくはハロゲンで置換されていてもよい、6～10員環のアリールもしくはヘテロアリール；-CONH ₂ ；または-COO-(C ₁ -C ₆ )アルキル（式中、アルキルは、1つもしくは複数のハロゲンで置換されていてもよい））；または
-(CH ₂ ) _n -ヘテロアリール、-O-(CH ₂ ) _n -ヘテロアリール、または-(CH ₂ ) _n -O-ヘテロアリール（式中、ヘテロアリールは、1つまたは複数の以下で置換されていてもよい：(C ₁ -C ₆ )アルキル、1つもしくは複数のハロゲンで置換されていてもよいそれ自体；(C ₁ -C ₆ )アルコキシ、1つもしくは複数のハロゲンで置換されているそれ自体；オキソ；アミノ；カルボキシル；シアノ；ヒドロキシル；ハロゲン；重水素；1つもしくは複数の(C ₁ -C ₆ )アルキル、(C ₁ -C ₆ )アルコキシ、もしくはハロゲンで置換されていてもよい、6～10員環のアリールもしくはヘテロアリール；-CONH ₂ ；または-COO-(C ₁ -C ₆ )アルキル（式中、アルキルは、1つもしくは複数のハロゲンで置換されていてもよい））
であり；かつ
nは、0、1、2、または3である、
本発明1001～1067のいずれかの方法。
[本発明1076]
前記化合物が、

またはその薬学的に許容される塩、溶媒和物、もしくは立体異性体である、本発明1001～1067および1075のいずれかの方法。
[本発明1077]
前記化合物が、

の塩酸塩のA型結晶形である、本発明1001～1067、1075、および1076のいずれかの方法。
[本発明1078]

