JP7295360B2 - 固形腫瘍細胞及びエスケープバリアントを治療するための足場 - Google Patents
固形腫瘍細胞及びエスケープバリアントを治療するための足場 Download PDFInfo
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Description
本発明は、国立衛生研究所により授与されたCA181413に基づき政府支援によって行われた。政府は、本発明において一定の権利を有する。
本出願は、2016年12月21日に出願された米国仮特許出願第62/437,572号に対する優先権を主張し、この全内容は参照により組み込まれる。
50KBのファイルサイズである、2017年11月30日に作成された又はこの付近に作成された「1QJ8796.txt(Sequence Listing.txt)」というタイトルのコンピューター可読テキストファイルは、本出願についての配列表を含み、この全体は参照により本明細書に組み込まれる。
本開示は、固形腫瘍及びエスケープバリアント(escape variant)を治療し、がん再発に対する有効なワクチン接種を提供する移植可能な足場を提供する。足場は、遺伝的に再プログラムされたリンパ球、及びリンパ球活性化部分を含む。
本開示は、改善された移植可能な足場を提供することによって、がん免疫療法を進化させ続ける。本明細書に開示される移植可能な足場には、(i)遺伝的に再プログラムされたリンパ球、及び(ii)少なくとも1つのリンパ球活性化部分が播種されている。したがって、特定の実施形態では、これらの移植可能な足場は、US2016/0008399に記載されているものよりも形態が単純であり得る。特定の実施形態では、本明細書に開示される移植可能な足場はまた、STINGアゴニストを含んでもよい。これらの実施形態は、全身性炎症毒性を伴わず、毎日の注射を必要としない、STINGアゴニストの有効な免疫賦活効果を利用する機構を提供する。
脳腫瘍(膠芽腫):米国では、1年当たり推定10,000の新たな症例が見られる。現在、利用可能な根治療法は存在しない。膠芽腫は、非常に浸潤性の成長を示し、完全に切除することはできない。腫瘍の90%は、最初に切除された腫瘍から2cmの縁内で再発する。化学療法剤を負荷した生体材料ウェハは、膠芽腫のために米国食品医薬品局(FDA)により承認されている(GLIADEL(登録商標)、MGI Pharma,Inc.、Woodcliff Lake、NJ)。しかしながら、不十分な組織透過性に起因して、生体材料インプラント送達化学療法は、ほとんど効果がない。対照的に、本明細書に開示される足場から展開される腫瘍反応性リンパ球は、罹患組織に能動的に移動することができ、残存腫瘍細胞を探し出し、破壊する。
1.(i)マイクロパターン化金属薄膜を含む足場マトリックス内に配置された遺伝的に再プログラムされたリンパ球、及び(ii)リンパ球活性化部分を含むリンパ球足場。
2.STINGアゴニストをさらに含む、実施形態1に記載のリンパ球足場。
3.STINGアゴニストが、c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2及び/又はDMXAAを含む、実施形態2に記載のリンパ球足場。
4.STINGアゴニストが、c-diGMPを含む、実施形態2に記載のリンパ球足場。
5.薬物溶出ポリマーをさらに含む、実施形態1~4のいずれかに記載のリンパ球足場。
6.STINGアゴニストが、薬物溶出ポリマー内に埋め込まれている、実施形態5に記載のリンパ球足場。
7.薬物溶出ポリマーがPLGAを含む、実施形態5又は6に記載のリンパ球足場。
8.リンパ球が、T細胞及び/又はナチュラルキラー細胞を含む、実施形態1~7のいずれかに記載のリンパ球足場。
