Tsis ntev los no, qhov kev tshawb fawb tshiab kawg ntawm Chunhong Ma, Chunyang Li thiab Xinyin Liu los ntawm Qilu Medical College ntawm Shandong University tau luam tawm hauv phau ntawv Journal Science Translational Medicine.
Tom qab tshuaj ntsuam ntau dua 200,000 cov khoom sib txuas, pab pawg tshawb fawb tau txheeb xyuas qhov sib xyaw me me, ML-T7, uas yog lub hom phiaj TIM-3. Cov txiaj ntsig ntawm vivo thiab ex vivo thwmsim tau pom tias ML-T7 tuaj yeem txhim kho cov qog qog ua haujlwm ntawm CD8-zoo T-cells thiab CAR-T-cells, thiab qhov kev kho mob ib leeg ncaj qha cuam tshuam cov qog nqaij hlav hauv nas, thiab muaj kev sib koom ua ke nrog PD-1 inhibitors.
TIM-3 yog ib daim nyias nyias nrog cov qauv tsim tshwj xeeb hauv nws cov qauv IgV lub npe hu ua FG-CC 'cleft, uas yog qhov chaw ruaj khov heev rau nws cov ligand phosphatidylserine (PtdSer) thiab carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1).
TIM-3 yog ib daim nyias nyias nrog cov qauv tsim tshwj xeeb hauv nws cov qauv IgV lub npe hu ua FG-CC 'cleft, uas yog qhov chaw ruaj khov heev rau nws cov ligand phosphatidylserine (PtdSer) thiab carcinoembryonic antigen-associated cell adhesion molecule 1 (CEACAM1).
Hauv txoj kev tshawb no, pab pawg tau txheeb xyuas ML-T7 los ntawm 204,380 me me molecule tebchaw hauv Specs database los ntawm kev tshuaj ntsuam virtual ua ke nrog kev tshuaj ntsuam xyuas zoo.
Siv cov tswv yim xws li nto plasmon resonance (SRP) thiab molecular dynamics thiab siv lead ua qauv tshuaj ntsuam xyuas, pab neeg tau lees tias ML-T7 tuaj yeem tsom rau FG-CC 'cleft ntawm TIM-3 thiab muaj kev sib raug zoo dua rau TIM{{ 4}} dua PtdSer thiab CEACAM1. ML-T7 txhim kho nws txoj kev khi rau TIM-3 los ntawm FG-CC 'cleft, cuam tshuam kev khi ntawm TIM-3 rau PtdSer, CEACAM1 khi thiab kev sib cuam tshuam.
Kev tshuaj ntsuam thiab tus yam ntxwv ntawm ML-T7
Cov txiaj ntsig ntawm kev sim vitro thiab nas qauv kev sim tau pom tias los ntawm kev tsom mus rau TIM-3, ML-T7 muaj peev xwm txhawb kev muaj sia nyob, kev loj hlob, thiab kev ua haujlwm antitumor ntawm CD8-zoo cytotoxic T hlwb thiab tiv thaiv kev ua haujlwm. depletion.ML-T7 kev kho mob ua rau muaj kev txhim kho ntawm IL-2/STAT5 teeb liab txoj hauv kev, kev nce qib ntawm cov txiaj ntsig zoo xws li IFN- , TNF- , thiab IL-2, thiab kev qhia ntawm cov cim ua kom muaj zog (CD25 thiab CD69), thiab qia cell characterization-related cytokine (TCF1) qhia qib tau nce; ntawm qhov tsis sib xws, qhov kev qhia ntawm cov cim depletion, xws li PD-1 thiab CTLA-4, tau txo qis, thiab qhov feem pua ntawm cov T cell tau raug txo qis.