の塩酸塩のA型結晶形のXRPDパターンが、以下の位置もしくはほぼ以下の位置：9.69、12.82、15.09、15.94、16.76、17.65、19.44、19.80、2230、22.47、22.95、23.02、24.29、24.48、24.70、26.27、26.77、27.60、29.43、29.72、および32.91度の2θのうち1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、またはすべてに位置するXRPDピークを特徴とする、本発明1077の方法。
[本発明1079]
前記免疫調節化合物が、1日当たり0.1 mg～1 mgまたは約0.1 mg～1 mg、1日当たり0.1 mg～0.6 mgまたは約0.1 mg～0.6 mg、0.1 mg～0.3 mgまたは約0.1 mg～0.3 mg投与され、任意で、該投与が、サイクリングレジメンにおける期間にわたって毎日である、本発明1020～1067および1075～1078のいずれかの方法。
[本発明1080]
前記化合物の投与が、T細胞療法の投与の開始に引き続いて開始される、本発明1020～1079のいずれかの方法。
[本発明1081]
前記がんが、B細胞悪性腫瘍、B細胞由来悪性腫瘍、非血液がん、または固形腫瘍である、本発明1059～1080のいずれかの方法。
[本発明1082]
前記標的抗原が、腫瘍抗原であり、任意で、該標的抗原が、がんの細胞または組織に関連し、それに特異的であり、かつ／またはその上に発現される、本発明1059～1081のいずれかの方法。
[本発明1083]
前記標的抗原が、B細胞成熟抗原（BCMA）、αvβ6インテグリン（avb6インテグリン）、BAFF-R、B7-H3、B7-H6、炭酸脱水酵素9（CA9；CAIXまたはG250としても知られている）、がん精巣抗原、がん／精巣抗原1B（CTAG；NY-ESO-1およびLAGE-2としても知られている）、がん胎児性抗原（CEA）、サイクリン、サイクリンA2、C-Cモチーフケモカインリガンド1（CCL-1）、CD5、CD19、CD20、CD21、CD22、CD23、CD24、CD30、CD38、CD44、CD44v6、CD44v7/8、CD45、CD79a、CD79b、CD123、CD133、CD138、CD171、CS-1、コンドロイチン硫酸プロテオグリカン4（CSPG4）、上皮成長因子タンパク質（EGFR）、短縮型上皮成長因子タンパク質（tEGFR）、III型上皮成長因子受容体変異（EGFR vIII）、上皮糖タンパク質2（EPG-2）、上皮糖タンパク質40（EPG-40）、エフリンB2、エフリン受容体A2（EPHa2）、エストロゲン受容体、Fc受容体様5（FCRL5；Fc受容体ホモログ5またはFCRH5としても知られている）、胎児型アセチルコリン受容体（胎児型AchR）、葉酸結合タンパク質（FBP）、葉酸受容体アルファ、ガングリオシドGD2、O-アセチル化GD2（OGD2）、ガングリオシドGD3、糖タンパク質100（gp100）、グリピカン-3（GPC3）、Gタンパク質結合受容体5D（GPCR5D）、Her2/neu（受容体型チロシンキナーゼerb-B2）、Her3（erb-B3）、Her4（erb-B4）、erbB二量体、ヒト高分子量-黒色腫関連抗原（HMW-MAA）、B型肝炎表面抗原、ヒト白血球型抗原A1（HLA-A1）、ヒト白血球型抗原A2（HLA-A2）、Igカッパ、Igラムダ、IL-22受容体アルファ（IL-22Rα）、IL-13受容体アルファ2（IL-13Rα2）、キナーゼインサートドメイン受容体（kdr）、L1細胞接着分子（L1-CAM）、L1-CAMのCE7エピトープ、ロイシンリッチリピート含有8ファミリーメンバーA（LRRC8A）、ルイスY、黒色腫関連抗原（MAGE）-A1、MAGE-A3、MAGE-A6、MAGE-A10、メソテリン（MSLN）、c-Met、マウスサイトメガロウイルス（CMV）、ムチン1（MUC1）、MUC16、ナチュラルキラーグループ2メンバーD（NKG2D）リガンド、メランA（MART-1）、神経細胞接着分子（NCAM）、腫瘍胎児抗原、黒色腫優先発現抗原（PRAME）、プロゲステロン受容体、前立腺特異抗原、前立腺幹細胞抗原（PSCA）、前立腺特異的膜抗原（PSMA）、ROR1、サバイビン、TACI、栄養膜糖タンパク質（TPBG；5T4としても知られている）、腫瘍関連糖タンパク質72（TAG72）、チロシナーゼ関連タンパク質1（TRP1；TYRP1またはgp75としても知られている）、チロシナーゼ関連タンパク質2（TRP2；ドパクロムトートメラーゼ、ドパクロムデルタ-イソメラーゼ、またはDCTとしても知られている）、血管内皮成長因子受容体（VEGFR）、血管内皮成長因子受容体2（VEGFR2）、ウィルムス腫瘍1（WT-1）、病原体特異的抗原もしくは病原体発現抗原から選択される、本発明1059～1082のいずれかの方法。
[本発明1084]
前記B細胞悪性腫瘍が、リンパ腫である、本発明1051、本発明1082、または本発明1083の方法。
[本発明1085]
前記リンパ腫が、非ホジキンリンパ腫（NHL）である、本発明1084の方法。
[本発明1086]
前記NHLが、侵襲性NHL、びまん性大細胞型B細胞リンパ腫（DLBCL）、DLBCL-NOS、任意で形質転換された低悪性度のもの；EBV陽性DLBCL-NOS；T細胞／組織球豊富型大細胞型B細胞リンパ腫；原発性縦隔大細胞型B細胞リンパ腫（PMBCL）；濾胞性リンパ腫（FL）、任意で、濾胞性リンパ腫グレード3B（FL3B）；ならびに／またはDLBCL組織像を有するMYCおよびBCL2および／もしくはBCL6の再編成を伴う高悪性度B細胞リンパ腫（ダブル／トリプルヒット）を含む、本発明1085の方法。
[本発明1087]
前記対象が、Eastern Cooperative Oncology Group Performance Status（ECOG）の1以下の状態を有するとして特定されるかまたは特定されている、本発明1001～1086のいずれかの方法。
[本発明1088]
前記標的抗原が、CD20、CD19、CD22、ROR1、CD45、CD21、CD5、CD33、Igカッパ、Igラムダ、CD79a、CD79b、またはCD30である、本発明1059～1087のいずれかの方法。
[本発明1089]
前記標的抗原が、CD19である、本発明1059～1088のいずれかの方法。
[本発明1090]
前記標的抗原が、CD20、CD19、CD22、ROR1、CD45、CD21、CD5、CD33、Igカッパ、Igラムダ、CD79a、CD79b、またはCD30ではない、本発明1059～1087のいずれかの方法。
[本発明1091]
前記がんが、多発性骨髄腫である、本発明1059～1081のいずれかの方法。
[本発明1092]
前記標的抗原が、BCMA、Gタンパク質結合受容体クラスCグループ5メンバーD（GPRC5D）、CD38（サイクリックADPリボースヒドロラーゼ）、CD138（シンデカン-1、シンデカン、SYN-1）、CS-1（CS1、CD2サブセット1、CRACC、SLAMF7、CD319、および19A24）、BAFF-R、TACI、またはFcRH5である、本発明1059～1091のいずれかの方法。
[本発明1093]
前記標的抗原が、BCMAである、本発明1059～1092のいずれかの方法。
[本発明1094]
前記化合物の投与が、T細胞療法の投与の開始後、3ヶ月または約3ヶ月または3ヶ月超に及ぶ期間にわたって継続する、本発明1020～1093のいずれかの方法。
[本発明1095]
前記有効量が、1日当たり4 mg以下または約4 mg以下である、本発明1074の方法。
[本発明1096]
前記有効量が、1日当たり1.0 mgまたは約1.0 mgから、4 mgまたは約4 mgである、本発明1074の方法。
[本発明1097]
前記有効量が、1日当たり3 mg以下または約3 mg以下である、本発明1074の方法。
[本発明1098]
前記有効量が、1.0 mgまたは約1.0 mgから、3 mgまたは約3 mgである、本発明1074および1097の方法。
[本発明1099]
前記有効量が、1日当たり2.5 mg以下または約2.5 mg以下である、本発明1074の方法。
[本発明1100]
サイクリングレジメンの各週について、またはサイクリングレジメンの少なくとも1週について、前記化合物の投与が、週の連続5日以下の各々での化合物の投与と、それに続く週の残りの化合物が投与されない休息期間を含む、本発明1074および1095～1099のいずれかの方法。
[本発明1101]
前記連続5日以下が、1週当たり連続3日と、それに続く化合物が投与されない4日の休息期間である、本発明1100の方法。
[本発明1102]
前記連続5日以下が、1週当たり連続4日と、それに続く化合物が投与されない3日の休息期間である、本発明1100の方法。
[本発明1103]
前記連続5日以下が、1週当たり連続5日と、それに続く化合物が投与されない2日の休息期間である、本発明1100の方法。
[本発明1104]
前記投与が、T細胞療法の投与の開始後、4ヶ月または約4ヶ月または4ヶ月超に及ぶ期間にわたって継続する、本発明1020～1103のいずれかの方法。
[本発明1105]
前記投与が、T細胞療法の投与の開始後、5ヶ月または約5ヶ月または5ヶ月超に及ぶ期間にわたって継続する、本発明1020～1104のいずれかの方法。
[本発明1106]
前記投与が、T細胞療法の投与の開始後、6ヶ月または約6ヶ月または6ヶ月超に及ぶ期間にわたって継続する、本発明1020～1105のいずれかの方法。
[本発明1107]
1日当たりの前記化合物の投与が、3 mgまたは約3 mgの量である、本発明1074および1095～1106のいずれかの方法。
[本発明1108]
1日当たりの前記化合物の投与が、2.5 mgまたは約2.5 mgの量である、本発明1074および1095～1106のいずれかの方法。
[本発明1109]
1日当たりの前記化合物の投与が、2 mgまたは約2 mgの量である、本発明1074および1095～1106のいずれかの方法。
[本発明1110]
1日当たりの前記化合物の投与が、1.5 mgまたは約1.5 mgの量である、本発明1074および1095～1106のいずれかの方法。
[本発明1111]
1日当たりの前記化合物の投与が、1日当たり1 mgまたは約1 mgの量である、本発明1074および1095～1106のいずれかの方法。
[本発明1112]
期間の終わりに、対象が処置後に完全奏効（CR）を示す場合には、前記化合物の投与が、該期間の終わりに中止される、本発明1020～1111のいずれかの方法。
[本発明1113]
期間の終わりに、がんが処置後に進行しているかまたは寛解に続いて再発している場合には、前記化合物の投与が、該期間の終わりに中止される、本発明1020～1112のいずれかの方法。
[本発明1114]
前記化合物の投与が、3ヶ月からまたは3ヶ月もしくは約3ヶ月から、6ヶ月もしくは6ヶ月に及ぶ期間にわたって継続する、本発明1020～1113のいずれかの方法。
[本発明1115]
前記化合物の投与が、T細胞療法の投与の開始後、3ヶ月または約3ヶ月に及ぶ期間にわたって継続する、本発明1020～1114のいずれかの方法。
[本発明1116]
対象が、3ヶ月または約3ヶ月に先立って、処置後に完全奏効（CR）を達成しているか、またはがんが、処置後に進行しているかもしくは寛解に続いて再発している場合には、前記化合物の投与が、T細胞療法の投与の開始後、3ヶ月または約3ヶ月に及ぶ期間にわたって継続する、本発明1020～1114のいずれかの方法。
[本発明1117]
対象が、3ヶ月で完全奏効（CR）を達成している場合には、前記化合物の投与が、T細胞療法の投与の開始後、3ヶ月または約3ヶ月に及ぶ期間にわたって継続する、本発明1116の方法。
[本発明1118]
前記化合物の投与が、T細胞療法の投与の開始後、6ヶ月または約6ヶ月に及ぶ期間にわたって継続する、本発明1020～1114のいずれかの方法。
[本発明1119]
対象が、6ヶ月または約6ヶ月に先立って、処置後に完全奏効（CR）を達成しているか、またはがんが、処置後に進行しているかもしくは寛解に続いて再発している場合には、前記化合物の投与が、T細胞療法の投与の開始後、6ヶ月または約6ヶ月に及ぶ期間にわたって継続する、本発明1020～1118のいずれかの方法。
[本発明1120]
対象が、6ヶ月で完全奏効（CR）を達成している場合には、前記期間が、T細胞療法の投与の開始後、6ヶ月または約6ヶ月に及ぶ、本発明1119の方法。
[本発明1121]
対象が期間の終わりに先立つ時点で完全奏効（CR）を達成している場合であっても、前記投与が継続期間にわたって継続される、本発明1020～1120のいずれかの方法。
[本発明1122]
前記対象が、投与期間中におよび投与期間の終わりに先立って、完全奏効（CR）を達成する、本発明1020～1121のいずれかの方法。
[本発明1123]
期間の終わりに、対象が部分奏効（PR）または安定疾患（SD）を示す場合には、期間の終わりの後に投与を継続することをさらに含む、本発明1020～1111、1114、1115、1119、1121、および1122のいずれかの方法。
[本発明1124]
6ヶ月または約6ヶ月で、対象が処置後に部分奏効（PR）または安定疾患（SD）を示す場合には、前記投与が、6ヶ月超にわたって継続される、本発明1020～1123のいずれかの方法。
[本発明1125]
対象が処置後に完全奏効（CR）を達成するまで、またはがんが処置後に進行するかもしくは寛解に続いて再発するまで、前記投与が継続される、本発明1123または本発明1124の方法。
[本発明1126]
T細胞療法の細胞のピークレベルまたは最大レベルが、対象の血液中で検出可能となる時点でまたはその後に、前記化合物の投与が開始される、本発明1020～1125のいずれかの方法。
[本発明1127]
前記化合物の投与が、T細胞療法の投与の開始の約14～約35日後に開始される、本発明1020～1126のいずれかの方法。
[本発明1128]
前記化合物の投与が、T細胞療法の投与の開始の約21～約35日後に開始される、本発明1020～1127のいずれかの方法。
[本発明1129]
前記化合物の投与が、T細胞療法の投与の開始の約21～約28日後に開始される、本発明1020～1128のいずれかの方法。
[本発明1130]
前記化合物の投与が、T細胞療法の投与の開始の21日後もしくは約21日後、22日後もしくは約22日後、23日後もしくは約23日後、24日後もしくは約24日後、25日後もしくは約25日後、26日後もしくは約26日後、27日後もしくは約27日後、または28日後もしくは約28日後に開始される、本発明1020～1129のいずれかの方法。
[本発明1131]
前記化合物の投与が、T細胞療法の投与の開始の28日後または約28日後に開始される、本発明1020～1130のいずれかの方法。
[本発明1132]
前記化合物の投与の開始時に、対象が、T細胞療法の投与後に重度の毒性を示さない、本発明1020～1131のいずれかの方法。
[本発明1133]
前記重度の毒性が、重度のサイトカイン放出症候群（CRS）、任意で、グレード3以上、長期にわたるグレード3以上、またはグレード4もしくは5のCRSである；かつ／または
前記重度の毒性が、重度の神経毒性、任意で、グレード3以上、長期にわたるグレード3以上、またはグレード4もしくは5の神経毒性である、
本発明1132の方法。
[本発明1134]
対象が、化合物の投与後に毒性、任意で血液毒性を示す場合には、前記化合物の投与が停止され、かつ／または前記投与が改変される、本発明1020～1133のいずれかの方法。
[本発明1135]
前記毒性が、重度の好中球減少症、任意で、発熱性好中球減少症、長期にわたるグレード3以上の好中球減少症から選択される、本発明1134の方法。
[本発明1136]
前記化合物の投与が、対象がもはや毒性を示さなくなった後に再開される、本発明1134または1135の方法。
[本発明1137]
前記投与が、化合物の投与が再開された後に改変される、本発明1136の方法。
[本発明1138]
前記改変された投与が、低減した量の化合物を投与すること、および／または化合物の投与の頻度を減少させることを含む、本発明1134～1137のいずれかの方法。
[本発明1139]
前記改変された投与が、低減した量の化合物を投与することを含む、本発明1134～1138のいずれかの方法。
[本発明1140]
前記化合物の用量が低減され、低減した量が、1週当たり5日間以下にわたり、1日当たり1 mgまたは約1 mgから、2 mgまたは約2 mgである、本発明1139の方法。
[本発明1141]
前記化合物が、(S)-3-[4-(4-モルホリン-4-イルメチル-ベンジルオキシ)-1-オキソ-1,3-ジヒドロ-イソインドール-2-イル]-ピペリジン-2,6-ジオンの薬学的に許容される塩であるかまたはそれを含む、本発明1001～1067および1075～1139のいずれかの方法。
[本発明1142]
前記化合物が、(S)-3-[4-(4-モルホリン-4-イルメチル-ベンジルオキシ)-1-オキソ-1,3-ジヒドロ-イソインドール-2-イル]-ピペリジン-2,6-ジオンの水和物であるかまたはそれを含む、本発明1001～1067および1075～1139のいずれかの方法。
[本発明1143]
前記化合物が、(S)-3-[4-(4-モルホリン-4-イルメチル-ベンジルオキシ)-1-オキソ-1,3-ジヒドロ-イソインドール-2-イル]-ピペリジン-2,6-ジオンの溶媒和物であるかまたはそれを含む、本発明1001～1067および1075～1139のいずれかの方法。
[本発明1144]
前記化合物が、(S)-3-[4-(4-モルホリン-4-イルメチル-ベンジルオキシ)-1-オキソ-1,3-ジヒドロ-イソインドール-2-イル]-ピペリジン-2,6-ジオンであるかまたはそれを含む、本発明1001～1067および1075～1139のいずれかの方法。
[本発明1145]
前記化合物が、3-(5-アミノ-2-メチル-4-オキソ-4H-キナゾリン-3-イル)-ピペリジン-2,6-ジオンの溶媒和物であるかまたはそれを含む、本発明1001～1074および1080～1140のいずれかの方法。
[本発明1146]
前記化合物が、3-(5-アミノ-2-メチル-4-オキソ-4H-キナゾリン-3-イル)-ピペリジン-2,6-ジオンの水和物であるかまたはそれを含む、本発明1001～1074および1080～1140のいずれかの方法。
[本発明1147]
前記化合物が、3-(5-アミノ-2-メチル-4-オキソ-4H-キナゾリン-3-イル)-ピペリジン-2,6-ジオンの薬学的に許容される塩であるかまたはそれを含む、本発明1001～1074および1080～1140のいずれかの方法。
[本発明1148]
前記化合物が、3-(5-アミノ-2-メチル-4-オキソ-4H-キナゾリン-3-イル)-ピペリジン-2,6-ジオンであるかまたはそれを含む、本発明1001～1074および1080～1140のいずれかの方法。
[本発明1149]
前記化合物が、経口で投与される、本発明1020～1148のいずれかの方法。
[本発明1150]
前記化合物の投与が、
対象における組換え受容体発現T細胞において消耗表現型を逆転させる；
対象における組換え受容体発現T細胞において消耗表現型の始まりを防止する、抑制する、もしくは遅らせる；
または、対象における組換え受容体発現T細胞において消耗表現型のレベルもしくは程度を低減させる；または
消耗表現型を有する、対象における組換え受容体発現T細胞の総数のパーセンテージを低減させる、
本発明1020～1149のいずれかの方法。
[本発明1151]
前記化合物の投与の開始が、T細胞療法の投与に引き続いて行われ、化合物の投与またはその開始後に、対象が、該対象における組換え受容体発現T細胞の抗原特異的または腫瘍特異的な活性または機能の回復または救出を示し、任意で、該回復、救出、および／または該化合物の投与の開始が、対象におけるまたは対象の血液における組換え受容体発現T細胞が消耗した表現型を示した後の時点である、本発明1003～1149のいずれかの方法。
[本発明1152]
前記化合物の投与が、
（a）抗原に対するもしくは抗原受容体特異的作用物質に対するT細胞の曝露後に、該化合物の該投与の非存在下と比較して、前記組換え受容体を発現するT細胞を任意で含む対象におけるナイーブなもしくは消耗していないT細胞の、抗原特異的なもしくは抗原受容体により駆動される活性の増加をもたらす；または
（b）抗原に対するもしくは抗原受容体特異的作用物質に対するT細胞の曝露後に、該化合物の該投与の非存在下と比較して、前記組換え受容体を発現するT細胞を任意で含む対象におけるナイーブなもしくは消耗していないT細胞のT細胞において、消耗表現型の始まりを防止する、抑制する、もしくは遅らせる；または
（c）対象において、該対象の該投与の非存在下と比較して、前記組換え受容体を発現するT細胞を任意で含む消耗したT細胞において、消耗表現型を逆転させる
のに有効な量、頻度、および／または継続期間での投与を含む、本発明1003～1149のいずれかの方法。
[本発明1153]
前記化合物の投与が、
（i）前記活性の増加をもたらし、かつ
（ii）前記消耗表現型の前記始まりを防止する、抑制する、または遅らせる、かつ／または前記消耗表現型を逆転させる
のに有効な量、頻度、および／または継続期間での投与を含む、本発明1152の方法。
[本発明1154]
前記対象におけるT細胞が、前記組換え受容体を発現するT細胞を含み、かつ／または前記抗原が、標的抗原である、本発明1152または1153の方法。
[本発明1155]
T細胞またはT細胞の集団に関する消耗表現型が、
1つまたは複数の消耗マーカー、任意で2つ、3つ、4つ、5つ、または6つの消耗マーカーの、1つもしくは複数のT細胞上の表面発現のレベルもしくは程度、または表面発現を示す該T細胞の集団のパーセンテージの、同じ条件下の参照T細胞集団と比較した増加；または
抗原または抗原受容体特異的作用物質に対する曝露時の、該T細胞またはT細胞の集団によって示される活性のレベルまたは程度の、同じ条件下の参照T細胞集団と比較した減少
を含む、本発明1150～1154のいずれかの方法。
[本発明1156]
前記レベル、程度、またはパーセンテージの増加が、1.2倍もしくは約1.2倍、1.5倍もしくは約1.5倍、2.0倍もしくは約2.0倍、3倍もしくは約3倍、4倍もしくは約4倍、5倍もしくは約5倍、6倍もしくは約6倍、7倍もしくは約7倍、8倍もしくは約8倍、9倍もしくは約9倍、10倍もしくは約10倍、またはそれ以上よりも大きい、本発明1155の方法。
[本発明1157]
前記レベル、程度、またはパーセンテージの減少が、1.2倍もしくは約1.2倍、1.5倍もしくは約1.5倍、2.0倍もしくは約2.0倍、3倍もしくは約3倍、4倍もしくは約4倍、5倍もしくは約5倍、6倍もしくは約6倍、7倍もしくは約7倍、8倍もしくは約8倍、9倍もしくは約9倍、10倍もしくは約10倍、またはそれ以上よりも大きい、本発明1155の方法。
[本発明1158]
前記参照T細胞集団が、任意で、消耗した表現型を有する1つまたは複数のT細胞が由来する同じ対象由来の、または対象と同じ種の、消耗していない表現型を有することが既知のT細胞の集団であるか、ナイーブT細胞の集団であるか、セントラルメモリーT細胞の集団であるか、またはステムセントラルメモリーT細胞の集団である、本発明1155～1157のいずれかの方法。
[本発明1159]
（a）前記参照T細胞集団が、消耗した表現型を有する1つまたは複数のT細胞が由来する対象の血液から単離されたバルクT細胞を含む対象に合った集団であり、任意で、該バルクT細胞が、組換え受容体を発現しない、かつ／または
（b）前記参照T細胞集団が、組換え受容体を発現するT細胞の用量の投与を受ける前に、消耗した表現型を有する1つまたは複数のT細胞が由来する対象から得られる、
本発明1155～1158のいずれかの方法。
[本発明1160]
前記参照T細胞集団が、対象に対するその投与の前の、T細胞療法の試料を含む組成物、または組換え受容体を発現するT細胞を含む薬学的組成物であり、任意で、該組成物が、凍結保存された試料である、本発明1155～1158のいずれかの方法。
[本発明1161]
前記1つまたは複数の消耗マーカーが、阻害性受容体である、本発明1155～1160のいずれかの方法。
[本発明1162]
前記1つまたは複数の消耗マーカーが、PD-1、CTLA-4、TIM-3、LAG-3、BTLA、2B4、CD160、CD39、VISTA、およびTIGITの中から選択される、本発明1155～1161のいずれかの方法。
[本発明1163]
前記活性が、増殖、細胞傷害性、または炎症性サイトカインの1つもしくは組み合わせの産生のうちの1つまたは複数であり、任意で、該サイトカインの1つもしくは組み合わせが、IL-2、IFN-ガンマ、およびTNF-アルファからなる群より選択される、本発明1155～1162のいずれかの方法。
[本発明1164]
前記抗原または抗原受容体特異的作用物質に対する曝露が、抗原または抗原受容体特異的作用物質、任意で、組換え受容体に結合する作用物質とのインキュベーションを含み、該抗原が、任意で標的抗原である、本発明1155～1163のいずれかの方法。
[本発明1165]
前記抗原または抗原受容体特異的作用物質が、抗原発現標的細胞、任意で、前記疾患、障害、または病態の細胞を含む、本発明1164の方法。
[本発明1166]
前記標的抗原が、ヒト抗原である、本発明1002および1011～1165のいずれかの方法。
[本発明1167]
前記対象が、ヒトである、本発明1001～1166のいずれかの方法。
[本発明1168]
前記組換え抗原受容体が、標的抗原に特異的に結合するキメラ抗原受容体である、本発明1001～1167のいずれかの方法。
[本発明1169]
前記キメラ抗原受容体（CAR）が、標的抗原に特異的に結合する細胞外抗原認識ドメインと、ITAMを含む細胞内シグナル伝達ドメインとを含む、本発明1016または本発明1168の方法。
[本発明1170]
前記細胞内シグナル伝達ドメインが、CD3-ゼータ（CD3ζ）鎖、任意でヒトCD3-ゼータ鎖のシグナル伝達ドメインを含む、本発明1169の方法。
[本発明1171]
前記キメラ抗原受容体（CAR）が、共刺激シグナル伝達領域をさらに含む、本発明1169または本発明1170の方法。
[本発明1172]
前記共刺激シグナル伝達領域が、CD28または4-1BB、任意でヒトCD28またはヒト4-1BBのシグナル伝達ドメインを含む、本発明1171の方法。
[本発明1173]
共刺激ドメインが、ヒト4-1BBのシグナル伝達ドメインであるかまたはそれを含む、本発明1171または本発明1172の方法。
[本発明1174]
前記CARが、標的抗原に特異的なscFv；膜貫通ドメイン；任意で、4-1BB、任意でヒト4-1BBであるかもしくはそれを含む、共刺激分子に由来する細胞質シグナル伝達ドメイン；および、任意で、CD3ゼータシグナル伝達ドメイン、任意でヒトCD3ゼータシグナル伝達ドメインであるかもしくはそれを含む、一次シグナル伝達ITAM含有分子に由来する細胞質シグナル伝達ドメインを含み；かつ任意で、該CARが、膜貫通ドメインとscFvとの間にスペーサーをさらに含む；
前記CARが、順番に、標的抗原に特異的なscFv；膜貫通ドメイン；任意で、4-1BBシグナル伝達ドメイン、任意でヒト4-1BBシグナル伝達ドメインであるかもしくはそれを含む、共刺激分子に由来する細胞質シグナル伝達ドメイン；および、任意で、CD3ゼータシグナル伝達ドメイン、任意でヒトCD3ゼータシグナル伝達ドメインである、一次シグナル伝達ITAM含有分子に由来する細胞質シグナル伝達ドメインを含む；または
前記CARが、順番に、標的抗原に特異的なscFv；スペーサー；膜貫通ドメイン、任意で、4-1BBシグナル伝達ドメインである、共刺激分子に由来する細胞質シグナル伝達ドメイン、および、任意で、CD3ゼータシグナル伝達ドメインであるかもしくはそれを含む、一次シグナル伝達ITAM含有分子に由来する細胞質シグナル伝達ドメインを含む、
本発明1016および1168～1173のいずれかの方法。
[本発明1175]
遺伝子操作されたT細胞の用量が、1×10 ⁵ ～5×10 ⁸ または約1×10 ⁵ ～5×10 ⁸ の総CAR発現T細胞、1×10 ⁶ ～2.5×10 ⁸ または約1×10 ⁶ ～2.5×10 ⁸ の総CAR発現T細胞、5×10 ⁶ ～1×10 ⁸ または約5×10 ⁶ ～1×10 ⁸ の総CAR発現T細胞、1×10 ⁷ ～2.5×10 ⁸ または約1×10 ⁷ ～2.5×10 ⁸ の総CAR発現T細胞、5×10 ⁷ ～1×10 ⁸ または約5×10 ⁷ ～1×10 ⁸ の総CAR発現T細胞（それぞれ両端の値を含む）を含む、本発明1021～1174のいずれかの方法。
[本発明1176]
遺伝子操作されたT細胞の用量が、少なくとも1×10 ⁵ もしくは少なくとも約1×10 ⁵ のCAR発現細胞、少なくとも2.5×10 ⁵ もしくは少なくとも約2.5×10 ⁵ のCAR発現細胞、少なくとも5×10 ⁵ もしくは少なくとも約5×10 ⁵ のCAR発現細胞、少なくとも1×10 ⁶ もしくは少なくとも約1×10 ⁶ のCAR発現細胞、少なくとも2.5×10 ⁶ もしくは少なくとも約2.5×10 ⁶ のCAR発現細胞、少なくとも5×10 ⁶ もしくは少なくとも約5×10 ⁶ のCAR発現細胞、少なくとも1×10 ⁷ もしくは少なくとも約1×10 ⁷ のCAR発現細胞、少なくとも2.5×10 ⁷ もしくは少なくとも約2.5×10 ⁷ のCAR発現細胞、少なくとも5×10 ⁷ もしくは少なくとも約5×10 ⁷ のCAR発現細胞、少なくとも1×10 ⁸ もしくは少なくとも約1×10 ⁸ のCAR発現細胞、少なくとも2.5×10 ⁸ もしくは少なくとも約2.5×10 ⁸ のCAR発現細胞、または少なくとも5×10 ⁸ もしくは少なくとも約5×10 ⁸ のCAR発現細胞を含む、本発明1021～1175のいずれかの方法。
[本発明1177]
遺伝子操作されたT細胞の用量が、5×10 ⁷ または約5×10 ⁷ の総CAR発現T細胞を含む、本発明1021～1176のいずれかの方法。
[本発明1178]