9.リンパ球が、CD8+T細胞を含む、実施形態1~8のいずれかに記載のリンパ球足場。
10.少なくとも2×106個のリンパ球を含む、実施形態1~9のいずれかに記載のリンパ球足場。
11.少なくとも7×106個のリンパ球を含む、実施形態1~9のいずれかに記載のリンパ球足場。
12.リンパ球活性化部分が、IL-15、又はCD3、CD28若しくはCD137に特異的な抗体のうちの少なくとも1つを含む、実施形態1~11のいずれかに記載のリンパ球足場。
13.リンパ球活性化部分が、CD3、CD128及びCD137に特異的な抗体を含む、実施形態1~12のいずれかに記載のリンパ球足場。
14.リンパ球活性化部分が、IL-15及びCD137を含む、実施形態1~13のいずれかに記載のリンパ球足場。
15.免疫刺激剤をさらに含む、実施形態1~14のいずれかに記載のリンパ球足場。
16.免疫刺激剤が、サイトカイン、抗体、小分子、siRNA、プラスミドDNA及び/又はワクチンアジュバントである、実施形態15に記載のリンパ球足場。
17.免疫刺激剤が、(i)CpG、Cpg-28、ポリ(I:C)、α-ガラクトセラミド、MPLA、VTX-2337、EMD1201081)イミキモド、MGN1703、G100、CBLB502、ヒルトノール及びイミキモドから選択されるToll様受容体リガンド並びに/又は(ii)17-ジメチルアミノエチルアミノ-17-デメトキシゲルダナマイシン)から選択される、実施形態15に記載のリンパ球足場。
18.免疫刺激剤が、薬物溶出ポリマー内に埋め込まれている、実施形態15~17のいずれかに記載のリンパ球足場。
19.リンパ球接着部分をさらに含む、実施形態1~18のいずれかに記載のリンパ球足場。
20.リンパ球接着部分及びリンパ球活性化部分が、共有結合している、実施形態19に記載のリンパ球足場。
21.リンパ球接着部分がフィブリンを含む、実施形態19又は20に記載のリンパ球足場。
22.リンパ球接着部分が、α1β1インテグリン、α2β1インテグリン、α4β1インテグリン、α5β1インテグリン又はリンパ球機能関連抗原(LFA-1)に結合するペプチドを含む、実施形態19~21のいずれかに記載のリンパ球足場。
23.リンパ球接着部分が、GFOGER(配列番号1)ペプチドを含む、実施形態19~22のいずれかに記載のリンパ球足場。
24.リンパ球接着部分が、配列番号1又は配列番号2のGFOGER(配列番号1)ペプチドを含む、実施形態19~23のいずれかに記載のリンパ球足場。
25.リンパ球接着部分が、ICAM-1ペプチドを含む、実施形態19~24のいずれかに記載のリンパ球足場。
26.リンパ球接着部分が、配列番号3のICAM-1ペプチドを含む、実施形態19~25のいずれかに記載のリンパ球足場。
27.リンパ球接着部分が、FNIII7~10ペプチドを含む、実施形態19~26のいずれかに記載のリンパ球足場。
28.リンパ球接着部分が、配列番号4のFNIII7~10ペプチドを含む、実施形態19~27のいずれかに記載のリンパ球足場。
29.STINGアゴニスト及び/又はリンパ球活性化部分が、足場マトリックスと連結している、実施形態2~28のいずれかに記載のリンパ球足場。
30.STINGアゴニスト及び/又はリンパ球活性化部分が、足場マトリックス内に埋め込まれている、実施形態2~29のいずれかに記載のリンパ球足場。
31.STINGアゴニスト及び/又はリンパ球活性化部分が、足場マトリックスの表面の少なくとも一部を覆う生物活性コーティング内にある、実施形態2~30のいずれかに記載のリンパ球足場。
32.生物活性コーティングが、薬物溶出ポリマーを含む、実施形態31に記載のリンパ球足場。
33.リンパ球接着部分をさらに含み、STINGアゴニストが薬物溶出ポリマー内にあり、薬物溶出ポリマーが足場マトリックスの表面上に単層を形成し、リンパ球接着部分が薬物溶出ポリマーを直接コーティングしている、実施形態32に記載のリンパ球足場。
