PD - (L) 1 Kev lag luam yeeb tshuaj tiv thaiv, sawv ntawm Lub xub pwg nyom ntawm Giants

Puas yog PD-1 tseem tsim nyog saib xyoo 2023?
Tsim nyog. Xyoo 2022, kev muag khoom ntawm ob PD-1 inhibitors, K-tshuaj thiab O-drug ib leeg, tau mus txog $ 29.1 billion, sib npaug rau RMB 202.2 billion. Hauv 2022, qhov ntsuas ntawm Tuam Tshoj txoj kev lag luam tshuaj yuav tsum tsis pub tshaj 164 billion yuan.
Nyob rau hauv lub ntsej muag ntawm cov ntaub ntawv ntau dhau, tsis muaj leej twg tsis ntseeg lub peev xwm ntawm PD-1.
Tej zaum koj yuav hais tias Tebchaws Meskas yog Tebchaws Meskas, thiab Tuam Tshoj tus PD-1 nws muaj nws lub tebchaws. Tom qab tag nrho, qhov tseeb nyob rau hauv Suav teb yog tias ntau tshaj li ib lub kaum os PD-1 qauv dov thiab tuag, thiab tus nqi ntawm PD-1 tawg hauv pem teb.
Tab sis qhov tseeb, tseem muaj ib daim av uas tsis tau siv nyob rau hauv lub lag luam PD-1, uas yog PD-1 kev lag luam tawm tsam.
Txawm hais tias PD-1 muaj cov txiaj ntsig zoo, nws tsis tuaj yeem dim txoj hmoo ntawm kev tiv thaiv tshuaj. Kev tshawb fawb qhia tau hais tias kwv yees li 60% ntawm cov neeg mob tsis teb rau PD-1 kev kho mob, thiab ntau tus neeg teb tau txais kev tiv thaiv tom qab thawj cov lus teb. Qhov tseem ceeb tshaj, lub peev xwm mechanisms ntawm kev tiv thaiv yeeb tshuaj tseem tsis tau paub ntau.
Qhov no ua rau muaj kev xav tau kev kho mob tseem ceeb hauv thaj tsam ntawm PD-1 tsis kam. Yuav ua li cas npaj kev kho mob rau cov neeg mob no thiab kov yeej qhov teeb meem ntawm PD-1 tsis kam yog qhov teeb meem tseem ceeb hauv kev kho mob qog.
Qhov tseem ceeb tshaj, raws li cov nqi poob qis, PD-1 twb nyob ze rau cov neeg mob hauv tsev. Qhov no kuj txhais tau hais tias kev lag luam loj npaum li cas rau PD-1 niaj hnub no, kev lag luam kub npaum li cas rau PD-1 kev tawm tsam yuav nyob rau yav tom ntej.
Rau PD-1, peb tseem muaj ntau yam tsis paub thiab yuav tsum ua kom muaj kev hwm thiab kev ua siab zoo.
Nyob rau hauv lub ntsej muag ntawm xws li ib tug cog lus Av, cov kws lag luam uas muaj lub siab xav hnov ​​tsw kuj tau ua.
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Lub Secret of Medicine King
Txawm hais tias PD-1 xav los ua tus huab tais yeeb tshuaj tshiab, tseem muaj teeb meem loj - tshuaj tiv thaiv.
Raws li kev tshawb fawb txog kev nyab xeeb, kev ua ub no, thiab kev tiv thaiv kev sib raug zoo ntawm PD-1 hauv phau ntawv xov xwm kho mob saum toj kawg nkaus The Lancet, txog li 60% ntawm cov neeg mob tsim thawj qhov kev tiv thaiv rau PD-1. Qhov ntawd yog hais tias, 60% ntawm cov neeg mob qog noj ntshav tsis muaj lus teb rau PD-1 kiag li.
Ntawm ob peb tus neeg mob uas tseem tshuav, tseem muaj qee tus uas yuav maj mam txhim kho kev tiv thaiv PD-1, uas tau txais kev tiv thaiv, raws li lub sijhawm tshuaj nce ntxiv.
Tam sim no, tsis muaj kev txheeb xyuas meej txog qhov tshwm sim ntawm cov tshuaj tiv thaiv tau txais, thiab qhov tshwm sim ntawm cov neeg mob tsim PD-1 tau txais cov tshuaj tiv thaiv nws txawv ntawm ntau hom qog.
Txawm li cas los xij, peb tseem tuaj yeem siv ntau qhov kev sim tshuaj raws li qhov rais kom nkag siab txog qhov xwm txheej ntawm PD-1 tau txais kev tiv thaiv.