遺伝子操作されたT細胞の用量が、1×10 ⁸ または約1×10 ⁸ のCAR発現細胞を含む、本発明1021～1177のいずれかの方法。
[本発明1179]
細胞の用量が、非経口的に、任意で静脈内に投与される、本発明1021～1178のいずれかの方法。
[本発明1180]
前記T細胞が、対象から得られた初代T細胞である、本発明1021～1179のいずれかの方法。
[本発明1181]
前記T細胞が、対象に対して自家である、本発明1021～1180のいずれかの方法。
[本発明1182]
前記T細胞が、対象に対して同種である、本発明1021～1180のいずれかの方法。
[本発明1183]
遺伝子操作されたT細胞の用量が、CARを発現するCD4+ T細胞およびCARを発現するCD8+ T細胞を含み、用量の投与が、複数の別々の組成物を投与することを含み、該複数の別々の組成物が、CD4+ T細胞およびCD8+ T細胞の一方を含む第1の組成物と、CD4+ T細胞またはCD8+ T細胞の他方を含む第2の組成物とを含む、本発明1021～1182のいずれかの方法。
[本発明1184]
前記投与の前に、対象が、フルダラビンおよび／またはシクロホスファミドの投与を含むリンパ球枯渇療法でプレコンディショニングされている、本発明1021～1183のいずれかの方法。
[本発明1185]
前記投与の直前に、フルダラビンおよび／またはシクロホスファミドの投与を含むリンパ球枯渇療法を対象に投与する工程をさらに含む、本発明1021～1184のいずれかの方法。
[本発明1186]
前記リンパ球枯渇療法が、約200～400 mg/m ² 、任意で300 mg/m ² もしくは約300 mg/m ² （両端の値を含む）のシクロホスファミド、および／または約20～40 mg/m ² 、任意で30 mg/m ² のフルダラビンの、2～4日間、任意で3日間の毎日の投与を含む、または、前記リンパ球枯渇療法が、約500 mg/m ² のシクロホスファミドの投与を含む、本発明1184または本発明1185の方法。
[本発明1187]
前記リンパ球枯渇療法が、300 mg/m ² または約300 mg/m ² のシクロホスファミドおよび約30 mg/m ² のフルダラビンの、3日間毎日の投与を含む；かつ／または
前記リンパ球枯渇療法が、500 mg/m ² または約500 mg/m ² のシクロホスファミドおよび約30 mg/m ² のフルダラビンの、3日間毎日の投与を含む、
本発明1184～1186のいずれかの方法。
[本発明1188]
前記方法に従って処置された対象の少なくとも35％、少なくとも40％、または少なくとも50％が、6ヶ月もしくは6ヶ月超または9ヶ月もしくは9ヶ月超にわたって、永続的であるか、またはCRを達成する対象の少なくとも60、70、80、90、もしくは95％において永続的である、完全奏効（CR）を達成し；かつ／または
6ヶ月までにCRを達成する対象の少なくとも60、70、80、90、または95％が、3ヶ月もしくは3ヶ月超および／または6ヶ月もしくは6ヶ月超および／または9ヶ月超よりも長くにわたって、奏効のままであり、CRのままであり、かつ／または生存しているかもしくは憎悪を伴わずに生存している；ならびに／または
前記方法に従って処置された対象の少なくとも50％、少なくとも60％、または少なくとも70％が、客観的奏効（OR）を達成し、任意で、該ORが、6ヶ月もしくは6ヶ月超または9ヶ月もしくは9ヶ月超にわたって、永続的であるか、またはORを達成する対象の少なくとも60、70、80、90、もしくは95％において永続的であり；かつ／または
6ヶ月までにORを達成する対象の少なくとも60、70、80、90、または95％が、3ヶ月もしくは3ヶ月超および／または6ヶ月もしくは6ヶ月超よりも長くにわたって、奏効のままであるか、または生存している、
本発明1020～1187のいずれかの方法。
[本発明1189]
（a）標的抗原に結合する組換え抗原受容体を発現するT細胞の用量を含む、T細胞療法；ならびに
（b）サリドマイド類似体；サリドマイド誘導体；セレブロン（CRBN）とおよび／またはCRBN E3ユビキチン-リガーゼ複合体の1つまたは複数のメンバーと相互作用しかつ／またはそれに結合する化合物；イカロス（IKZF1）の阻害剤；アイオロス（IKZF3）の阻害剤；ならびにイカロス（IKZF1）および／またはアイオロス（IKZF3）のユビキチン化および／または枯渇および／または分解を増強するかまたは促進する化合物からなる群より選択される、免疫調節化合物；ならびに
（c）本発明1001～1187のいずれかの方法に従って、該化合物および／または該T細胞療法を投与するための、指示書
を含む、キット。
Also provided herein are kits comprising:
(a) a T cell therapy comprising a dose of T cells expressing recombinant antigen receptors that bind the target antigen; and
(b) thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibition of Ikaros (IKZF1) inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination and/or depletion and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3); and
(c) instructions for administering said compound and/or said T cell therapy according to any of the methods provided herein;
[Invention 1001]
A method for rescuing T cell activity, comprising:
thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibition of Ikaros (IKZF1) inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3). exposing a plurality of T cells having an exhausted phenotype to an effective amount of an immunomodulatory compound.
[Invention 1002]
1001. The method of invention 1001, wherein the one or more T cells comprise T cells expressing a recombinant receptor that specifically binds to the target antigen.
[Invention 1003]
A method for increasing T cell activity or efficacy and for preventing or inhibiting, reducing or delaying the onset of T cell exhaustion, comprising:
thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); (IKZF3); and a compound that enhances or promotes the ubiquitination, depletion, and/or degradation of Icarus (IKZF1) and/or Aeolus (IKZF3). exposing a plurality of T cells to
at least a portion of said exposing is performed under conditions that induce or are capable of inducing an exhausted phenotype in a plurality of T cells in the absence of a compound;
the aforementioned method.
[Invention 1004]
A method for reducing or delaying the onset of T cell exhaustion comprising:
thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); (IKZF3); and a compound that enhances or promotes the ubiquitination, depletion, and/or degradation of Icarus (IKZF1) and/or Aeolus (IKZF3). exposing a plurality of T cells to
at least a portion of said exposing is performed under conditions that induce or are capable of inducing an exhausted phenotype in a plurality of T cells in the absence of a compound;
the aforementioned method.
[Invention 1005]
Said conditions comprise T cell stimulatory conditions comprising exposure to at least one T cell stimulatory agent capable of stimulating a signal in a plurality of T cells, said signal optionally comprising a primary signal and/or a co-stimulatory signal. A method of the invention 1003 or invention 1004, comprising:
[Invention 1006]
1006. The method of invention 1005, wherein said condition comprises sustained, repeated, prolonged or prolonged exposure to at least one T cell stimulating agent.
[Invention 1007]
The at least one T cell stimulating agent is a polyclonal agent, an antigen specifically recognized by receptors expressed on multiple T cells, or an effect of binding antigen receptors expressed by multiple T cells. The method of invention 1005 or invention 1006 comprising a substance.
[Invention 1008]
The method of any of inventions 1005-1007, wherein said at least one T cell stimulating agent comprises an anti-CD3 antibody.
[Invention 1009]
Said at least one T cell stimulatory agent further comprises an agent that specifically binds to a T cell co-stimulatory molecule, optionally wherein said T cell co-stimulatory molecule is CD28, CD137 (4-1-BB), OX40 , CD40L, or ICOS.
[Invention 1010]
1009. The method of invention 1009, wherein said at least one T cell stimulating agent comprises an anti-CD28 antibody.
[Invention 1011]
1010. The method of any of inventions 1003-1010, wherein one or more of said plurality of T cells express a recombinant antigen receptor that binds to the target antigen.
[Invention 1012]
1012. The method of invention 1011, wherein said at least one T cell stimulating agent binds to a recombinant antigen receptor.
[Invention 1013]
1013. The method of invention 1012, wherein said at least one T cell stimulating agent is or comprises an anti-idiotypic antibody specific for a recombinant antigen receptor.
[Invention 1014]
said at least one T-cell stimulating agent is or comprises a target antigen or a portion thereof that is recognized by or bound by a recombinant antigen receptor, and/or said conditions prevent exposure to a target antigen. A method of the invention 1012, comprising:
[Invention 1015]
The method of any of inventions 1012-1014, wherein said recombinant antigen receptor is a recombinant T cell receptor (TCR).
[Invention 1016]
The method of any of inventions 1012-1014, wherein said recombinant antigen receptor is a chimeric antigen receptor (CAR).
[Invention 1017]
The method of any of the inventions 1001-1016, wherein the one or more T cells are primary human T cells, optionally from the subject.
[Invention 1018]
1018. The method of any of inventions 1001-1017, wherein said exposing step is performed ex vivo.
[Invention 1019]
The method of any of inventions 1001-1017, wherein said exposing step is performed in vivo.
[Invention 1020]
1019. The method of invention 1019, wherein said exposing step comprises administration of a compound to a subject, optionally the T cells are from the subject and administration of the compound is to said subject.
[Invention 1021]
wherein said exposing comprises said administration of said compound, wherein, prior to the exposing step, said subject has been administered a composition comprising a plurality of T cells to the subject for treating a disease or condition; The method of invention 1020, wherein the target antigen is associated with a disease or condition.
[Invention 1022]
of Inventions 1019-1021, wherein said exposing comprises administration of said plurality of T cells to a subject, and optionally, if the T cells are derived from said subject, administration of a compound is to said subject. either way.
[Invention 1023]
Said exposing comprises administering said plurality of T cells to said subject to treat a disease or condition, optionally wherein the target antigen is associated with the disease or condition, and prior to the exposing step, said subject has being administered the compound; or
said exposing comprises administering said plurality of T cells to said subject to treat a disease or condition, optionally wherein the target antigen is associated with the disease or condition, and administering said compound to said subject; include,
The method of the invention 1022.
[Invention 1024]
A method of treatment comprising administering an immunomodulatory compound to a subject,
thalidomide derivatives; cereblon (CRBN) and/or compounds that interact with and/or bind to one or more members of the CRBN E3 ubiquitin-ligase complex; Ikaros (IKZF1 ); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3);
(a) the subject has been administered T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds the target antigen prior to administration of the compound, or
(b) prior to or at the time of administration of the compound, the subject or a blood sample from the subject contains or may contain one or more T cells expressing a recombinant antigen receptor; has been confirmed,
one or more of the recombinant receptor-expressing T cells in the subject have an exhausted phenotype upon administration of the compound;
the aforementioned method.
[Invention 1025]
One or more exhausted phenotypes of recombinant receptor-expressing T cells, or markers or parameters indicative thereof, are detected or measured in the subject or in a biological sample derived from the subject upon administration of said compound The method of the present invention 1024, wherein:
[Invention 1026]
at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about The method of invention 1024 or invention 1025, wherein 40%, or at least 50% or at least about 50%, have an exhausted phenotype.
[Invention 1027]
Greater than 10% of recombinant receptor-expressing T cells in a subject-derived biological sample compared to the percentage of recombinant receptor-expressing cells with an exhausted phenotype in a comparable biological sample at the previous time point or more than about 10%, more than 20% or about 20%, more than 30% or about 30%, more than 40% or about 40%, or more than 50% or about 50% have an exhausted phenotype , the method of any of the inventions 1024-1026.
[Invention 1028]
(a) selecting a subject as a candidate for administration of an immunomodulatory compound, wherein the selected subject has depleted recombinant receptor-expressing T cells; and
(b) administering an immunomodulatory compound to the subject, wherein the immunomodulatory compound comprises one or more of a thalidomide analogue; a thalidomide derivative; cerebron (CRBN) and/or a CRBN E3 ubiquitin-ligase complex; compounds that interact with and/or bind to members; inhibitors of Ikaros (IKZF1); inhibitors of Aiolos (IKZF3); a step selected from the group consisting of compounds that enhance or promote degradation
methods of treatment, including
[Invention 1029]
a tissue, tumor, biological fluid, or biological sample of or derived from said selected subject,
One or more T cells that express a recombinant antigen receptor that binds the target antigen and have an exhausted phenotype
A method of the invention 1028, comprising:
[Invention 1030]
said tissue, tumor, biological fluid, or biological sample comprises a plurality of T cells expressing a recombinant antigen receptor that binds to a target antigen, said tissue, fluid, tumor, or biological sample expressing a recombinant receptor; at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about 40%, at least 50% or at least about 50% of the T cells in the sample; The method of invention 1029, wherein at least 60% or at least about 60%, at least 70% or at least about 70%, or at least 80% or at least about 80% have an exhausted phenotype.
[Invention 1031]
said tissue, tumor, biological fluid, or biological sample comprises a plurality of T cells expressing recombinant antigen receptors that bind to a target antigen;
T cells in a tissue, tumor, fluid or sample from or of a selected subject expressing the recombinant antigen receptor at an earlier time point in a fluid, tissue, tumor or sample from said subject; or greater than or about 10% greater than the percentage or number of T cells expressing the recombinant receptor that had an exhausted phenotype in comparable body fluids, tissues, tumors, or samples, greater than 20% or more than about 20% more, or more than about 30% or about 30% more, or more than 40% or about 40% more, or more than 50% or about 50% more, or more than 2 times more, or more than 3 times more, or 5-fold more, or 10-fold more have the exhausted phenotype
A method of the invention 1029 or invention 1030.
[Invention 1032]
Prior to administration of the compound, the subject had been administered a plurality of T cells expressing the recombinant receptor, and an earlier time point was to the subject a plurality of T cells expressing the recombinant antigen receptor. A method of the invention 1027 or invention 1030 at a time immediately prior to administration.
[Invention 1033]
prior to administration of said compound, said subject has been administered a plurality of T cells expressing recombinant receptors, and said earlier time point is after administration of said T cells and prior to said selection; The method of the invention 1027 or the invention 1030.