34.STINGアゴニスト及び/又はリンパ球活性化部分が、粒子と連結している、実施形態2~33のいずれかに記載のリンパ球足場。
35.粒子が、足場と連結しており、及び/又は足場マトリックス内に埋め込まれている、実施形態34に記載のリンパ球足場。
36.STINGアゴニスト及び/又はリンパ球活性化部分が、原細胞のリポソームと結合している、実施形態2~35のいずれかに記載のリンパ球足場。
37.原細胞と足場マトリックス内のリンパ球との比が、0.5:1、1:1、5:1又は10:1である、実施形態36のリンパ球足場。
38.7×106個~1×1010個の原細胞を含む、実施形態1~37のいずれかに記載のリンパ球足場。
39.マイクロパターン化金属薄膜が、TFNマイクロメッシュを含む、実施形態1~38のいずれかに記載のリンパ球足場。
40.足場マトリックス、遺伝的に再プログラムされたリンパ球及び3つのリンパ球活性化部分からなる、リンパ球足場。
41.足場マトリックスが、アルギネート足場、コラーゲン/アルギネート足場、キトサン足場、自己集合ペプチド足場、メソ多孔質シリカ足場、マイクロパターン化金属薄膜足場又はPLGA足場を含む、実施形態40に記載のリンパ球足場。
42.マイクロパターン化金属薄膜足場が、TFNマイクロメッシュ足場を含む、実施形態40又は41に記載のリンパ球足場。
43.足場マトリックスが、アルギネート足場を含む、実施形態40~42のいずれかに記載のリンパ球足場。
44.足場マトリックスが、ポリマーカルシウム架橋アルギネート足場を含む、実施形態40~43のいずれかに記載のリンパ球足場。
45.遺伝的に再プログラムされたリンパ球が、遺伝的に再プログラムされたT細胞及び/又はナチュラルキラー細胞である、実施形態40~44のいずれかに記載のリンパ球足場。
46.遺伝的に再プログラムされたリンパ球が、CD8+T細胞である、実施形態40~45のいずれかに記載のリンパ球足場。
47.少なくとも2×106個の遺伝的に再プログラムされたリンパ球を含む、実施形態40~46のいずれかに記載のリンパ球足場。
48.少なくとも7×106個の遺伝的に再プログラムされたリンパ球を含む、実施形態40~46のいずれかに記載のリンパ球足場。
49.リンパ球活性化部分が、CD3、CD28及び/又はCD137に特異的な抗体を含む、実施形態40~48のいずれかに記載のリンパ球足場。
50.リンパ球活性化部分が、足場と連結している、実施形態40~49のいずれかに記載のリンパ球足場。
51.リンパ球活性化部分が、足場内に埋め込まれている、実施形態40~50のいずれかに記載のリンパ球足場。
52.足場マトリックス、遺伝的に再プログラムされたリンパ球、及びリンパ球活性化部分を含むリンパ球足場。
53.STINGアゴニストをさらに含む、実施形態52に記載のリンパ球足場。
54.STINGアゴニストが、c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2及び/又はDMXAAを含む、実施形態53に記載のリンパ球足場。
55.STINGアゴニストが、c-diGMPを含む、実施形態52又は53に記載のリンパ球足場。
56.遺伝的に再プログラムされたリンパ球が、遺伝的に再プログラムされたT細胞及び/又はナチュラルキラー細胞である、実施形態52~55のいずれかに記載のリンパ球足場。
57.遺伝的に再プログラムされたリンパ球が、CD8+T細胞である、実施形態52~56のいずれかに記載のリンパ球足場。
58.少なくとも2×106個又は少なくとも7×106個の遺伝的に再プログラムされたリンパ球を含む、実施形態52~57のいずれかに記載のリンパ球足場。
59.リンパ球活性化部分が、IL-15並びに/又はCD3、CD28及び/若しくはCD137に特異的な抗体を含む、実施形態52~58のいずれかに記載のリンパ球足場。