Hauv kev sim Checkmate032 ua los ntawm cov tshuaj O thiab Keynote180 kev sim ua los ntawm cov tshuaj K, qhov tshwm sim ntawm PD-1 tau txais kev tiv thaiv hauv cov neeg mob qog noj ntshav hauv plab muaj li ntawm 42% mus rau 71%; Hauv kev sim Keynote048 ua los ntawm cov tshuaj O thiab HAWK kev soj ntsuam ntawm cov tshuaj D, qhov tshwm sim ntawm PD-1 tau txais kev tiv thaiv ntawm cov neeg mob qog noj ntshav hauv taub hau thiab caj dab muaj li ntawm 35% txog 54%.
Los ntawm cov ntaub ntawv sim saum toj no, nws tuaj yeem pom tau tias qhov kev faib ua feem ntawm PD-1 kuj tsis qis. Xav txog tias yog tias peb tuaj yeem daws qhov teeb meem ntawm PD-1 tsis kam, ntau tus neeg mob yuav tau txais txiaj ntsig los ntawm nws.
Yog li cas peb yuav daws tau qhov teeb meem no? Raws li cov lus hais mus, paub txog tus kheej thiab tus yeeb ncuab yog invincible nyob rau hauv tag nrho cov kev sib ntaus sib tua, tshwj xeeb tshaj yog nyob rau hauv kev sib ntaus sib tua tiv thaiv cov qog nqaij hlav cancer. Txhawm rau daws qhov teeb meem tshuaj tiv thaiv ntawm PD-1, nws yog ib qho tsim nyog yuav tsum nkag siab txog cov txheej txheem ntawm cov tshuaj tiv thaiv.
Qhov tseeb, cov txheej txheem ntawm PD-1 tsis kam yog qhov nyuaj heev, thiab cov kws tshawb fawb tseem tsis tau kawm tag nrho cov txheej txheem ntawm PD-1 tsis kam. Txawm li cas los xij, raws li kev tshawb fawb uas twb muaj lawm, cov tshuaj tiv thaiv ntawm PD-1 muaj ntau dua los yog tsawg dua rau T cell teeb meem.
Peb paub tias txoj haujlwm ntawm PD-1 inhibitors yog "brake", txo kev tiv thaiv kab mob hauv lub cev, thiab ua kom lub cev tiv thaiv kab mob T hlwb tua cov qog nqaij hlav cancer.
Tab sis cov tub rog uas sib ntaus nrog hlau kuj tseem xav "ntses", thiab T hlwb tsis muaj kev zam. Thaum T hlwb tsis xav tawm tsam, txawm tias ntau npaum li cas PD-1 sib ntaus cov ntshav nqaij qaib hauv qhov xwm txheej no, nws tsis tuaj yeem txhawb T hlwb 'sib ntaus sib tua.
Cov laj thawj rau T cell inactivity tsis yog tsawg. Thaum cov txheej txheem kev nthuav qhia antigen raug thaiv lossis txo qis, cov teeb liab tsis tuaj yeem txais thiab cov qog nqaij hlav cancer tsis tuaj yeem lees paub, ua rau T cell proliferation; Thaum IFN- Poob qhov txawv txav ntawm txoj hauv kev thiab T cell tawm tsam; Thaum tsis tu ncua txhawb los ntawm kev mob ntev, ua rau T cell depletion thiab lwm qhov kev tawm tsam.
Ntxiv rau cov laj thawj sab hauv, cov laj thawj sab nraud kuj tseem tuaj yeem ua rau PD-1 tshuaj tiv thaiv, xws li inhibition ntawm qog microenvironment.
Txhawm rau kom muaj sia nyob zoo dua, cov qog yuav tsim cov av tsim nyog rau kev loj hlob, uas yog, qog microenvironment. Cov qog microenvironment tsis tsuas yog ua rau cov hlwb nyob ib puag ncig tiv thaiv kab mob, tab sis kuj pab cov qog hlwb kom dim ntawm kev tiv thaiv kab mob.
Piv txwv li, thaum chemokines nyob rau hauv cov qog xws li CCL2, CCL5, CCL7 thiab CXCL8 khi rau receptors, lub cev tiv thaiv kab mob yuav raug recruited rau hauv cov qog microenvironment los inhibit T cell muaj nuj nqi, yog li ua rau tshwm sim ntawm PD-1 tshuaj tiv thaiv.