[Invention 1034]
The previous point was
after administration of said recombinant receptor-expressing T cells to said selected subject and when peak or maximum levels of recombinant receptor-expressing T cells become detectable in the subject's blood, or before that;
1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or more prior to said determination or selection within
The method of the invention 1027 or the invention 1030 or the invention 1033 when the time is .
[Invention 1035]
the subject had a disease or condition at the time of administration of the T cell therapy; or
the subject has a disease or condition upon administration of the T cell therapy and upon administration of the compound;
The method of any of the inventions 1024-1034.
[Invention 1036]
the subject has a disease or condition at the time of administration of the T cell therapy, and at the time of administration of the compound, the disease or condition is recurring or progressing in the subject after administration of the T cell therapy; Or the method of any of Inventions 1020-1035 which is considered non-responsive to said compound.
[Invention 1037]
the wasting phenotype for a T cell or population of T cells is
indicating the level or degree of surface expression on one or more T cells or surface expression of one or more exhaustion markers, optionally 2, 3, 4, 5, or 6 exhaustion markers an increase in the percentage of said T population of T cells compared to a reference T cell population under the same conditions; or
Reduction in the level or extent of activity displayed by said T cell or population of T cells upon exposure to an antigen or antigen receptor specific agent compared to a reference T cell population under the same conditions
The method of any of the inventions 1001-1036, comprising:
[Invention 1038]
said level, degree, or percentage increase is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more, the method of the invention 1037 .
[Invention 1039]
said level, degree, or percentage reduction is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more, the method of the invention 1037 .
[Invention 1040]
Said reference T cell population is optionally known to have a non-exhausted phenotype from the same subject from which the one or more T cells with an exhausted phenotype are derived or of the same species as the subject The method of any of the inventions 1037-1039, which is a population of T cells, a population of naive T cells, a population of central memory T cells, or a population of stem central memory T cells.
[Invention 1041]
(a) said reference T cell population is a matched population comprising bulk T cells isolated from the blood of a subject from which one or more T cells with an exhausted phenotype are derived; said bulk T cells do not express the recombinant receptor and/or
(b) said reference T cell population is obtained from a subject from which one or more T cells with an exhausted phenotype were derived prior to being administered a dose of T cells expressing the recombinant receptor;
The method of any of the inventions 1037-1040.
[Invention 1042]
wherein said reference T cell population is a composition comprising a sample of T cell therapy or a pharmaceutical composition comprising T cells expressing a recombinant receptor prior to its administration to a subject; is a cryopreserved sample.
[Invention 1043]
The method of any of inventions 1037-1042, wherein one or more of said one or more exhaustion markers is an inhibitory receptor.
[Invention 1044]
one or more of said one or more markers of exhaustion are selected from among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT The method of any one of Inventions 1037-1043.
[Invention 1045]
said activity is one or more of the production of one or a combination of proliferative, cytotoxic, or inflammatory cytokines, optionally one or a combination of said cytokines is IL-2, IFN-gamma , and TNF-alpha.
[Invention 1046]
Exposure to said antigen or antigen receptor specific agent comprises incubation with an antigen or antigen receptor specific agent, optionally an agent that binds to the recombinant receptor, wherein said antigen optionally binds to a target antigen The method of any one of Inventions 1037-1045, wherein
[Invention 1047]
1046. The method of the invention 1046, wherein said antigen or antigen receptor specific agent comprises antigen-expressing target cells, optionally cells of said disease, disorder, or condition.
[Invention 1048]
The method of any of the inventions 1002 and 1011-1047, wherein said target antigen is associated with, specific for and/or expressed on cells or tissues of a disease, disorder or condition.
[Invention 1049]
The method of any of inventions 1002 and 1011-1048, wherein said target antigen is a tumor antigen.
[Invention 1050]
said target antigen is αvβ6 integrin (avb6 integrin), B cell maturation antigen (BCMA), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250); cancer testis antigen, cancer/testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclins, cyclin A2, CC motif chemokine ligand 1 (CCL-1), CD19, CD20, CD22, CD23, CD24, CD30, CD33, CD38, CD44, CD44v6, CD44v7/8, CD123, CD133, CD138, CD171, CS-1, chondroitin sulfate proteoglycan 4 (CSPG4), Epidermal Growth Factor Protein (EGFR), Truncated Epidermal Growth Factor Protein (tEGFR), Epidermal Growth Factor Receptor Type III Mutant (EGFR vIII), Epidermal Glycoprotein 2 (EPG-2), Epidermal Glycoprotein 40 (EPG-40) , ephrinB2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-coupled receptor 5D (GPCR5D) , Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight-melanoma-associated antigen (HMW-MAA), hepatitis B surface antigens, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), IL-22 receptor alpha (IL-22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), kappa light chain, L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A), Lewis Y, melanoma-associated antigen ( MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c-Met, mouse cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan A (MART-1), neural cell adhesion molecule (NCAM), oncofetal antigen, melanoma preferentially expressed antigen (PRAME), progesterone receptor, Prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), receptor tyrosine kinase-like orphan receptor 1 (ROR1), survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4) ), tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2; dopachrome tautomerase, dopachrome delta-isomerase, or DCT ), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), pathogen-specific or pathogen-expressed antigen, or universal tag and/or biotinylated molecules and/or molecules expressed by HIV, HCV, HBV or other pathogens.
[Invention 1051]
The method of any of inventions 1001-1042, wherein said disease or condition is a B-cell malignancy or a B-cell derived malignancy.
[Invention 1052]
The method of any of inventions 1002 and 1011-1051, wherein said target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30.
[Invention 1053]
The method of any of invention 1002 and 1011-1052, wherein said target antigen is CD19.
[Invention 1054]
The method of any of inventions 1001-1051, wherein said disease or condition is multiple myeloma.
[Invention 1055]
said target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5.
[Invention 1056]
The method of any of the inventions 1002 and 1011-1051 and 1055, wherein said target antigen is BCMA.
[Invention 1057]
The method of any of the inventions 1026, 1027, and 1029-1056, wherein said biological sample is a blood sample.
[Invention 1058]
The method of any of the inventions 1026, 1027, and 1029-1056, wherein said biological sample is a tumor sample, optionally a tumor biopsy sample.
[Invention 1059]
(a) administering T cell therapy to a subject with cancer, said T cell therapy comprising a dose of T cells expressing recombinant antigen receptors that bind to the target antigen; and
(b) thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibition of Ikaros (IKZF1) inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination and/or depletion and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3). the compound,
(1) in a subject optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agonist, compared to the absence of said administration of said compound; result in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells; or
(2) in a subject optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agonist, compared to the absence of said administration of said compound; preventing, suppressing, or delaying the onset of the exhausted phenotype in T cells of naive or non-exhausted T cells; or
(3) reversing the exhausted phenotype in exhausted T cells optionally comprising T cells expressing said recombinant receptor in a subject compared to the absence of said administration of said subject;
administering to the subject in an amount, duration, and/or frequency effective to
methods of treatment, including
[Invention 1060]
wherein the amount, duration, and/or frequency are
(i) results in an increase in said antigen-specific or antigen receptor-driven activity, and
(ii) prevent, suppress or delay the onset of said wasting phenotype and/or reverse said wasting phenotype
The method of the present invention 1059, which is effective for
[Invention 1061]
wherein the amount, duration, and/or frequency are
(i) results in an increase in said antigen-specific or antigen receptor-driven activity, and
(ii) prevent, suppress or delay the onset of said wasting phenotype
A method of the invention 1059 or the invention 1060, which is effective for
[Invention 1062]
wherein the amount, duration, and/or frequency are
(i) results in an increase in said antigen-specific or antigen receptor-driven activity, and
(ii) preventing, suppressing or delaying the onset of said wasting phenotype and reversing said wasting phenotype
A method of the invention 1059 or the invention 1060, which is effective for
[Invention 1063]
(a) administering T cell therapy to a subject with cancer, said T cell therapy comprising a dose of T cells expressing recombinant antigen receptors that bind to the target antigen; and
(b) thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibition of Ikaros (IKZF1) inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination and/or depletion and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3). the compound,
(1) in a subject optionally comprising T cells expressing said recombinant receptor after exposure of T cells to an antigen or to an antigen receptor-specific agonist, compared to the absence of said administration of said compound; result in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells; or
(2) in a subject optionally comprising T cells expressing said recombinant receptor after exposure of T cells to an antigen or to an antigen receptor-specific agonist, compared to the absence of said administration of said compound; preventing, suppressing, or delaying the onset of the exhausted phenotype in T cells of naive or non-exhausted T cells; or
(3) reversing the exhausted phenotype in exhausted T cells optionally comprising T cells expressing said recombinant receptor in a subject compared to the absence of said administration of said subject;
administering to the subject in an amount, duration, and/or frequency effective to
methods of treatment, including
[Invention 1064]
wherein the amount, duration, and/or frequency are
(i) results in an increase in said antigen-specific or antigen receptor-driven activity, and
(ii) prevent, suppress or delay the onset of said wasting phenotype and/or reverse said wasting phenotype
The method of the invention 1063, which is effective for
[Invention 1065]
wherein the amount, duration, and/or frequency are
(i) results in an increase in said antigen-specific or antigen receptor-driven activity, and
(ii) prevent, suppress or delay the onset of said wasting phenotype
A method of the invention 1063 or the invention 1064, which is effective for
[Invention 1066]
wherein the amount, duration, and/or frequency are
(i) results in an increase in said antigen-specific or antigen receptor-driven activity, and
(ii) preventing, suppressing or delaying the onset of said wasting phenotype and reversing said wasting phenotype
A method of the invention 1063 or the invention 1064, which is effective for
[Invention 1067]
The method of any of Inventions 1001-1066, wherein said compound depletes or degrades Icarus (IKZF1).
[Invention 1068]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof,
During the ceremony,
one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH ₂ -is;
(1) R ¹ , R ² , R ³ , and R ^Four is independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or
(2) R ¹ , R ³ , R ^Four , and R ^Five one of -NHR ^a and R ¹ , R ² , R ³ , and R ^Four is hydrogen, where R ^a is hydrogen or alkyl of 1 to 8 carbon atoms;
R. ^Five is hydrogen or alkyl of 1 to 8 carbon atoms, benzyl, or halo;
provided that X and Y are -C(O)- and (i) R ¹ , R ² , R ³ , and R ^Four is fluoro, or (ii) R ¹ , R ² , R ³ , and R ^Four is amino, then R ^Five is other than hydrogen,
The method of any of Inventions 1001-1067.
[Invention 1069]
The compound has the following structure:

or a pharmaceutically acceptable salt thereof,
wherein one of X and Y is -C(O)- and the other of X and Y is -C(O)- or -CH ₂ - and R ^Five is hydrogen or lower alkyl,
The method of any of Inventions 1001-1068.
[Invention 1070]
The compound has the following structure:

3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione having a The method of any of Inventions 1001-1069 which is or comprises a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph.
[Invention 1071]
The method of any of Inventions 1001-1070, wherein said compound is 3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione .
[Invention 1072]
The compound has the following structure:

a compound that is or comprises 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having or an enantiomer or enantiomer thereof or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof.
[Invention 1073]
The method of any of Inventions 1001-1067 and 1072, wherein said compound is 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione .
[Invention 1074]
1 mg to 50 mg or about 1 mg to 50 mg per day; 1 mg to 25 mg or about 1 mg to 25 mg per day; , 1 mg to 5 mg or about 1 mg to 5 mg per day, 5 mg to 50 mg or about 5 mg to 50 mg per day, 5 mg to 25 mg or about 5 mg to 25 mg per day, 5 mg per day The method of any of inventions 1020-1073, administered in an effective amount of -10 mg or about 5 mg to 10 mg, optionally wherein said administration is daily for the duration of the cycling regimen.
[Invention 1075]
The compound has the following structure:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
During the ceremony,
Z is C=O or CH ₂ is;
R. ¹¹ is -Z ¹ -R ¹³ is;
R. ¹² is H or (C ₁ -C ₆ ) alkyl;
Z. ¹ is a 6-10 membered aryl, heteroaryl, or heterocycle, each of which is optionally substituted with one or more halogens; or a bond;
R. ¹³ teeth,
-(CH ₂ ) _n -Aryl, -O-(CH ₂ ) _n -aryl, or -(CH ₂ ) _n -O-aryl, wherein aryl is optionally substituted with one or more of: (C ₁ -C ₆ ) alkyl; itself optionally substituted with one or more halogens; (C ₁ -C ₆ )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or 6- to 10-membered aryl or heteroaryl optionally substituted with halogen; -CONH ₂ ; or -COO-(C ₁ -C ₆ ) alkyl (wherein alkyl is optionally substituted with one or more halogens));
-(CH ₂ ) _n -heterocycle, -O-(CH ₂ ) _n -heterocycle, or -(CH ₂ ) _n -O-heterocycle, wherein the heterocycle is optionally substituted with one or more of the following: (C ₁ -C ₆ ) alkyl, itself optionally substituted with one or more halogens; (C ₁ -C ₆ )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or 6- to 10-membered aryl or heteroaryl optionally substituted with halogen; -CONH ₂ ; or -COO-(C ₁ -C ₆ ) alkyl, wherein the alkyl is optionally substituted with one or more halogens); or
-(CH ₂ ) _n -heteroaryl, -O-(CH ₂ ) _n -heteroaryl, or -(CH ₂ ) _n -O-heteroaryl, wherein heteroaryl is optionally substituted with one or more of: (C ₁ -C ₆ ) alkyl, itself optionally substituted with one or more halogens; (C ₁ -C ₆ )alkoxy, itself substituted with one or more halogen; oxo; amino; carboxyl; cyano; hydroxyl; ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, or 6- to 10-membered aryl or heteroaryl optionally substituted with halogen; -CONH ₂ ; or -COO-(C ₁ -C ₆ )alkyl (wherein the alkyl is optionally substituted with one or more halogens))
is; and
n is 0, 1, 2, or 3;
The method of any of Inventions 1001-1067.
[Invention 1076]
The compound is