60.免疫刺激剤をさらに含む、実施形態52~59のいずれかに記載のリンパ球足場。
61.免疫刺激剤が、サイトカイン、抗体、小分子、siRNA、プラスミドDNA及び/又はワクチンアジュバントを含む、実施形態60に記載のリンパ球足場。
62.免疫刺激剤が、(i)CpG、Cpg-28、ポリ(I:C)、α-ガラクトセラミド、MPLA、VTX-2337、EMD1201081)イミキモド、MGN1703、G100、CBLB502、ヒルトノール及びイミキモドから選択されるToll様受容体リガンド並びに/又は(ii)17-ジメチルアミノエチルアミノ-17-デメトキシゲルダナマイシン)を含む、実施形態60又は61に記載のリンパ球足場。
63.リンパ球接着部分をさらに含む、実施形態52~62のいずれかに記載のリンパ球足場。
64.リンパ球接着部分がフィブリンを含む、実施形態63に記載のリンパ球足場。
65.リンパ球接着部分が、α1β1インテグリン、α2β1インテグリン、α4β1インテグリン、α5β1インテグリン又はリンパ球機能関連抗原(LFA-1)に結合するペプチドを含む、実施形態63又は64に記載のリンパ球足場。
66.リンパ球接着部分が、GFOGER(配列番号1)ペプチドを含む、実施形態63~65のいずれかに記載のリンパ球足場。
67.リンパ球接着部分が、配列番号1又は配列番号2のGFOGER(配列番号1)ペプチドを含む、実施形態63~66のいずれかに記載のリンパ球足場。
68.リンパ球接着部分が、ICAM-1ペプチドを含む、実施形態63~67のいずれかに記載のリンパ球足場。
69.リンパ球接着部分が、配列番号3のICAM-1ペプチドを含む、実施形態63~68のいずれかに記載のリンパ球足場。
70.リンパ球接着部分が、FNIII7~10ペプチドを含む、実施形態63~69のいずれかに記載のリンパ球足場。
71.リンパ球接着部分が、配列番号4のFNIII7~10ペプチドを含む、実施形態63~70のいずれかに記載のリンパ球足場。
72.STINGアゴニスト及び/又はリンパ球活性化部分が、足場マトリックスと連結している、実施形態53~71のいずれかに記載のリンパ球足場。
73.STINGアゴニスト及び/又はリンパ球活性化部分が、足場マトリックス内に埋め込まれている、実施形態53~72のいずれかに記載のリンパ球足場。
74.STINGアゴニスト及び/又はリンパ球活性化部分が、足場マトリックスの表面の少なくとも一部を覆う生物活性コーティング内にある、実施形態53~73のいずれかに記載のリンパ球足場。
75.STINGアゴニスト及び/又はリンパ球活性化部分が、粒子と連結している、実施形態53~74のいずれかに記載のリンパ球足場。
76.粒子が、足場マトリックスと連結している及び/又は足場マトリックス内に埋め込まれている、実施形態75に記載のリンパ球足場。
77.STINGアゴニスト及び/又はリンパ球活性化部分が、原細胞のリポソームと結合している、実施形態53~76のいずれかに記載のリンパ球足場。
78.原細胞と足場マトリックス内のリンパ球との比が、0.5:1、1:1、5:1又は10:1である、実施形態77のリンパ球足場。
79.7×106個~1×1010個の原細胞を含む、実施形態53~78のいずれかに記載のリンパ球足場。
80.足場マトリックスが、アルギネート足場、コラーゲン/アルギネート足場、キトサン足場、自己集合ペプチド足場、メソ多孔質シリカ足場、マイクロパターン化金属薄膜足場又はPLGA足場を含む、実施形態52~79のいずれかに記載のリンパ球足場。
81.マイクロパターン化金属薄膜足場が、TFNマイクロメッシュ足場を含む、実施形態80に記載のリンパ球足場。
82.足場マトリックスが、アルギネート足場を含む、実施形態80又は81に記載のリンパ球足場。
