DK2817620T3 - System til immunterapi rettet mod tumorformering og -progression - Google Patents
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Claims (15)
1. Fremgangsmåde til identificering af regenereringsdygtige (C-RC)-populationer af cancerceller hos et individ, omfattende (a) at dyrke en tumorprøve opnået fra et individ under betingelser, der inducerer en stressreaktion i differentierende og differentierede celler, men tillader C-RC-celler at formere sig, og som aktiverer en regenerativ reaktion; (b) at isolere den dominerende, aktivt ekspanderende, hurtigst delende population af celler fra trin (a); og (c) at dyrke cellerne til 60 til 95 % konfluens til opnåelse af en population på 51 % til 100 % C-RC, hvor celledyrkningsbetingelserne er udvalgt fra gruppen bestående af: (i) serumfrit, defineret celledyrkningsmedium, der inducerer apoptose og/eller nekrose af de differentierende og differentierede celler, (ii) medium indeholdende cAMP-forøgende midler og (iii) medium udformet til at inhibere eller bryde celle-celle-adhæsion.
2. Fremgangsmåde ifølge krav 1, hvor mediet, der inducerer apoptose og/eller nekrose af cellerne, omfatter et middel udvalgt fra gruppen bestående af tumornekrosefaktor-alfa (TNF-α), interleukin 1-beta og interferongamma (IFN-y).
3. Fremgangsmåde ifølge krav 1, hvor mediet udformet til at inhibere eller bryde celle-celle-adhæsion omfatter et middel udvalgt fra gruppen bestående af nitrogenoxid, hydrokolloid, dextran og mindre end ca. 1 mM calcium.
4. Fremgangsmåde ifølge krav 1, hvor den dyrkede tumorprøve er et tumor-eksplantat, idet fremgangsmåden yderligere omfatter at bekræfte C-RC-cellernes tumorformerende potentiale.
5. Fremgangsmåde ifølge krav 1, yderligere omfattende at dyrke de isolerede celler fra trin (a), hvor 80 % til 100 % af cellerne opnået fra trin (c) er C-RC-celler udvalgt fra gruppen bestående af VSEC-, SDEC- og SCEC-celler.
6. Fremgangsmåde til identificering af C-RC-celle-specifikke T-celler, omfattende at blande C-RC-celler isoleret i henhold til fremgangsmåden ifølge krav 1 med isolerede CD8+ T-celler fra normale donorer eller cancerdonorer, og at isolere T-celler, der reagerer med de behandlede C-RC-celler, hvor de reaktive T-celler omfatter T-celle-receptorer (TCR), der er rettet mod et C-RC-specifikt antigen.
7. Fremgangsmåde ifølge krav 6, omfattende (et) yderligere trin udvalgt fra gruppen bestående af; (i) at behandle C-RC-cellerne med en interferon-gamma-agonist til øgning af ekspression af HLA-peptid-komplekser; (ii) at tilsætte en in v/Yro-aktiveringsprotokol, der selekterer for CD8+ T-celler, der er reaktive over for passende præsenteret peptidantigen i forbindelse med patientrelevante HLA-molekyler; (iii) at isolere det C-RC-specifikke antigen; (iv) at isolere og sekventere det C-RC-specifikke antigen; (v) at isolere det C-RC-specifikke antigen og fremstille antistoffer eller molekylære sonder til det C-RC-specifikke antigen; (vi) at isolere det C-RC-specifikke antigen, at fordøje det C-RC-specifikke antigen til fremstilling af en flerhed af peptider og præsentere et eller flere af peptiderne for CD8+ T-celler og udvælge T-celler, der er reaktive over for det ene eller de flere af peptiderne; og (vii) at klone T-celle-receptorerne fra de reaktive T-celler til fremstilling af et klonet TCR-konstrukt.
8. Fremgangsmåde ifølge krav 7, omfattende at sammenligne det C-RC-specifikke antigen, eller antistoffer eller sonder dertil, med antigen fra ikke-tumorceller eller celler af forskellige typer af tumorer.
9. Fremgangsmåde ifølge krav 7, yderligere omfattende at transducere en population af T-celler med det klonede TCR-konstrukt og at teste de transdu-cerede T-celler for deres evne til at binde og reagere på eksprimeret HLA-begrænset peptidkompleks.
10. Isoleret tumor-C-RC-cellepopulation fremstillet ved fremgangsmåden ifølge krav 1.
11. Isoleret tumorantigen, der kan opnås ved fremgangsmåden ifølge krav 7.
12. Klonet TCR, der kan opnås ved fremgangsmåden ifølge krav 7.
13. T-celler til anvendelse ved behandling af cancer hos en patient, hvor T-cellerne er transduceret med en ekspressionsvektor, der koder for T-celle-receptorer, der er reaktive over for det ene eller de flere antigener, der er identificeret eller opnået ved at analysere en cancerbiopsi fra patienten til bestemmelse af forekomsten af et eller flere antigener identificeret under anvendelse af fremgangsmåden ifølge krav 9, hvor T-cellerne er opnået fra patienten eller fra en donor, inden transduktion.
14. T-celler til anvendelse ifølge krav 13, hvor patienten er identificeret som værende positiv for et eller flere antigener med tilsvarende HLA klasse I-begrænsning.
15. T-celler til anvendelse ifølge krav 13, hvor T-cellerne er transduceret til at eksprimere cytokin eller adjuvans til at øge T-celle-responset.
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US201261601893P | 2012-02-22 | 2012-02-22 | |
PCT/US2013/027445 WO2013126785A1 (en) | 2012-02-22 | 2013-02-22 | A system for immunotherapy targeting tumor propagation and progression |
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GB201501175D0 (en) * | 2015-01-23 | 2015-03-11 | Univ Oslo Hf | A universal T-cell for personalised medicine |
US10767164B2 (en) | 2017-03-30 | 2020-09-08 | The Research Foundation For The State University Of New York | Microenvironments for self-assembly of islet organoids from stem cells differentiation |
CA3130930A1 (en) * | 2019-03-19 | 2020-09-24 | Kyuson Yun | Methods and systems for evaluation of cell samples |
CN112649614A (zh) * | 2020-12-09 | 2021-04-13 | 中国医学科学院肿瘤医院 | Cd8+肿瘤浸润淋巴细胞作为标志物在食管小细胞癌预后判断中的应用 |
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US6984522B2 (en) * | 2000-08-03 | 2006-01-10 | Regents Of The University Of Michigan | Isolation and use of solid tumor stem cells |
KR20060032958A (ko) | 2003-06-03 | 2006-04-18 | 올간 리커버리 시스템즈, 인코포레이티드 | 전구 세포의 분리 및 증식 |
US20070244046A1 (en) * | 2006-03-29 | 2007-10-18 | Margarita Gutova | Identification and characterization of cancer stem cells and methods of use |
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US7781179B2 (en) * | 2006-12-07 | 2010-08-24 | The Board Of Trustees Of The Leland Stanford Junior University | Identification and isolation of transitional cell carcinoma stem cells |
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US9945842B2 (en) * | 2010-09-03 | 2018-04-17 | Abbvie Stemcentrx Llc | Identification and enrichment of cell subpopulations |
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