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.
[Invention 1077]
The compound is

The method of any of inventions 1001-1067, 1075, and 1076, which is the Form A crystalline form of the hydrochloride salt of
[Invention 1078]

Form A crystalline form of the hydrochloride of the XRPD pattern at or near the following positions: 9.69, 12.82, 15.09, 15.94, 16.76, 17.65, 19.44, 19.80, 2230, 22.47, 22.95, 23.02, 24.29, 24.48, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 out of 24.70, 26.27, 26.77, 27.60, 29.43, 29.72, and 32.91 degrees 2-theta , 17, 18, 19, 20, or all.
[Invention 1079]
The immunomodulatory compound is administered 0.1 mg to 1 mg or about 0.1 mg to 1 mg per day, 0.1 mg to 0.6 mg or about 0.1 mg to 0.6 mg, 0.1 mg to 0.3 mg or about 0.1 mg to 0.3 mg per day. , optionally, the administration is daily for the duration of the cycling regimen.
[Invention 1080]
The method of any of inventions 1020-1079, wherein administration of said compound is initiated subsequent to initiation of administration of T cell therapy.
[Invention 1081]
The method of any of inventions 1059-1080, wherein said cancer is a B-cell malignancy, a B-cell derived malignancy, a non-hematological cancer, or a solid tumor.
[Invention 1082]
of the invention 1059-1081, wherein said target antigen is a tumor antigen, optionally said target antigen is associated with, specific for and/or expressed on a cancer cell or tissue. either way.
[Invention 1083]
said target antigen is B cell maturation antigen (BCMA), αvβ6 integrin (avb6 integrin), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250); cancer testis antigen, cancer/testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclins, cyclin A2, CC motif chemokine ligand 1 (CCL-1), CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7/8, CD45, CD79a, CD79b, CD123, CD133, CD138, CD171, CS-1, Chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor type III mutation (EGFR vIII), epidermal glycoprotein 2 (EPG-2), epithelium glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), fetal acetylcholine receptor (fetal AchR), folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3), G protein-binding receptor 5D (GPCR5D), Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight-melanoma-associated antigen ( HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), Ig kappa, Ig lambda, IL-22 receptor alpha (IL-22Rα) , IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, leucine-rich repeat-containing 8 family member A (LRRC8A ), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN), c- Met, mouse cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan A (MART-1), neuronal cell adhesion molecule (NCAM), oncofetal antigen, black tumor preferentially expressed antigen (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), ROR1, survivin, TACI, trophoblast glycoprotein (TPBG; also known as 5T4) ), tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2; dopachrome tautomerase, dopachrome delta-isomerase, or DCT ), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), pathogen-specific antigen or pathogen-expressed antigen , the method of any of the inventions 1059-1082.
[Invention 1084]
The method of Invention 1051, Invention 1082, or Invention 1083, wherein said B-cell malignancy is lymphoma.
[Invention 1085]
1084. The method of invention 1084, wherein said lymphoma is non-Hodgkin's lymphoma (NHL).
[Invention 1086]
Aggressive NHL, diffuse large B-cell lymphoma (DLBCL), DLBCL-NOS, optionally transformed low-grade; EBV-positive DLBCL-NOS; T-cell/histiocyte-rich large Cellular B-cell lymphoma; primary mediastinal large B-cell lymphoma (PMBCL); follicular lymphoma (FL), optionally follicular lymphoma grade 3B (FL3B); and/or MYC and BCL2 with DLBCL histology and/or high-grade B-cell lymphoma with rearrangement of BCL6 (double/triple hit).
[Invention 1087]
1086. The method of any of inventions 1001-1086, wherein said subject is identified or has been identified as having an Eastern Cooperative Oncology Group Performance Status (ECOG) of 1 or less.
[Invention 1088]
The method of any of inventions 1059-1087, wherein said target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30.
[Invention 1089]
The method of any of inventions 1059-1088, wherein said target antigen is CD19.
[Invention 1090]
The method of any of inventions 1059-1087, wherein said target antigen is not CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30.
[Invention 1091]
The method of any of inventions 1059-1081, wherein said cancer is multiple myeloma.
[Invention 1092]
said target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319, and 19A24), BAFF-R, TACI, or FcRH5.
[Invention 1093]
The method of any of inventions 1059-1092, wherein said target antigen is BCMA.
[Invention 1094]
The method of any of inventions 1020-1093, wherein administration of said compound continues for a period of up to 3 months or about 3 months or more than 3 months after initiation of administration of the T cell therapy.
[Invention 1095]
1074. The method of invention 1074, wherein said effective amount is 4 mg or less or about 4 mg or less per day.
[Invention 1096]
1074. The method of invention 1074, wherein said effective amount is from or about 1.0 mg to 4 mg or about 4 mg per day.
[Invention 1097]
1074. The method of invention 1074, wherein said effective amount is 3 mg or less or about 3 mg or less per day.
[Invention 1098]
The method of inventions 1074 and 1097, wherein said effective amount is from or about 1.0 mg to 3 mg or about 3 mg.
[Invention 1099]
1074. The method of invention 1074, wherein said effective amount is 2.5 mg or less or about 2.5 mg or less per day.
[Invention 1100]
For each week of the cycling regimen, or for at least one week of the cycling regimen, administration of the compound comprises administration of the compound on each of no more than 5 consecutive days of the week, followed by a rest period during which no compound is administered for the remainder of the week. , the method of any of the inventions 1074 and 1095-1099.
[Invention 1101]
1100. The method of the invention 1100, wherein said 5 or fewer consecutive days are 3 consecutive days per week followed by a rest period of 4 days in which no compound is administered.
[Invention 1102]
1100. The method of the invention 1100, wherein said 5 or fewer consecutive days are 4 consecutive days per week followed by a 3-day rest period in which no compound is administered.
[Invention 1103]
The method of invention 1100, wherein said 5 or fewer consecutive days are 5 consecutive days per week followed by a rest period of 2 days in which no compound is administered.
[Invention 1104]
The method of any of inventions 1020-1103, wherein said administration continues for a period of up to 4 months or about 4 months or more than 4 months after initiation of administration of T cell therapy.
[Invention 1105]
The method of any of inventions 1020-1104, wherein said administration continues for a period of 5 months or about 5 months or greater than 5 months after initiation of administration of T cell therapy.
[Invention 1106]
The method of any of the inventions 1020-1105, wherein said administration continues for a period of 6 months or about 6 months or greater than 6 months after initiation of administration of the T cell therapy.
[Invention 1107]
The method of any of Inventions 1074 and 1095-1106, wherein the administration of said compound per day is in an amount of or about 3 mg.
[Invention 1108]
The method of any of Inventions 1074 and 1095-1106, wherein the administration of said compound per day is in an amount of or about 2.5 mg.
[Invention 1109]
The method of any of Inventions 1074 and 1095-1106, wherein the administration of said compound per day is in an amount of 2 mg or about 2 mg.
[Invention 1110]
The method of any of Inventions 1074 and 1095-1106, wherein the administration of said compound per day is in an amount of or about 1.5 mg.
[Invention 1111]
The method of any of Inventions 1074 and 1095-1106, wherein administration of said compound per day is in an amount of or about 1 mg per day.
[Invention 1112]
The method of any of inventions 1020-1111, wherein at the end of the period, administration of said compound is discontinued at the end of the period if the subject exhibits a complete response (CR) after treatment.
[Invention 1113]
Any of invention 1020-1112, wherein if at the end of the period the cancer is progressing after treatment or is in remission followed by recurrence, administration of said compound is discontinued at the end of the period. the method of.
[Invention 1114]
The method of any of inventions 1020-1113, wherein administration of said compound continues for a period of from 3 months, or from 3 months or about 3 months, to 6 months or up to 6 months.
[Invention 1115]
The method of any of inventions 1020-1114, wherein administration of said compound continues for a period of up to 3 months or about 3 months after initiation of administration of the T cell therapy.
[Invention 1116]
If the subject has achieved a complete response (CR) after treatment at or about 3 months prior to treatment, or the cancer is progressing or remission followed by recurrence after treatment, The method of any of inventions 1020-1114, wherein administration of said compound continues for a period of up to 3 months or about 3 months after initiation of administration of the T cell therapy.
[Invention 1117]
The present invention, wherein if the subject achieves a complete response (CR) at 3 months, administration of said compound is continued for a period of 3 months or up to about 3 months after initiation of administration of the T cell therapy. 1116 ways.
[Invention 1118]
The method of any of inventions 1020-1114, wherein administration of said compound continues for a period of up to 6 months or about 6 months after initiation of administration of the T cell therapy.
[Invention 1119]
If the subject has achieved a complete response (CR) after treatment at or about 6 months prior to treatment, or the cancer has progressed or relapsed following treatment, The method of any of inventions 1020-1118, wherein administration of said compound continues for a period of up to 6 months or about 6 months after initiation of administration of the T cell therapy.
[Invention 1120]
1119. The method of invention 1119, wherein if the subject achieves a complete response (CR) in 6 months, said time period extends to or about 6 months after initiation of administration of T cell therapy.
[Invention 1121]
The method of any of inventions 1020-1120, wherein said administration is continued for a continuous period of time even if the subject has achieved a complete response (CR) prior to the end of the period.
[Invention 1122]
The method of any of inventions 1020-1121, wherein said subject achieves a complete response (CR) during the dosing period and prior to the end of the dosing period.
[Invention 1123]
1020-1111, 1114, 1115, 1119 of the invention further comprising continuing administration after the end of the period if the subject has a partial response (PR) or stable disease (SD) at the end of the period; Either method of 1121, and 1122.
[Invention 1124]
The administration of any of inventions 1020-1123 is continued for more than 6 months if at or about 6 months the subject exhibits a partial response (PR) or stable disease (SD) after treatment. Method.
[Invention 1125]
The method of invention 1123 or invention 1124, wherein said administration is continued until the subject achieves a complete response (CR) after treatment or until the cancer progresses after treatment or recurs following remission.
[Invention 1126]
The method of any of inventions 1020-1125, wherein administration of said compound is initiated at or after peak or maximal levels of T cell therapy cells are detectable in the subject's blood.
[Invention 1127]
The method of any of inventions 1020-1126, wherein administration of said compound is initiated from about 14 to about 35 days after initiation of administration of T cell therapy.
[Invention 1128]
The method of any of inventions 1020-1127, wherein administration of said compound is initiated from about 21 to about 35 days after initiation of administration of T cell therapy.
[Invention 1129]
The method of any of inventions 1020-1128, wherein administration of said compound begins about 21 to about 28 days after initiation of administration of T cell therapy.
[Invention 1130]
21 days or about 21 days, 22 days or about 22 days, 23 days or about 23 days, 24 days or about 24 days, 25 days or about 25 days, 26 The method of any of the inventions 1020-1129 initiated after or about 26 days, after 27 days or about 27 days, or after 28 days or about 28 days.
[Invention 1131]
The method of any of inventions 1020-1130, wherein administration of said compound begins at or about 28 days after initiation of administration of the T cell therapy.
[Invention 1132]
The method of any of inventions 1020-1131, wherein at the start of administration of said compound, the subject does not exhibit severe toxicity following administration of T cell therapy.
[Invention 1133]
said severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or greater, prolonged grade 3 or greater, or grade 4 or 5 CRS; and/or
said severe toxicity is severe neurotoxicity, optionally grade 3 or greater, chronic grade 3 or greater, or grade 4 or 5 neurotoxicity;
The method of the invention 1132.
[Invention 1134]
The method of any of inventions 1020-1133, wherein administration of said compound is discontinued and/or said administration is modified if the subject exhibits toxicity, optionally hematological toxicity, following administration of the compound.
[Invention 1135]
1134. The method of the invention 1134, wherein said toxicity is selected from severe neutropenia, optionally febrile neutropenia, prolonged grade 3 or greater neutropenia.
[Invention 1136]
The method of invention 1134 or 1135, wherein administration of said compound is resumed after the subject no longer exhibits toxicity.
[Invention 1137]
1136. The method of invention 1136, wherein said administration is modified after administration of the compound is resumed.
[Invention 1138]
The method of any of Inventions 1134-1137, wherein said modified administration comprises administering a reduced amount of the compound and/or reducing the frequency of administration of the compound.
[Invention 1139]
The method of any of Inventions 1134-1138, wherein said modified administration comprises administering a reduced amount of the compound.
[Invention 1140]
The method of Invention 1139, wherein the dose of said compound is reduced, wherein the reduced amount is from 1 mg or about 1 mg to 2 mg or about 2 mg per day for no more than 5 days per week.
[Invention 1141]
The compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The method of any of inventions 1001-1067 and 1075-1139 which is or comprises a pharmaceutically acceptable salt of a dione.
[Invention 1142]
The compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The method of any of inventions 1001-1067 and 1075-1139 which is or comprises a hydrate of a dione.
[Invention 1143]
The compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The method of any of inventions 1001-1067 and 1075-1139 which is or comprises a solvate of a dione.
[Invention 1144]
The compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The method of any of inventions 1001-1067 and 1075-1139 which is or comprises a dione.
[Invention 1145]
Invention 1001 wherein said compound is or comprises a solvate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione Either way ~1074 and 1080~1140.
[Invention 1146]
Invention 1001 wherein said compound is or comprises a hydrate of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione Either way ~1074 and 1080~1140.
[Invention 1147]
said compound is or comprises a pharmaceutically acceptable salt of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione , the method of any of the inventions 1001-1074 and 1080-1140.
[Invention 1148]
Inventions 1001-1074 and 1080 wherein said compound is or comprises 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione Any method from ~1140.
[Invention 1149]
The method of any of inventions 1020-1148, wherein said compound is administered orally.
[Invention 1150]
administration of the compound,
reversing the wasting phenotype in recombinant receptor-expressing T cells in a subject;
preventing, suppressing, or delaying the onset of a wasting phenotype in recombinant receptor-expressing T cells in a subject;
or reduce the level or extent of a wasting phenotype in recombinant receptor-expressing T cells in the subject; or
reducing the percentage of the total number of recombinant receptor-expressing T cells in the subject that have an exhaustive phenotype;
The method of any of Inventions 1020-1149.
[Invention 1151]
Initiation of administration of said compound is followed by administration of T-cell therapy, and after administration of the compound or initiation thereof, the subject reduces the antigen-specific or tumor-specific activity of recombinant receptor-expressing T cells in said subject. or demonstrated restoration or rescue of function, optionally wherein said restoration, rescue and/or initiation of administration of said compound showed a depleted phenotype of recombinant receptor-expressing T cells in the subject or in the subject's blood The method of any of the inventions 1003-1149 at a later point in time.
[Invention 1152]
administration of the compound,
(a) in a subject optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agonist, compared to the absence of said administration of said compound; result in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells; or
(b) in a subject optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agonist, compared to the absence of said administration of said compound; preventing, suppressing, or delaying the onset of the exhausted phenotype in T cells of naive or non-exhausted T cells; or
(c) reversing the exhausted phenotype in exhausted T cells optionally comprising T cells expressing said recombinant receptor in a subject compared to the absence of said administration of said subject;
The method of any of the inventions 1003-1149, comprising administration in an amount, frequency, and/or duration effective to
[Invention 1153]
administration of the compound,
(i) results in an increase in said activity, and
(ii) prevent, suppress or delay said onset of said wasting phenotype and/or reverse said wasting phenotype
The method of the invention 1152, comprising administration in an amount, frequency, and/or duration effective to
[Invention 1154]
The method of invention 1152 or 1153, wherein the T cells in said subject comprise T cells expressing said recombinant receptor and/or said antigen is a target antigen.
[Invention 1155]
the wasting phenotype for a T cell or population of T cells is
indicating the level or degree of surface expression on one or more T cells or surface expression of one or more exhaustion markers, optionally 2, 3, 4, 5, or 6 exhaustion markers an increase in the percentage of said population of T cells compared to a reference T cell population under the same conditions; or
Reduction in the level or extent of activity displayed by said T cell or population of T cells upon exposure to an antigen or antigen receptor specific agent compared to a reference T cell population under the same conditions
The method of any of the inventions 1150-1154, comprising:
[Invention 1156]
said level, degree, or percentage increase is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more, the method of the invention 1155 .
[Invention 1157]
said level, degree, or percentage reduction is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold, 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more, the method of the invention 1155 .
[Invention 1158]
Said reference T cell population is optionally known to have a non-exhausted phenotype from the same subject from which the one or more T cells with an exhausted phenotype are derived or of the same species as the subject The method of any of the inventions 1155-1157, which is a population of T cells, a population of naive T cells, a population of central memory T cells, or a population of stem central memory T cells.
[Invention 1159]
(a) said reference T cell population is a matched population comprising bulk T cells isolated from the blood of a subject from which one or more T cells with an exhausted phenotype are derived; said bulk T cells do not express the recombinant receptor and/or
(b) said reference T cell population is obtained from a subject from which one or more T cells with an exhausted phenotype were derived prior to being administered a dose of T cells expressing the recombinant receptor;
The method of any of the inventions 1155-1158.
[Invention 1160]
wherein said reference T cell population is a composition comprising a sample of T cell therapy or a pharmaceutical composition comprising T cells expressing a recombinant receptor prior to its administration to a subject; is a cryopreserved sample.
[Invention 1161]
The method of any of inventions 1155-1160, wherein said one or more exhaustion markers are inhibitory receptors.
[Invention 1162]
1155-1161 of the invention, wherein said one or more markers of exhaustion are selected among PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT Either method.
[Invention 1163]
said activity is one or more of the production of one or a combination of proliferative, cytotoxic, or inflammatory cytokines, optionally one or a combination of said cytokines is IL-2, IFN-gamma , and TNF-alpha.
[Invention 1164]
Exposure to said antigen or antigen receptor specific agent comprises incubation with an antigen or antigen receptor specific agent, optionally an agent that binds to the recombinant receptor, wherein said antigen optionally binds to a target antigen The method of any one of Inventions 1155-1163, wherein
[Invention 1165]
1164. The method of the invention 1164, wherein said antigen or antigen receptor specific agent comprises antigen-expressing target cells, optionally cells of said disease, disorder, or condition.
[Invention 1166]
The method of any of inventions 1002 and 1011-1165, wherein said target antigen is a human antigen.
[Invention 1167]
The method of any of inventions 1001-1166, wherein said subject is a human.
[Invention 1168]
The method of any of inventions 1001-1167, wherein said recombinant antigen receptor is a chimeric antigen receptor that specifically binds to a target antigen.
[Invention 1169]
The method of Invention 1016 or Invention 1168, wherein said chimeric antigen receptor (CAR) comprises an extracellular antigen recognition domain that specifically binds to a target antigen and an intracellular signaling domain comprising an ITAM.
[Invention 1170]
1169. The method of invention 1169, wherein said intracellular signaling domain comprises the signaling domain of the CD3-zeta (CD3ζ) chain, optionally the human CD3-zeta chain.
[Invention 1171]
The method of Invention 1169 or Invention 1170, wherein said chimeric antigen receptor (CAR) further comprises a co-stimulatory signaling region.
[Invention 1172]
1171. The method of invention 1171, wherein said co-stimulatory signaling region comprises the signaling domain of CD28 or 4-1BB, optionally human CD28 or human 4-1BB.
[Invention 1173]
The method of invention 1171 or invention 1172, wherein the co-stimulatory domain is or comprises the signaling domain of human 4-1BB.
[Invention 1174]
said CAR is a scFv specific for a target antigen; a transmembrane domain; a cytoplasmic signaling domain derived from a co-stimulatory molecule, optionally 4-1BB, optionally human 4-1BB, or comprising it; optionally a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule that is or comprises a CD3 zeta signaling domain, optionally a human CD3 zeta signaling domain; further comprising a spacer between the spanning domain and the scFv;
said CAR, in turn, to a co-stimulatory molecule that is or comprises a scFv specific for a target antigen; a transmembrane domain; optionally a 4-1BB signaling domain, optionally a human 4-1BB signaling domain and optionally a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule that is a CD3 zeta signaling domain, optionally a human CD3 zeta signaling domain; or
a spacer; a transmembrane domain, optionally a cytoplasmic signaling domain derived from a co-stimulatory molecule, and optionally CD3, wherein said CAR is in turn a scFv specific for a target antigen; a cytoplasmic signaling domain derived from a primary signaling ITAM-containing molecule that is or comprises a zeta signaling domain;
The method of any of the inventions 1016 and 1168-1173.
[Invention 1175]
The dose of genetically engineered T cells was 1 x 10 ^Five ～5×10 ⁸ or about 1 x 10 ^Five ～5×10 ⁸ total CAR-expressing T cells, 1 x 10 ⁶ ～2.5×10 ⁸ or about 1 x 10 ⁶ ～2.5×10 ⁸ total CAR-expressing T cells, 5 x 10 ⁶ ～1×10 ⁸ or about 5 x 10 ⁶ ～1×10 ⁸ total CAR-expressing T cells, 1 x 10 ⁷ ～2.5×10 ⁸ or about 1 x 10 ⁷ ～2.5×10 ⁸ total CAR-expressing T cells, 5 x 10 ⁷ ～1×10 ⁸ or about 5 x 10 ⁷ ～1×10 ⁸ of total CAR-expressing T cells (each inclusive).
[Invention 1176]
A dose of genetically engineered T cells of at least 1 x 10 ^Five or at least about 1 x 10 ^Five CAR-expressing cells, at least 2.5 x 10 ^Five or at least about 2.5 x 10 ^Five CAR-expressing cells, at least 5 x 10 ^Five or at least about 5 x 10 ^Five CAR-expressing cells, at least 1 x 10 ⁶ or at least about 1 x 10 ⁶ CAR-expressing cells, at least 2.5 x 10 ⁶ or at least about 2.5 x 10 ⁶ CAR-expressing cells, at least 5 x 10 ⁶ or at least about 5 x 10 ⁶ CAR-expressing cells, at least 1 x 10 ⁷ or at least about 1 x 10 ⁷ CAR-expressing cells, at least 2.5 x 10 ⁷ or at least about 2.5 x 10 ⁷ CAR-expressing cells, at least 5 x 10 ⁷ or at least about 5 x 10 ⁷ CAR-expressing cells, at least 1 x 10 ⁸ or at least about 1 x 10 ⁸ CAR-expressing cells, at least 2.5 x 10 ⁸ or at least about 2.5 x 10 ⁸ CAR-expressing cells, or at least 5 x 10 ⁸ or at least about 5 x 10 ⁸ CAR-expressing cells of the invention 1021-1175.
[Invention 1177]
The dose of genetically engineered T cells was 5 x 10 ⁷ or about 5 x 10 ⁷ The method of any of inventions 1021-1176, comprising total CAR-expressing T cells of
[Invention 1178]
The dose of genetically engineered T cells was 1 x 10 ⁸ or about 1 x 10 ⁸ The method of any of the inventions 1021-1177, comprising the CAR-expressing cells of
[Invention 1179]
The method of any of inventions 1021-1178, wherein the dose of cells is administered parenterally, optionally intravenously.
[Invention 1180]
The method of any of inventions 1021-1179, wherein said T cells are primary T cells obtained from the subject.
[Invention 1181]
The method of any of inventions 1021-1180, wherein said T cells are autologous to the subject.
[Invention 1182]
The method of any of inventions 1021-1180, wherein said T cells are allogeneic to the subject.
[Invention 1183]
The dose of genetically engineered T cells comprises CAR-expressing CD4+ T cells and the CAR-expressing CD8+ T cells, and administration of the dose comprises administering a plurality of separate compositions, wherein the plurality of separate comprises a first composition comprising one of CD4+ T cells and CD8+ T cells and a second composition comprising the other of CD4+ T cells or CD8+ T cells. method.
[Invention 1184]
The method of any of inventions 1021-1183, wherein prior to said administering, the subject has been preconditioned with lymphocyte depleting therapy comprising administration of fludarabine and/or cyclophosphamide.
[Invention 1185]
The method of any of inventions 1021-1184, further comprising administering to the subject a lymphocyte depletion therapy comprising administration of fludarabine and/or cyclophosphamide immediately prior to said administering.
[Invention 1186]
The lymphocyte depletion therapy is about 200-400 mg/m ² , optionally 300 mg/m ² or about 300 mg/m ² of cyclophosphamide (inclusive) and/or about 20-40 mg/m ² , optionally 30 mg/m ² of fludarabine daily for 2 to 4 days, optionally 3 days, or said lymphodepleting therapy comprises about 500 mg/m ² The method of Invention 1184 or Invention 1185 comprising administration of cyclophosphamide.
[Invention 1187]
The lymphocyte depleting therapy is 300 mg/m ² or about 300 mg/m ² of cyclophosphamide and about 30 mg/m ² of fludarabine daily for 3 days; and/or
The lymphocyte depleting therapy is 500 mg/m ² or about 500 mg/m ² of cyclophosphamide and about 30 mg/m ² of fludarabine, including daily administration for 3 days,
The method of any of the inventions 1184-1186.
[Invention 1188]
at least 35%, at least 40%, or at least 50% of subjects treated according to the method are permanent or achieve CR for 6 or more than 6 months or 9 or more than 9 months; achieve a complete response (CR) that is durable in at least 60, 70, 80, 90, or 95%; and/or
At least 60, 70, 80, 90, or 95% of subjects achieving a CR by 6 months for 3 months or more than 3 months and/or 6 months or more than 6 months and/or more than 9 months, remain in response, remain in CR, and/or are alive or alive without exacerbation; and/or
At least 50%, at least 60%, or at least 70% of subjects treated according to the method achieve an objective response (OR), optionally the OR is 6 months or greater than 6 months or 9 months or 9 months. Persistent, or persistent in at least 60, 70, 80, 90, or 95% of subjects achieving an OR for more than a month; and/or
At least 60, 70, 80, 90, or 95% of subjects achieving OR by 6 months remain in response for 3 months or longer and/or 6 months or longer , or alive,
The method of any of Inventions 1020-1187.
[Invention 1189]
(a) a T cell therapy comprising a dose of T cells expressing recombinant antigen receptors that bind the target antigen; and
(b) thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibition of Ikaros (IKZF1) inhibitors of Aiolos (IKZF3); and compounds that enhance or promote ubiquitination and/or depletion and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3). modulating compounds; and
(c) instructions for administering said compound and/or said T cell therapy according to any of the methods of inventions 1001-1187;
kit, including