83.足場マトリックスが、ポリマーカルシウム架橋アルギネート足場を含む、実施形態80~82のいずれかに記載のリンパ球足場。
84.(i)足場マトリックス材料、(ii)抗がん活性を有するナチュラルキラー細胞並びに(iii)IL-15、及びCD137に特異的な抗体を含むリンパ球活性化部分を含むリンパ球足場。
85.足場マトリックス材料が、マイクロパターン化金属薄膜を含む、実施形態84に記載のリンパ球足場。
86.マイクロパターン化金属薄膜が、TFNマイクロメッシュを含む、実施形態84又は85に記載のリンパ球足場。
87.STINGアゴニストをさらに含む、実施形態84~86のいずれかに記載のリンパ球足場。
88.STINGアゴニストが、c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2及び/又はDMXAAを含む、実施形態113に記載のリンパ球足場。
89.薬物溶出ポリマーをさらに含む、実施形態84~88のいずれかに記載のリンパ球足場。
90.薬物溶出ポリマーがPLGAを含む、実施形態89に記載のリンパ球足場。
91.STINGアゴニストが、薬物溶出ポリマー内に埋め込まれている、実施形態87又は88に記載のリンパ球足場。
92.リンパ球接着部分をさらに含む、実施形態84~91のいずれかに記載のリンパ球足場。
93.リンパ球接着部分がフィブリンを含む、実施形態92に記載のリンパ球足場。
94.リンパ球接着部分が、α1β1インテグリン、α2β1インテグリン、α4β1インテグリン、α5β1インテグリン又はリンパ球機能関連抗原(LFA-1)に結合するペプチドを含む、実施形態92又は93に記載のリンパ球足場。
95.リンパ球接着部分が、GFOGER(配列番号1)ペプチドを含む、実施形態92~94のいずれかに記載のリンパ球足場。
96.リンパ球接着部分が、配列番号1又は配列番号2のGFOGER(配列番号1)ペプチドを含む、実施形態92~95のいずれかに記載のリンパ球足場。
97.リンパ球接着部分が、ICAM-1ペプチドを含む、実施形態84~96のいずれかに記載のリンパ球足場。
98.リンパ球接着部分が、配列番号3のICAM-1ペプチドを含む、実施形態84~97のいずれかに記載のリンパ球足場。
99.リンパ球接着部分が、FNIII7~10ペプチドを含む、実施形態84~98のいずれかに記載のリンパ球足場。
100.リンパ球接着部分が、配列番号4のFNIII7~10ペプチドを含む、実施形態84~99のいずれかに記載のリンパ球足場。
101.対象におけるエスケープバリアント腫瘍細胞を含む不均一な固形腫瘍を治療する方法であって、対象における不均一な固形腫瘍の破壊を導くのに十分な不均一な固形腫瘍細胞の近位内に、実施形態1~100のいずれかに記載のリンパ球足場を対象に移植し、それによってエスケープバリアント腫瘍細胞を含む不均一な固形腫瘍を治療するステップを含む、方法。
102.がん再発の発生に対して対象にワクチン接種をする方法であって、実施形態1~100のいずれかに記載のリンパ球足場を、対象の不均一な固形腫瘍の近位内に、又は対象の固形腫瘍切除床内に移植し、それによってがん再発の発生に対して対象にワクチン接種をするステップを含む、方法。
103.腫瘍細胞の治療を必要とする対象において腫瘍細胞を治療する方法であって、実施形態1~100のいずれかに記載のリンパ球足場を、腫瘍切除床内で対象に移植し、それによって対象において腫瘍細胞を治療するステップを含む、方法。
104.治療される腫瘍細胞が、副腎がん細胞、脳がん細胞、乳がん細胞、子宮頸がん細胞、結腸がん細胞、大腸がん細胞、耳、鼻及び咽喉(ENT)がん細胞、子宮内膜がん細胞、食道がん細胞、消化管がん細胞、グリオーマ細胞、頭頸部がん細胞、腸がん細胞、腎臓がん細胞、肝臓がん細胞、肺がん細胞、リンパ節がん細胞、黒色腫細胞、神経芽腫細胞、卵巣がん細胞、膵臓がん細胞、前立腺がん細胞、直腸がん細胞、セミノーマ細胞、皮膚がん細胞、胃がん細胞、奇形腫細胞、甲状腺がん細胞又は子宮がん細胞である、実施形態103に記載の方法。