Ntuj tua cov hlwb los ntawm lub cev tsis muaj zog tiv thaiv kab mob, cov hlwb dendritic, thiab lawv cov haujlwm tau zoo sib xws los ntawm TIM-3. Tshwj xeeb tshaj yog nyob rau hauv cov hlwb dendritic, kuj muaj ib qho kev qhia siab ntawm TIM-4. Pab neeg tshawb fawb pom tias ML-T7 tsis yog tsuas yog txhim kho cov kev ua haujlwm ntawm cov neeg tua neeg lub cev, tab sis kuj txhawb kev loj hlob ntawm cov hlwb dendritic thiab txhim kho lawv cov antigen-kev muaj peev xwm los ntawm kev ua ntawm TIM-3 thiab TIM-4 .
Siv ntau hom kab mob hepatocellular carcinoma nas qauv, lawv tau soj ntsuam cov teebmeem ntawm ML-T7. Cov txiaj ntsig tau pom tias kev kho mob nrog ML-T7 ntawm koob tshuaj 20 mg / kg lossis 50 mg / kg txhaj tshuaj intraperitoneally txhua ob hnub cuam tshuam cov qog loj hlob thiab ua rau lub sijhawm muaj sia nyob ntawm cov nas thiab txo qis kev tiv thaiv kab mob ntawm cov qog microenvironment piv nrog tswj pawg.
Cov kev tshawb fawb ntxiv tau pom tias 20 mg / kg ML-T7 kev kho mob ib leeg muaj kev tiv thaiv qog nqaij hlav zoo sib xws rau 100 mg / kg PD-1 inhibitor kev kho ib leeg, thiab ob qho tib si muaj kev sib koom ua ke thaum siv ua ke. , reactivating CD8-T cells zoo thiab cov kab mob ntuj tsim nyob rau hauv cov qog microenvironment. Thaum 120 hnub tom qab kev kho mob nrog kev sib xyaw ua ke, 50% ntawm cov nas muaj sia nyob (3/6 nas), thaum nas kho nrog ML-T7 lossis PD-1 inhibitor ib leeg xwb tsis muaj sia nyob (0/6 nas lossis 1/6 nas. ciaj sia).
Cov txiaj ntsig ntawm kev kho ua ke nrog PD-1 inhibitors
Tsis tas li ntawd, ML-T7 kev kho mob tuaj yeem txhim kho cytotoxicity ntawm CAR-T hlwb tiv thaiv qog hlwb, thaum ua rau CAR-T hlwb kom txo qis apoptosis thiab txhim kho kev loj hlob tom qab overt metastasis. Dab tsi ntxiv, ML-T7 kev kho mob tau zoo dhau qhov teeb meem nyuaj hauv CAR-T cell kho, piv txwv li, tiv thaiv kev ua haujlwm tsis zoo, yog li txhim kho CAR-T cell ua tau zoo, uas 10 μM ML-T7 yog qhov zoo tshaj plaws hauv kev thim rov qab CAR-T cell. kev poob qis.
Rau kev txhim kho ntawm CAR-T hlwb
Hais txog kev nyab xeeb, ML-T7 tau txais txiaj ntsig zoo, thiab kev kho mob nrog 50 mg / kg koob tshuaj ML-T7 txhaj tshuaj intraperitoneally txhua ob hnub tsis ua rau muaj kev phom sij tseem ceeb hauv cov nas.
Zuag qhia tag nrho, txoj kev tshawb no pom tau tias muaj peev xwm zoo ntawm ML-T7, ib qho me me molecule inhibitor ntawm TIM-3, siv rau hauv cov qog immunotherapy.ML-T7 tsis yog tsuas yog zoo ntawm kev sib ntaus sib tua ib leeg xwb, tab sis kuj tuaj yeem txhim kho cov tshuaj tiv thaiv. qog ua haujlwm ntawm CAR-T cell therapy thiab PD-1 inhibitor therapy, uas muaj kev nyab xeeb thiab siv tau, thiab tsim nyog yuav tsum tau tsim kho ntxiv rau kev txhais lus kho mob.