Claims (49)

A medicament for treating cancer in a subject comprising a combination of a composition for T cell therapy and an immunomodulatory compound,
the composition for T cell therapy comprises a dose of T cells expressing a recombinant antigen receptor that binds to the target antigen; and
The immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The medicament, which is a dione or a pharmaceutically acceptable salt thereof. A medicament for treating cancer in a subject comprising a composition for T cell therapy, said medicament being used in combination with an immunomodulatory compound,
the composition for T cell therapy comprises a dose of T cells expressing a recombinant antigen receptor that binds to the target antigen; and
The immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The medicament, which is a dione or a pharmaceutically acceptable salt thereof. A medicament for treating cancer in a subject comprising an immunomodulatory compound, said medicament being used in combination with a composition for T cell therapy to treat cancer in a subject,
the composition for T cell therapy comprises a dose of T cells expressing a recombinant antigen receptor that binds to the target antigen; and
The immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The medicament, which is a dione or a pharmaceutically acceptable salt thereof. A medicament for treating cancer in a subject comprising a composition for T cell therapy,
a composition for T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen;
Subject is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-iso prior to administration of the composition for T cell therapy Said medicament being administered an immunomodulatory compound that is indol-2-yl]-piperidine-2,6-dione or a pharmaceutically acceptable salt thereof. A medicament for treating cancer in a subject comprising an immunomodulatory compound,
the subject has been administered a composition for T cell therapy to treat cancer in the subject prior to administration of the immunomodulatory compound;
the composition for T cell therapy comprises a dose of T cells expressing a recombinant antigen receptor that binds to the target antigen; and
The immunomodulatory compound is (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2,6- The medicament, which is a dione or a pharmaceutically acceptable salt thereof. A medicament for treating cancer in a subject comprising an immunomodulatory compound ,
thalidomide derivatives; cereblon (CRBN) and/or compounds that interact with and/or bind to one or more members of the CRBN E3 ubiquitin-ligase complex; Ikaros (IKZF1 ); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3);
(a) the subject has been administered a composition for T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds the target antigen prior to administration of the immunomodulatory compound, or (b) prior to or at the time of administration of said immunomodulatory compound, said subject or blood sample from said subject contains or contains one or more T cells expressing a recombinant antigen receptor; It has been confirmed that
one or more of the recombinant receptor-expressing T cells in the subject have an exhausted phenotype upon administration of the immunomodulatory compound;
Said medicament . One or more exhausted phenotypes of recombinant receptor-expressing T cells, or a marker or parameter indicative thereof, upon administration of said immunomodulatory compound, in or in a biological sample derived from a subject , optionally a blood sample or has been detected or measured in a tumor sample , optionally
(a) at least 10% or at least about 10%, at least 20% or at least about 20%, at least 30% or at least about 30%, at least 40% or at least about the total recombinant receptor-expressing T cells in the biological sample; 40%, or at least 50% or at least about 50%, have an exhausted phenotype; and/or
(b) the percentage of recombinant receptor-expressing T cells in a subject-derived biological sample compared to the percentage of recombinant receptor-expressing cells with an exhausted phenotype in a comparable biological sample at the previous time point; greater than or about 10%, greater than or about 20%, greater than or about 30%, greater than or about 30%, greater than or greater than 40%, or greater than or about 40%, or greater than or about 50%, is an exhaustive expression A medicament according to any one of claims 1 to 3, 5 and 6, having a mold . A medicament for treating cancer in a subject comprising an immunomodulatory compound,
The subject is (a) selected as a candidate for administration of an immunomodulatory compound, said selected subject having exhausted recombinant antigen receptor-expressing T cells, wherein the recombinant antigen receptor binds the target antigen ; And
thalidomide derivatives; cereblon (CRBN) and/or compounds that interact with and/or bind to one or more members of the CRBN E3 ubiquitin-ligase complex; Ikaros (IKZF1 ); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3) . , said medicaments . a tissue, tumor, biological fluid, or biological sample of or derived from said selected subject, optionally a blood or tumor sample from said selected subject ,
comprising one or more T cells expressing a recombinant antigen receptor that binds to a target antigen and having an exhausted phenotype ;
(a) at least 10%, or at least about 10%, at least 20%, or at least about 20%, at least 30%, or at least about, of the recombinant antigen receptor-expressing T cells in said tissue, tumor, biological fluid, or biological sample; 30%, at least 40% or at least about 40%, at least 50% or at least about 50%, at least 60% or at least about 60%, at least 70% or at least about 70%, or at least 80% or at least about 80% have an exhausted phenotype and/or
(b) recombinant antigen receptor-expressing T cells in said tissue, tumor, biological fluid or biological sample at an earlier time point in a tissue, tumor, biological fluid or biological sample from said subject; or greater than or about 10% greater than or about 10% greater than the percentage or number of T cells expressing the recombinant receptor that had an exhausted phenotype in a comparable body fluid, tissue, tumor, or sample, 20% more than or about 20% more, more than 30% or about 30% more, more than 40% or about 40% more, more than 50% or about 50% more, more than 2 times more, more than 3 times more, 5 times more more than 10-fold more, or more than 10-fold, have the exhausted phenotype
The medicament according to claim 8 . A medicament for treating cancer in a subject comprising a combination of a composition for T cell therapy and an immunomodulatory compound,
a composition for T cell therapy comprising a dose of T cells expressing a recombinant antigen receptor that binds to a target antigen ;
thalidomide derivatives; cereblon (CRBN) and/or compounds that interact with and/or bind to one or more members of the CRBN E3 ubiquitin-ligase complex; Ikaros (IKZF1 ); inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination and/or depletion and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3). and _
( a ) optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agent, as compared to the absence of said administration of said immunomodulatory compound; result in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject; and/ or ( b ) T cells against antigen or against antigen receptor-specific agents after exposure to a naive or non-exhausted T cell exhaustion phenotype in a subject optionally comprising T cells expressing said recombinant receptor compared to the absence of said administration of said immunomodulatory compound and/ or ( c ) exhaustion in a subject, optionally comprising T cells expressing said recombinant receptor, compared to the absence of said administration of said subject said immunomodulatory compound is administered to the subject in an effective amount, duration, and/or frequency to reverse the exhausted phenotype in the T cells that have been infected . An ex vivo method for increasing T cell activity or potency and for preventing, inhibiting, reducing or delaying the onset of T cell exhaustion comprising:
thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); (IKZF3); and a compound that enhances or promotes the ubiquitination, depletion, and/or degradation of Icarus (IKZF1) and/or Aeolus (IKZF3). exposing a plurality of T cells to
at least a portion of said exposing is performed under conditions that induce or are capable of inducing an exhausted phenotype in a plurality of T cells in the absence of an immunomodulatory compound;
the aforementioned method. An ex vivo method for reducing or delaying the onset of T cell exhaustion comprising:
thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibitors of Ikaros (IKZF1); (IKZF3); and a compound that enhances or promotes the ubiquitination, depletion, and/or degradation of Icarus (IKZF1) and/or Aeolus (IKZF3). exposing a plurality of T cells to
at least a portion of said exposing is performed under conditions that induce or are capable of inducing an exhausted phenotype in a plurality of T cells in the absence of an immunomodulatory compound;
the aforementioned method. T cell stimulation, wherein said condition comprises exposure to at least one T cell stimulatory agent capable of stimulating a signal in multiple T cells, optionally sustained, repeated, prolonged or prolonged exposure 13. A method according to claim 11 or claim 12, comprising a condition, said signal optionally comprising a primary signal and/or a co-stimulatory signal. The at least one T cell stimulating agent is a polyclonal agent, an antigen specifically recognized by receptors expressed on multiple T cells, or an effect of binding antigen receptors expressed by multiple T cells. contains a substance and/or
wherein one or more of said plurality of T cells express a recombinant antigen receptor that binds to a target antigen, and said at least one T cell stimulatory agent binds to said recombinant antigen receptor; and said at least one T cell stimulator is
(i) is or comprises an anti-idiotypic antibody specific for a recombinant antigen receptor, or
(ii) is or comprises a target antigen or a portion thereof recognized by or bound by a recombinant antigen receptor;
A method according to any one of claims 11-13. The at least one T cell stimulatory agent comprises an anti-CD3 antibody and optionally an agent that specifically binds to a T cell co-stimulatory molecule, optionally wherein the T cell co-stimulatory molecule is CD28, CD137 (4-1 -BB), OX40, CD40L, or ICOS, and optionally, the at least one T cell stimulating agent comprises an anti-CD28 antibody. An ex vivo method for rescuing T cell activity comprising:
thalidomide analogues; thalidomide derivatives; compounds that interact with and/or bind to cereblon (CRBN) and/or one or more members of the CRBN E3 ubiquitin-ligase complex; inhibition of Ikaros (IKZF1) inhibitors of Aiolos (IKZF3); and compounds that enhance or promote the ubiquitination, depletion, and/or degradation of Ikaros (IKZF1) and/or Aiolos (IKZF3). exposing a plurality of T cells having an exhausted phenotype to an effective amount of an immunomodulatory compound. 17. The method of any one of claims 11-16, wherein one or more of said plurality of T cells express a recombinant receptor that binds to a target antigen . The immunomodulatory compound has the following structure:

or a pharmaceutically acceptable salt thereof,
During the ceremony,
one of X and Y is -C(O)- and the other of X and Y is -C(O)- or _-CH2- ;
(1) each of R ¹ , R ² , R ³ , and R ⁴ is independently halo, alkyl of 1 to 4 carbon atoms, or alkoxy or 1 to 4 carbon atoms, or (2) ^one of R1, R3 ^{, R4} , and ^R5 is ^-NHRa and the remainder of ^R1 , ^R2 , R3 ^, and ^R4 are hydrogen, where R ^a is hydrogen or alkyl of 1 to 8 carbon atoms;
R ⁵ is hydrogen or alkyl of 1-8 carbon atoms, benzyl, or halo;
provided that X and Y are -C(O)- and (i) each of ^R1 , ^R2 , R3 ^, and ^R4 is fluoro, or (ii) ^R1 , ^R2 , R ³ , and if one of ^R4 is amino, then ^R5 is other than hydrogen;
A medicament according to any one of claims 6-10 or a method according to any one of claims 11-17 . The immunomodulatory compound has the following structure:

or a pharmaceutically acceptable salt thereof,
wherein one of X and Y is -C(O)-, the other of X and Y is -C ⁽ O)- or _-CH2- , and R5 is hydrogen or lower alkyl ,
A medicament according to any one of claims 6-10 and 18 or a method according to any one of claims 11-18 . The immunomodulatory compound has the following structure:

3-(4-amino-1-oxo-1,3-dihydro-2H-isoindol-2-yl)piperidine-2,6-dione having a 20. Any one of claims 6-10, 18 and 19, which is or comprises a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph. or a method according to any one of claims 11-19 . The immunomodulatory compound has the following structure:

or a compound that is or comprises 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione having or an enantiomer or enantiomer thereof or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or polymorph thereof, or A method according to any one of claims 11-17 . 1 mg to 50 mg or about 1 mg to 50 mg per day; 1 mg to 25 mg or about 1 mg to 25 mg per day; , 1 mg to 5 mg or about 1 mg to 5 mg per day, 5 mg to 50 mg or about 5 mg to 50 mg per day, 5 mg to 25 mg or about 5 mg to 25 mg per day, 5 mg per day Claims 6-10 and 18 , administered in an effective amount of ~10 mg or between about 5 mg and 10 mg, optionally characterized in that administration of said immunomodulatory compound is daily for the duration of the cycling regimen. 22. The medicament according to any one of -21. The immunomodulatory compound has the following structure:

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,
During the ceremony,
Z is C=O or _CH2 ;
R ¹¹ is -Z ¹ -R ¹³ ;
R ¹² is H or (C ₁ -C ₆ )alkyl;
Z ¹ is a 6-10 membered aryl, heteroaryl, or heterocycle, each of which is optionally substituted with one or more halogens; or a bond;
^R13 is
-( _CH2 ) _n -aryl, -O-( _CH2 ) _n -aryl, or -( _CH2 ) _n -O-aryl, wherein aryl may be substituted with one or more of may be: (C1 _- C6)alkyl; itself optionally substituted with _one or more halogens; (C1 _{- C6} )alkoxy, itself substituted with one or more halogens; _oxo ; amino; carboxyl; _cyano ; _hydroxyl ; _halogen ; ₁₀ -membered aryl or heteroaryl; _-CONH2 ; or -COO-(C1 _- C6)alkyl (wherein alkyl is optionally substituted with one or more halogens));
-( _CH2 ) _n -heterocycle, -O-( _CH2 ) _n -heterocycle, or -( _CH2 ) _n -O-heterocycle, wherein heterocycle is substituted with one or more of (C ₁ -C ₆ )alkyl, itself optionally substituted with one or more halogens; (C ₁ -C ₆ )alkoxy, substituted with one or more halogens _oxo ; amino; carboxyl; _cyano ; _hydroxyl ; _halogen ; _6-10 membered aryl or heteroaryl; _-CONH2 ; or -COO-(C1 _- C6)alkyl (wherein alkyl is optionally substituted with one or more halogens) );or
-( _CH2 ) _n -heteroaryl, -O-( _CH2 ) _n -heteroaryl, or -( _CH2 ) _n -O-heteroaryl, wherein heteroaryl is substituted with one or more of (C ₁ -C ₆ )alkyl, itself optionally substituted with one or more halogens; (C ₁ -C ₆ )alkoxy, substituted with one or more halogens _oxo ; amino; carboxyl; _cyano ; _hydroxyl ; _halogen ; _6-10 membered aryl or heteroaryl; _-CONH2 ; or -COO-(C1 _- C6)alkyl (wherein alkyl is optionally substituted with one or more halogens) )
is; and
n is 0, 1, 2, or 3;
A medicament according to any one of claims 6-10 or a method according to any one of claims 11-17 . (S) -3- [4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2, A medicament according to any one of claims 6 to 10 and 23 or a method according to any one of claims 11 to 17 and 23 , which is a 6-dione or a pharmaceutically acceptable salt thereof . (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2, A medicament according to any one of claims 1-10, 23 and 24 or a method according to any one of claims 11-17, 23 and 24, which is a 6-dione. (S)-3-[4-(4-morpholin-4-ylmethyl-benzyloxy)-1-oxo-1,3-dihydro-isoindol-2-yl]-piperidine-2, The medicament according to any one of claims 1-10, 23 and 24 or the method according to any one of claims 11-17, 23 and 24, which is the hydrochloride salt of 6-dione. The immunomodulatory compound is administered 0.1 mg to 1 mg or about 0.1 mg to 1 mg per day, 0.1 mg to 0.6 mg or about 0.1 mg to 0.6 mg, 0.1 mg to 0.3 mg or about 0.1 mg to 0.3 mg per day. , optionally administration of the immunomodulatory compound is daily for the duration of the cycling regimen, and/or
0.1 mg to about 100 mg or about 0.1 mg to about 100 mg; 0.1 mg to 50 mg or about 0.1 mg to 50 mg; 10 mg or about 0.1 mg to 10 mg, 0.1 mg to 5 mg or about 0.1 mg to 5 mg, 0.1 mg to 1 mg or about 0.1 mg to 1 mg, 1 mg to 100 mg or about 1 mg to 100 mg, 1 mg to 50 mg or about 1 mg to 50 mg, 1 mg to 25 mg or about 1 mg to 25 mg, 1 mg to 10 mg or about 1 mg to 10 mg, 1 mg to 5 mg or about 1 mg to 5 mg , 5 mg to 100 mg or about 5 mg to 100 mg, 5 mg to 50 mg or about 5 mg to 50 mg, 5 mg to 25 mg or about 5 mg to 25 mg, 5 mg to 10 mg or about 5 mg 10 mg, 10 mg to 100 mg or about 10 mg to 100 mg, 10 mg to 50 mg or about 10 mg to 50 mg, 10 mg to 25 mg or about 10 mg to 25 mg, 25 mg to 100 mg or about 25 mg to 100 mg, 25 mg to 50 mg or about 25 mg to 50 mg, or 50 mg to 100 mg or about 50 mg to 100 mg, inclusive, and optionally the amount is , a once daily amount of the immunomodulatory compound . said target antigen is associated with, specific for, and/or expressed on a cancer cell or tissue;
Optionally, said target antigen is B cell maturation antigen (BCMA), αvβ6 integrin (avb6 integrin), BAFF-R, B7-H3, B7-H6, carbonic anhydrase 9 (CA9; also known as CAIX or G250). cancer testis antigen, cancer/testis antigen 1B (CTAG; also known as NY-ESO-1 and LAGE-2), carcinoembryonic antigen (CEA), cyclin, cyclin A2, CC motif Chemokine ligand 1 (CCL-1), CD5, CD19, CD20, CD21, CD22, CD23, CD24, CD30, CD38, CD44, CD44v6, CD44v7/8, CD45, CD79a, CD79b, CD123, CD133, CD138, CD171, CS -1, chondroitin sulfate proteoglycan 4 (CSPG4), epidermal growth factor protein (EGFR), truncated epidermal growth factor protein (tEGFR), epidermal growth factor receptor type III mutation (EGFR vIII), epidermal glycoprotein 2 (EPG-2) ), epithelial glycoprotein 40 (EPG-40), ephrin B2, ephrin receptor A2 (EPHa2), estrogen receptor, Fc receptor-like 5 (FCRL5; also known as Fc receptor homolog 5 or FCRH5), Fetal acetylcholine receptor (fetal AchR), folate binding protein (FBP), folate receptor alpha, ganglioside GD2, O-acetylated GD2 (OGD2), ganglioside GD3, glycoprotein 100 (gp100), glypican-3 (GPC3 ), G protein-coupled receptor 5D (GPCR5D), Her2/neu (receptor tyrosine kinase erb-B2), Her3 (erb-B3), Her4 (erb-B4), erbB dimer, human high molecular weight-melanoma Related antigen (HMW-MAA), hepatitis B surface antigen, human leukocyte antigen A1 (HLA-A1), human leukocyte antigen A2 (HLA-A2), Ig kappa, Ig lambda, IL-22 receptor alpha (IL -22Rα), IL-13 receptor alpha 2 (IL-13Rα2), kinase insert domain receptor (kdr), L1 cell adhesion molecule (L1-CAM), CE7 epitope of L1-CAM, 8 family members containing leucine-rich repeats A (LRRC8A), Lewis Y, melanoma-associated antigen (MAGE)-A1, MAGE-A3, MAGE-A6, MAGE-A10, mesothelin (MSLN) ), c-Met, mouse cytomegalovirus (CMV), mucin 1 (MUC1), MUC16, natural killer group 2 member D (NKG2D) ligand, Melan A (MART-1), neuronal cell adhesion molecule (NCAM), tumor Fetal antigen, preferentially expressed melanoma antigen (PRAME), progesterone receptor, prostate-specific antigen, prostate stem cell antigen (PSCA), prostate-specific membrane antigen (PSMA), ROR1, survivin, TACI, trophoblast glycoprotein (TPBG; 5T4) ), tumor-associated glycoprotein 72 (TAG72), tyrosinase-related protein 1 (TRP1; also known as TYRP1 or gp75), tyrosinase-related protein 2 (TRP2; dopachrome tautomerase, dopachrome delta- isomerase, or DCT), vascular endothelial growth factor receptor (VEGFR), vascular endothelial growth factor receptor 2 (VEGFR2), Wilms tumor 1 (WT-1), pathogen-specific or pathogen-expressed antigen selected from
A medicament according to any one of claims 1-10 and 18-27 or a method according to any one of claims 14 and 16-27. claims 1-10, wherein said target antigen is CD20, CD19, CD22, ROR1, CD45, CD21, CD5, CD33, Ig kappa, Ig lambda, CD79a, CD79b, or CD30 , optionally CD19, and A medicament according to any one of claims 18-28 or a method according to any one of claims 14 and 16-28 . said target antigen is BCMA, G protein-coupled receptor class C group 5 member D (GPRC5D), CD38 (cyclic ADP ribose hydrolase), CD138 (syndecan-1, syndecan, SYN-1), CS-1 (CS1, CD2 subset 1, CRACC, SLAMF7, CD319 and 19A24), BAFF-R, TACI, or FcRH5 , optionally BCMA, according to any one of claims 1-10 and 18-28. Or the method of any one of claims 14 and 16-28 . The administration of said immunomodulatory compound is at or about 3 months or more than 3 months, 4 months or about 4 months or more than 4 months, 5 months or about 5 months after initiation of administration of the composition for T cell therapy. or lasting for more than 5 months, or for a period extending from or about 6 months or more than 6 months , optionally from 3 months or from 3 months or about 3 months to 6 months or 6 months The medicament according to any one of claims 1 to 10 and 18 to 30 , wherein 32. According to any one of claims 1-3, 5-10 and 18-31, characterized in that administration of the immunomodulatory compound is initiated subsequent to initiation of administration of the composition for T-cell therapy. medicine. administration of said immunomodulatory compound is initiated at or after the peak or maximum level of T cells of the composition for T cell therapy is detectable in the blood of the subject ;
1 hour, 2 hours, 6 hours, 12 hours, 24 hours, 48 hours, 96 hours, 4 days, 5 days, 6 days, or within 7 days, 14 days, 15 days, 21 days, 24 days, 28 days, 30 days, 36 days, 42 days, 60 days, 72 days, or 90 days, or approximately 1 hour, 2 hours, 6 hours; 12 hours, 24 hours, 48 hours, 96 hours, 4 days, 5 days, 6 days, or 7 days, 14 days, 15 days, 21 days, 24 days, 28 days, 30 days, 36 days, 42 days, 60 days days, 72 days, or 90 days, and/or
at least 1 day or about at least 1 day, at least 2 days or about at least 2 days, at least 3 days or about at least 3 days after initiation of administration of the composition for T cell therapy; at least 4 days or about at least 4 days, at least 5 days or about at least 5 days, at least 6 days or about at least 6 days, at least 7 days or about at least 7 days, at least 8 days or about at least 8 days, at least 9 days or about at least 9 days, at least 10 days, or about at least 10 days, at least 12 days, or at least about 12 days, at least 14 days, or about at least 14 days, at least 15 days, or at least about 15 days, at least 21 days, or about at least 21 days, at least 24 days or at least about 24 days, at least 28 days or about at least 28 days, at least 30 days or about at least 30 days, at least 35 days or about at least 35 days, or at least 42 days or about at least 42 days, at least 60 days or about after at least 60 days, or after at least 90 days or about at least 90 days;
The medicament according to any one of claims 1-3 , 5-10 and 18-32 , characterized in that 32. Any one of claims 1-4, 10 and 18-31, characterized in that administration of said immunomodulatory compound is initiated prior to initiation of administration of the composition for T cell therapy. medicine. The immunomodulatory compound is 0-30 days or about 0-30 days, 0-15 days or about 0-15 days, 0-6 days or about 0-6 days before initiation of the composition for T cell therapy , 0 to 96 hours or about 0 to 96 hours before, 0 to 24 hours or about 0 to 24 hours before, 0 to 12 hours or about 0 to 12 hours before, 0 to 6 hours or about 0 to 6 hours before hours before, or 0-2 hours before or about 0-2 hours before, 2-15 days before or about 2-15 days before, 2-6 hours before or about 2-6 hours before, 2-96 hours before or 2 to 96 hours, 2 to 24 hours, or 2 to 24 hours, 2 to 12 hours, or 2 to 12 hours, 2 to 6 hours, or 2 to 6 hours 6 hours to 30 days before or about 6 hours to 30 days before 6 to 96 hours before, 6 to 24 hours or about 6 to 24 hours before, 6 to 12 hours or about 6 to 12 hours before, 12 to 30 days or about 12 to 30 hours before, 12 hours to 15 days ago or about 12 hours to 15 days ago, 12 hours to 6 days ago or about 12 hours to 6 days ago, 12 hours to 96 hours ago or about 12 hours to 96 hours before 24 hours to 30 days ago, or about 24 hours to 30 days before, 24 hours to 15 days before, or about 24 hours to 15 days before, 24 hours to 6 days before, or about 24 hours to 6 days before, 24 hours to 96 hours before before or about 24 hours to 96 hours before, 96 hours to 30 days before or about 96 hours to 30 days before, 96 hours to 15 days before or about 96 hours to 15 days before, 96 hours to 6 days before or about 96 hours to 6 days before, 6 days to 30 days or about 6 to 30 days, 6 to 15 days or about 6 to 15 days, or 15 to 30 days or about 15 to 30 days before The medicament according to any one of 1-4, 10, 18-31 and 34. optionally, at the start of administration of said immunomodulatory compound, the subject does not exhibit severe toxicity following administration of the composition for T cell therapy;
(a) said severe toxicity is severe cytokine release syndrome (CRS), optionally grade 3 or greater, prolonged grade 3 or greater, or grade 4 or 5 CRS; and/or
(b) said severe toxicity is severe neurotoxicity, optionally grade 3 or greater, chronic grade 3 or greater, or grade 4 or 5 neurotoxicity;
A medicament according to any one of claims 1-10 and 18-35. administration of the immunomodulatory compound
(a) optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agent, as compared to the absence of said administration of said immunomodulatory compound; resulting in increased antigen-specific or antigen receptor-driven activity of naive or non-exhausted T cells in the subject ;
( b) optionally comprising T cells expressing said recombinant receptor after exposure of said T cells to an antigen or to an antigen receptor specific agent, as compared to the absence of said administration of said immunomodulatory compound; prevents, suppresses, or delays the onset of an exhausted phenotype in T cells of naive or non-exhausted T cells in a subject; or (c) in a subject, compared to the absence of said administration of said subject. administration in an amount, frequency, and/or duration effective to reverse the exhaustion phenotype in exhausted T cells, optionally including T cells expressing said recombinant receptor. The medicament according to any one of claims 1-9 and 18-36, wherein the wasting phenotype for a T cell or population of T cells is
indicating the level or degree of surface expression on one or more T cells or surface expression of one or more exhaustion markers, optionally 2, 3, 4, 5, or 6 exhaustion markers an increase in the percentage of said population of T cells compared to a reference T cell population under the same conditions; or an increase in activity exhibited by said T cell or population of T cells upon exposure to an antigen or antigen receptor specific agent. including a decrease in the level or degree compared to a reference T cell population under the same conditions;
Optionally, said level, degree, or percentage increase or decrease is 1.2-fold or about 1.2-fold, 1.5-fold or about 1.5-fold, 2.0-fold or about 2.0-fold, 3-fold or about 3-fold, 4-fold or about 4-fold , 5-fold or about 5-fold, 6-fold or about 6-fold, 7-fold or about 7-fold, 8-fold or about 8-fold, 9-fold or about 9-fold, 10-fold or about 10-fold, or more,
A medicament according to any one of claims 6-10 and 18-37 or a method according to any one of claims 11-37 . Said reference T cell population is optionally known to have a non-exhausted phenotype from the same subject from which the one or more T cells with an exhausted phenotype are derived or of the same species as the subject The medicament of claim 38 or the medicament of claim 38, which is a population of T cells, a population of naive T cells, a population of central memory T cells, or a population of stem central memory T cells Method. optionally in PD-1, CTLA-4, TIM-3, LAG-3, BTLA, 2B4, CD160, CD39, VISTA, and TIGIT, wherein said one or more exhaustion markers are inhibitory receptors 40. A medicament according to claim 38 or 39 or a method according to one of claims 38 or 39, selected from : said activity is one or more of the production of one or a combination of proliferative, cytotoxic, or inflammatory cytokines, optionally one or a combination of said cytokines is IL-2, IFN-gamma , and TNF- alpha . Exposure to said antigen or antigen receptor specific agent comprises incubation with an antigen or antigen receptor specific agent, optionally wherein said antigen or antigen receptor specific agent binds to the recombinant receptor. A medicament according to any one of claims 38 to 41 or a medicament according to any one of claims 38 to 41, comprising an agent, a target antigen, and/or an antigen-expressing target cell, optionally a cell of a cancer Method. The medicament of any one of claims 1-10 and 18-42 or any of claims 14 and 16-42 , wherein said recombinant antigen receptor is a chimeric antigen receptor that specifically binds to a target antigen or the method described in item 1. T cell dose of 1×10 ⁵ to 5×10 ⁸ or about 1×10 ⁵ to 5×10 ⁸ total CAR-expressing T cells, 1×10 ⁶ to 2.5×10 ⁸ or about 1×10 ⁶ to 2.5 ×10 ⁸ total CAR-expressing T cells, 5×10 ⁶ to 1×10 ⁸ or about 5×10 ⁶ to 1×10 ⁸ total CAR-expressing T cells, 1×10 ⁷ to 2.5×10 ⁸ or about 1× Contains 10 ⁷ to 2.5×10 ⁸ total CAR-expressing T cells, 5×10 ⁷ to 1×10 ⁸ or approximately 5×10 ⁷ to 1×10 ⁸ total CAR-expressing T cells (each inclusive) , and/or
The dose of T cells is at least 1×10 ⁵ or at least about 1×10 ⁵ CAR-expressing cells, at least 2.5×10 ⁵ or at least about 2.5×10 ⁵ CAR-expressing cells, at least 5×10 ⁵ or at least about 5× 10 ⁵ CAR-expressing cells, at least 1 x 10 ⁶ or at least about 1 x 10 ⁶ CAR-expressing cells, at least 2.5 x 10 ⁶ or at least about 2.5 x 10 ⁶ CAR-expressing cells, at least 5 x 10 ⁶ or at least about 5 x10 ⁶ CAR-expressing cells, at least 1 x 10 ⁷ or at least about 1 x 10 ⁷ CAR-expressing cells, at least 2.5 x 10 ⁷ or at least about 2.5 x 10 ⁷ CAR-expressing cells, at least 5 x 10 ⁷ or at least about 5×10 ⁷ CAR-expressing cells, at least 1×10 ⁸ or at least about 1×10 ⁸ CAR-expressing cells, at least 2.5×10 ⁸ or at least about 2.5×10 ⁸ CAR-expressing cells, or at least 5×10 ⁸ or comprising at least about 5×10 ⁸ CAR-expressing cells,
A medicament according to any one of claims 1-7 and 10-43. The medicament according to any one of claims 1-10 and 18-44, wherein said T cells are autologous to the subject. The medicament according to any one of claims 1-10 and 18-44, wherein said T cells are allogeneic to the subject. the subject has been administered one or more compositions for lymphodepletion therapy comprising fludarabine and/or cyclophosphamide immediately prior to administration of said composition for T cell therapy ; A medicament according to any one of claims 1-10 and 18-46. The lymphocyte depleting therapy is about 200-400 mg/m ² , optionally 300 mg/m ² or about 300 mg/m ² inclusive of cyclophosphamide, and/or about 20-40 mg/m 2 mg/m ² , optionally 30 mg/m ² fludarabine is administered daily for 2-4 days, optionally 3 days, or said lymphocyte depletion therapy comprises about 500 mg/m 48. A medicament according to claim 47 , characterized in that ^m2 of cyclophosphamide is administered. At least 35%, at least 40%, or at least 50% of treated subjects are durable for 6 or more than 6 months or 9 or more than 9 months, or at least 60 of the subjects achieve CR achieve a complete response (CR) that is durable in , 70, 80, 90, or 95%; and/or
At least 60, 70, 80, 90, or 95% of subjects achieving a CR by 6 months for 3 months or more than 3 months and/or 6 months or more than 6 months and/or more than 9 months, remain in response, remain in CR, and/or are alive or alive without exacerbation; and/or
At least 50%, at least 60%, or at least 70% of the treated subjects achieve an objective response (OR), optionally the OR is 6 months or more or 9 months or more than 9 months or persistent in at least 60, 70, 80, 90, or 95% of subjects achieving OR; and/or
At least 60, 70, 80, 90, or 95% of subjects achieving OR by 6 months remain in response for 3 months or longer and/or 6 months or longer , or alive,
A medicament according to any one of claims 1-10 and 18-48.