105.治療される腫瘍細胞が、膠芽腫細胞、膵臓腺がん細胞又は卵巣がん細胞である、実施形態103に記載の方法。
106.原発腫瘍の切除後、転移性再発によって引き起こされる外科治療の失敗を低減させる方法であって、実施形態1~100のいずれかに記載のリンパ球足場を対象の腫瘍切除床に投与し、それによって原発腫瘍の切除後、転移性再発によって引き起こされる外科治療の失敗を低減させるステップを含む、方法。
107.原発腫瘍が、セミノーマ細胞、黒色腫細胞、奇形腫細胞、神経芽腫細胞、グリオーマ細胞、直腸がん細胞、子宮内膜がん細胞、腎臓がん細胞、副腎がん細胞、甲状腺がん細胞、皮膚がん細胞、脳がん細胞、子宮頸がん細胞、腸がん細胞、肝臓がん細胞、結腸がん細胞、胃がん細胞、頭頸部がん細胞、消化管がん細胞、リンパ節がん細胞、食道がん細胞、大腸がん細胞、膵臓がん細胞、耳、鼻及び咽喉(ENT)がん細胞、乳がん細胞、前立腺がん細胞、子宮がん細胞、卵巣がん細胞又は肺がん細胞を含む、実施形態106に記載の方法。
108.がんについて対象を治療する方法であって、TFNマイクロメッシュ、遺伝的に修飾されたリンパ球、及びリンパ球活性化部分を含むリンパ球足場によりコーティングされた医療装置を対象に移植するステップを含む、方法。
109.移植するステップが、低侵襲性処置を含む、実施形態108に記載の方法。
110.医療装置が、ステントを含む、実施形態108に記載の方法。
111.対象における固形腫瘍を治療するためのリンパ球足場を形成するためのキットであって、(i)足場マトリックス、及び(ii)CD3、CD28及びCD137に特異的な抗体を含むリンパ球活性化部分を含む、キット。
112.多孔質粒子をさらに含む、実施形態111に記載のキット。
113.リポソームをさらに含む、実施形態111又は112に記載のキット。
114.原細胞をさらに含む、実施形態111~113のいずれかに記載のキット。
115.STINGアゴニストをさらに含む、実施形態111~114のいずれかに記載のキット。
116.STINGアゴニストが、c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2及び/又はDMXAAを含む、実施形態115に記載のキット。
117.STINGアゴニストが、c-diGMPを含む、実施形態115に記載のキット。
118.免疫刺激剤をさらに含む、実施形態111~117のいずれかに記載のキット。
119.免疫刺激剤が、サイトカイン、抗体、小分子、siRNA、プラスミドDNA及び/又はワクチンアジュバントを含む、実施形態118に記載のキット。
120.免疫刺激剤が、(i)CpG、Cpg-28、ポリ(I:C)、α-ガラクトセラミド、MPLA、VTX-2337、EMD1201081)イミキモド、MGN1703、G100、CBLB502、ヒルトノール及びイミキモドから選択されるToll様受容体リガンド並びに/又は(ii)17-ジメチルアミノエチルアミノ-17-デメトキシゲルダナマイシン)を含む、実施形態118又は119に記載のキット。
121.リンパ球接着部分をさらに含む、実施形態111~120のいずれかに記載のキット。
122.リンパ球接着部分がフィブリンを含む、実施形態121に記載のキット。
123.リンパ球接着部分が、α1β1インテグリン、α2β1インテグリン、α4β1インテグリン、α5β1インテグリン又はリンパ球機能関連抗原(LFA-1)に結合するペプチドを含む、実施形態121又は122に記載のキット。
124.リンパ球接着部分が、GFOGER(配列番号1)ペプチドを含む、実施形態121~123のいずれかに記載のキット。