Yooj yim to taub, T hlwb nyob ib puag ncig los ntawm ib pab pawg phooj ywg hma liab thiab aub phooj ywg. Hauv qhov xwm txheej no, txawm tias PD-1 quaj nrov, T hlwb uas tau raug bewitched tsis kam ua haujlwm.
Tau kawg, cov laj thawj rau kev tiv thaiv tshuaj nyob rau hauv PD-1 yog ntau thiab nyuaj, thiab cov saum toj no tsuas yog qee qhov laj thawj. Txawm li cas los xij, qhov no tseem muab cov kws tshawb fawb txog cov tswv yim los tsim cov tswv yim los tawm tsam cov tshuaj tiv thaiv.
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Countermeasures rau PD-1 Resistance
Raws li cov lus hais mus, pab tub rog rau yeeb ncuab, lub ntiaj teb rau dej nyab. Tam sim no, cov kws tshawb fawb tab tom tshawb nrhiav ntau txoj hauv kev los daws PD-1 kev tawm tsam.
Piv txwv li, pib ntawm cov qog microenvironment, txij li cov qog microenvironment yuav cuam tshuam cov nyhuv ntawm PD-1, peb tuaj yeem pib los ntawm kev hloov cov qog microenvironment.
Muaj ntau txoj hauv kev los hloov cov qog microenvironment. Piv txwv li, PD-1 kev sib xyaw ua ke tuaj yeem siv los hloov cov qog microenvironment thiab teb rau PD-1 tsis kam.
Tshwj xeeb, kws khomob tuaj yeem txhim kho kev tiv thaiv kab mob qog noj ntshav los ntawm kev ntxiv cov antigen complexes tshiab, ua rau kev tuag ntawm lub cev tiv thaiv kab mob, thiab hloov cytokine ib puag ncig hauv cov qog microenvironment.
Kev ua tau zoo ntawm PD-1 ua ke nrog kev kho tshuaj khomob kuj tau lees paub hauv kev sim tshuaj. Hauv kev sim tshuaj, cov neeg mob uas tsim lawv tus mob tom qab tau txais PD-1 kev kho mob tau rov kho nrog cov tshuaj kho mob dexcitabine ua ke nrog PD-1 carlizumab. Cov txiaj ntsig tau pom tias lub sijhawm muaj sia nyob dawb ntawm cov neeg mob tau ntev dua li cov neeg mob siv PD-1 ib leeg.
Ib yam li ntawd, PD-1 ua ke nrog cov tshuaj tiv thaiv vascular kuj tuaj yeem hloov cov qog microenvironment.
Kev loj hlob thiab kev loj hlob ntawm cov qog tsis tuaj yeem cais tawm ntawm cov hlab ntsha. Cov hlab ntsha tsis tsuas yog muab cov pa oxygen thiab cov as-ham, tab sis kuj tshem tawm cov khoom pov tseg, ua rau lawv ua haujlwm loj hauv cov qog nqaij hlav. Cov tshuaj tiv thaiv angiogenesis tuaj yeem thim rov qab cov tshuaj tiv thaiv kab mob los ntawm cov ntaub so ntswg hypoxia thiab immunosuppressive hlwb, ua rau cov qog microenvironment hloov los ntawm kev tiv thaiv kab mob mus rau kev tiv thaiv kab mob, uas yog qhov tseem ceeb rau kev loj hlob ntawm kev mob qog noj ntshav.
Nyob rau hauv teb rau depletion ntawm T hlwb, peb tuaj yeem nrhiav txoj hauv kev los ua kom lawv lub siab sib ntaus sib tua.
Txij li tsuas yog tso siab rau cov teeb liab stimulation tawm los ntawm PD-1, T hlwb uas tsis sawv thiab ua txuj pw tsaug zog tuaj yeem txhawb nqa los ntawm kev ua ntawm ntau lub hom phiaj ua ke. Piv txwv li, kev sib koom tes kev kho mob nrog cov tshuaj tiv thaiv kab mob xws li PD-1, CTLA-4, thiab LAG-3. Lub upregulation ntawm co inhibitory tiv thaiv kab mob checkpoint receptors tuaj yeem ua kom cov co stimulatory signals los qhib lub zog sib ntaus sib tua ntawm T hlwb.
Cov khub ntawm LAG-3 thiab PD-1 tab tom sim kov yeej qhov teeb meem ntawm PD-1 tsis kam. Ntawm 2023 ELC lub rooj sib tham, kev sim tshuaj ntsuam xyuas ntawm LAG-3 monoclonal antibody ua ke nrog K-drug tau pom tias muaj peev xwm kov yeej PD-1 tsis kam. Cov kev sim tshuaj ntsuam xyuas tau pom tias rau PD-1/PD-L1 resistant thib ob kab metastatic non-small cell ntsws cancer, 83% ntawm cov neeg mob tau ntsib cov qog loj hlob qeeb thiab lub hom phiaj txo qis tom qab tau txais kev kho dual immunotherapy.