125.リンパ球接着部分が、配列番号1又は配列番号2のGFOGER(配列番号1)ペプチドを含む、実施形態121~124のいずれかに記載のキット。
126.リンパ球接着部分が、ICAM-1ペプチドを含む、実施形態121~125のいずれかに記載のキット。
127.リンパ球接着部分が、配列番号3のICAM-1ペプチドを含む、実施形態121~126のいずれかに記載のキット。
128.リンパ球接着部分が、FNIII7~10ペプチドを含む、実施形態121~127のいずれかに記載のキット。
129.リンパ球接着部分が、配列番号4のFNIII7~10ペプチドを含む、実施形態121~128のいずれかに記載のキット。
130.7×106~1×1010個の粒子、リポソーム又は原細胞を含む、実施形態111~129のいずれかに記載のキット。
131.遺伝的に再プログラムされたリンパ球をさらに含む、実施形態111~130のいずれかに記載のキット。
132.遺伝的に再プログラムされたリンパ球が、T細胞及び/又はナチュラルキラー細胞を含む、実施形態131に記載のキット。
133.遺伝的に再プログラムされたリンパ球が、CD8+T細胞を含む、実施形態131又は132に記載のキット。
134.リンパ球が、少なくとも7×106個のリンパ球を含む、実施形態131~133のいずれかに記載のキット。
135.足場マトリックスが、アルギネート、コラーゲン、キトサン、自己集合ペプチド、メソ多孔質シリカ、TFNマイクロメッシュ又はPLGAを含む、実施形態131~134のいずれかに記載のキット。
136.足場マトリックスが、アルギネートを含む、実施形態135に記載のキット。
137.カルシウムをさらに含む、実施形態111~136のいずれかに記載のキット。
138.薬物溶出ポリマーをさらに含む、実施形態111~137のいずれかに記載のキット。
139.薬物溶出ポリマーが、足場マトリックス上にコーティングされる、実施形態138に記載のキット。
140.STINGアゴニスト又は免疫刺激剤が、薬物溶出ポリマー内に埋め込まれている、実施形態138に記載のキット。
141.薬物溶出ポリマーがPLGAを含む、実施形態111~140のいずれかに記載のキット。
142.(i)マイクロパターン化金属薄膜足場、(ii)遺伝的に再プログラムされたリンパ球、及び(iii)リンパ球活性化部分を含む、移植可能な医療装置。
143.STINGアゴニスト及び/又は免疫刺激剤をさらに含む、実施形態142に記載の移植可能な医療装置。
144.薬物溶出ポリマーをさらに含み、STINGアゴニスト及び/又は免疫刺激剤が、薬物溶出ポリマー内に埋め込まれている、実施形態143に記載の移植可能な医療装置。
145.マイクロパターン化金属薄膜足場が、三次元形状を有する、実施形態142~144のいずれかに記載の移植可能な医療装置。
146.三次元形状が円筒形である、実施形態145に記載の移植可能な医療装置。
147.ステントを含む、実施形態142~146のいずれかに記載の移植可能な医療装置。
148.低侵襲性医療装置を含む、実施形態142~147のいずれかに記載の移植可能な医療装置。
149.マイクロパターン化金属薄膜足場が、層内に積層される、実施形態142~148のいずれかに記載の移植可能な医療装置。
150.マイクロパターン化金属薄膜が、TFNマイクロメッシュを含む、実施形態142~149のいずれかに記載の移植可能な医療装置。
151.遺伝的に再プログラムされたリンパ球が、少なくとも細胞7×106個/cm3の濃度にて存在する、実施形態142~150のいずれかに記載の移植可能な医療装置。
Claims (9)
- (i)薄膜ニチノール(TFN)マイクロメッシュを含む足場マトリックス内に配置された遺伝的に再プログラムされたリンパ球、(ii)フィブリンを含むリンパ球接着部分、及び(iii)CD137に特異的な抗体を含むリンパ球活性化部分を含む、リンパ球足場。
- 遺伝的に再プログラムされたリンパ球が、T細胞を含み、リンパ球活性化部分が、CD3、CD28及びCD137に特異的な抗体を含む、請求項1に記載のリンパ球足場。
- 遺伝的に再プログラムされたリンパ球が、ナチュラルキラー(NK)細胞を含み、リンパ球活性化部分が、インターロイキン15、及びCD137に特異的な抗体を含む、請求項1に記載のリンパ球足場。
- 遺伝的に再プログラムされたリンパ球が、T細胞及びNK細胞を含み、リンパ球活性化部分が、CD137に特異的な抗体を含む、請求項1に記載のリンパ球足場。
- STINGアゴニストをさらに含む、請求項1に記載のリンパ球足場。
- STINGアゴニストが、c-diGMP、c-diAMP、c-GAMP、c-AIMP、(3’,2’)c-AIMP、(2’,2’)c-AIMP、(2’,3’)c-AIMP、c-AIMP(S)、c-(dAMP-dIMP)、c-(dAMP-2’FdIMP)、c-(2’FdAMP-2’FdIMP)、(2’,3’)c-(AMP-2’FdIMP)、c-[2’FdAMP(S)-2’FdIMP(S)]、c-[2’FdAMP(S)-2’FdIMP(S)](POM)2及び/又はDMXAAを含む、請求項5に記載のリンパ球足場。
- 請求項1に記載のリンパ球足場を含む、対象におけるエスケープバリアント腫瘍細胞を含む不均一な固形腫瘍を治療するための医薬組成物であって、請求項1に記載のリンパ球足場は、対象における不均一な固形腫瘍の破壊を導くのに十分な不均一な固形腫瘍細胞の近位内に、移植され、それによってエスケープバリアント腫瘍細胞を含む不均一な固形腫瘍を治療する、医薬組成物。
- 治療される腫瘍細胞が、副腎がん細胞、脳がん細胞、乳がん細胞、子宮頸がん細胞、結腸がん細胞、大腸がん細胞、耳、鼻及び咽喉(ENT)がん細胞、子宮内膜がん細胞、食道がん細胞、消化管がん細胞、グリオーマ細胞、頭頸部がん細胞、腸がん細胞、腎臓がん細胞、肝臓がん細胞、肺がん細胞、リンパ節がん細胞、黒色腫細胞、神経芽腫細胞、卵巣がん細胞、膵臓がん細胞、前立腺がん細胞、直腸がん細胞、セミノーマ細胞、皮膚がん細胞、胃がん細胞、奇形腫細胞、甲状腺がん細胞又は子宮がん細胞である、請求項7に記載の医薬組成物。
- 治療される腫瘍細胞が、膠芽腫細胞、膵臓腺がん細胞又は卵巣がん細胞である、請求項7に記載の医薬組成物。
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- 2017-12-21 US US16/472,764 patent/US20190336532A1/en not_active Abandoned
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EP3558327A4 (en) | 2020-12-09 |
CN110167566A (zh) | 2019-08-23 |
JP2022130502A (ja) | 2022-09-06 |
US20190336532A1 (en) | 2019-11-07 |
EP3558327A1 (en) | 2019-10-30 |
US20220339195A1 (en) | 2022-10-27 |
JP2023065362A (ja) | 2023-05-12 |
EP4371584A2 (en) | 2024-05-22 |
WO2018119274A1 (en) | 2018-06-28 |
JP2020514280A (ja) | 2020-05-21 |
US20240033293A1 (en) | 2024-02-01 |
EP4371584A3 (en) | 2024-08-28 |
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