Tau kawg, ntxiv rau cov txheej txheem saum toj no, tseem muaj ntau lub tswv yim los tawm tsam PD-1 tiv thaiv, xws li kab mob oncolytic ua ke nrog PD-1 kev kho, ADC ua ke nrog PD-1 kho, tus kheej cov tshuaj tiv thaiv antigen tshiab, thiab lwm yam.
Hauv cov ntsiab lus, cov khawv koob nce los ntawm ko taw, thiab los ntawm kev tshawb nrhiav tas li, qhov teeb meem ntawm PD-1 tsis kam yuav ib txwm nrhiav kev daws teeb meem.
03
Next Promised Land
Puas muaj txoj hauv kev hauv PD-1 teb?
Tau kawg muaj. Hauv thaj teb ntawm PD-1 tsis kam, muaj qhov kev thov kho mob loj heev.
Vim muaj qhov sib txawv ntawm PD-1 tsis kam ntawm ntau hom mob qog noj ntshav, peb yuav coj tus mob qog noj ntshav ua piv txwv.
Raws li cov ntaub ntawv tshaj tawm los ntawm National Cancer Center hauv 2022, muaj 828000 tus neeg mob qog noj ntshav tshiab hauv Suav teb xyoo 2016, ntawm 70% cov neeg mob uas mob qog noj ntshav siab tau ntsib PD-1/L1 inhibitor ib leeg tshuaj lossis tshuaj khomob ua ke. raws li thawj kab kev kho mob.
Ntawm cov neeg mob no, kwv yees li 70% ntawm lawv yuav tsim cov tshuaj tiv thaiv. Qhov no kuj txhais tau tias 400000 tus neeg mob tuaj yeem tsim PD-1/PD-L1 tsis kam. Thiab rau pawg neeg mob no, tseem tsis tau muaj ntau txoj kev kho mob zoo.
Qhov no tsuas yog mob ntsws cancer xwb, xav txog qhov xwm txheej ntawm PD-1 broad-spectrum anticancer tshuaj, kev txhim kho tshuaj rau PD-1 cov neeg mob resistant tuaj yeem hu ua dej hiav txwv xiav tshiab.
Qhov no kuj muab kev daws teeb meem rau PD-1 kev ua lag luam, pib los ntawm kev daws qhov teeb meem ntawm PD-1 tsis kam.
Qhov tseeb, ntau tus neeg ua si hauv Suav teb tau tshaj tawm qhov teeb tsa nyob ib puag ncig qhov kev xav tau kev kho mob tsis zoo. Piv txwv li, cov neeg ua si hauv tsev xws li Xinda Biotech / Laikai Pharmaceutical, ThinkTok / Microchip Biotech, thiab Wanchun Pharmaceutical tau ua txhua yam kev sim tshuaj ntsuam xyuas ntawm PD-1 kev sib xyaw ua ke rau PD-1 tsis kam.
Qee tus neeg ua si kuj tau siv txoj hauv kev sib txawv thiab tau xaiv los teb rau PD-1 tsis kam nyob rau hauv daim ntawv ntawm cov tshuaj tiv thaiv dual. Tam sim no, kev tshawb fawb soj ntsuam tau ua tiav ntawm PD-1/CTLA-4 dual antibody Cardenilli los ntawm Kangfang Biotechnology, tsom mus rau qib siab uas tsis yog me me ntawm lub ntsws cancer tiv taus PD-1/PD-L1.
Yav dhau los, cov tshuaj tiv thaiv kab mob uas sawv cev los ntawm PD-1/PD-L1 cov tshuaj tiv thaiv kab mob tiv thaiv kab mob tau hloov kho tus qauv ntawm cov qog, tab sis cov teeb meem tshuaj tiv thaiv tau txwv qhov chaw xav ntawm PD-1.
Nrhiav thiab nthuav cov neeg tau txais txiaj ntsig ntawm PD-1 yog qhov kev sib tw tshiab thiab lub sijhawm nyob rau lub sijhawm ntawm kev tiv thaiv kab mob. Leej twg ua tau zoo qhib qhov rooj no yuav tau txais khoom plig nplua nuj.
Koj puas npaj txhij los tshawb txog thaj av uas tau cog lus tseg no?