nhau

Immunotherapy yakaunza shanduko yekuchinja kurapwa kwemamota akaipa, asi kuchine vamwe varwere vasingakwanise kubatsirwa. Naizvozvo, ma biomarker akakodzera anodiwa nekukurumidza mumakiriniki ekushandisa kufanotaura kushanda kwe immunotherapy, kuitira kuti kuwedzere kushanda uye kudzivirira huturu husina kufanira.

FDA yakabvumidza biomarkers

PD-L1 kutaura. Ongororo yePD-L1 mazinga ekutaura ne immunohistochemistry (IHC) inopa bundu chikamu chibodzwa (TPS), inova chikamu chechikamu kana zvachose membrane yakasvibiswa bundu masero ehupi simba mukupona bundu maseru. Mumiyedzo yekiriniki, bvunzo iyi inoshanda seyebetsero yekuongorora bvunzo yekurapwa kwepamusoro isiri-diki cell kenza yemapapu (NSCLC) ine pembrolizumab. Kana iyo TPS yemuenzaniso iri ≥ 1%, kutaura kwePD-L1 kunofungidzirwa; TPS ≥ 50% inoratidza kutaura kwepamusoro kwePD-L1. Muchikamu chekutanga cheChikamu chekutanga (KEYNOTE-001), chiyero chekupindura kwevarwere muPD-L1 TPS> 50% boka rekushandisa pembrolizumab raiva 45.2%, asi pasinei neTPS, chiyero chekupindura kwevarwere vose vanowana iyi immune checkpoint inhibitor (ICI) kurapwa kwaiva 19.4%. Chikamu chinotevera 2/3 kuyedzwa (KEYNOTE-024) kurongeka kwakapihwa varwere vane PD-L1 TPS> 50% kuti vagamuchire pembrolizumab uye yakajairika chemotherapy, uye mhedzisiro yakaratidza kuvandudzwa kukuru mukupona kwese (OS) kune varwere vanowana pembrolizumab kurapwa.

Nekudaro, kushandiswa kwePD-L1 mukufanotaura mhinduro dzeICI kunogumira nezvinhu zvakasiyana. Chekutanga, mukana wakakwana wemhando dzakasiyana dzegomarara unosiyana. Semuyenzaniso, Pabolizumab inogona kushandiswa kana bundu PD-L1 kutaura kwevarwere vane gomarara remudumbu, gomarara resophageal, kenza yedundira uye kenza yemapapu iri 1%, 10% uye 50% zvichiteerana. Kechipiri, kuongorora huwandu hwesero hwePD-L1 kutaura kunosiyana zvichienderana nerudzi rwegomarara. Semuenzaniso, kurapwa kwekudzokororwa kana metastatic squamous cell carcinoma yemusoro nemutsipa inogona kusarudza kushandisa imwe FDA yakabvumidzwa nzira yekuyedza, iyo Comprehensive Positive Score (CPS). Chetatu, panenge pasina kuwirirana pakati pePD-L1 kutaura mumakenza akasiyana-siyana uye ICI mhinduro, zvichiratidza kuti bundu rekumashure rinogona kunge riri chinhu chakakosha mukufanotaura ICI biomarkers. Semuenzaniso, maererano nemhedzisiro yeCheckMate-067 bvunzo, iyo yakaipa yekufungidzira kukosha kwePD-L1 kutaura mu melanoma inongova 45%. Chekupedzisira, zvidzidzo zvakawanda zvakaona kuti PD-L1 kutaura hakuenderane kune akasiyana bundu maronda mumurwere mumwechete, kunyangwe mukati mebundu rimwe chete. Muchidimbu, kunyangwe miedzo yekiriniki yekutanga yeNSCLC yakakurudzira kutsvagisa nezvePD-L1 kutaura senge inofanofungidzira biomarker, yayo yekiriniki yekushandisa mumhando dzakasiyana dzegomarara inoramba isina kujeka.

Tumor mutation mutoro. Tumor Mutation Burden (TMB) yakashandiswa seimwe chiratidzo che tumor immunogenicity. Zvinoenderana nemhedzisiro yekuyedzwa kwekiriniki yeKEYNOTE-158, pakati pemhando gumi dzemamota akasimba airapwa nepembrolizumab, varwere vane kanenge gumi mutations per megabase (yakakwirira TMB) vaive neredhiyo yepamusoro pane avo vane yakaderera TMB. Zvakakosha kucherechedza kuti muchidzidzo ichi, TMB yaive fungidziro yePFS, asi haina kukwanisa kufanotaura OS.

Iyo immune therapy mhinduro inonyanya kufambiswa neT cell kuzivikanwa kwemaantigen matsva. The immunogenicity yakabatana nepamusoro TMB inobvawo pane zvakasiyana-siyana, kusanganisira bundu neoantigen rinoratidzwa nebundu; Iyo immune system inoziva bundu neoantigens; Kugona kwemugamuchiri kutangisa maantigen-chaiwo mhinduro. Semuenzaniso, data inoratidza kuti mapundu ane yakanyanya kupinda mukati memamwe maseru edziviriro anogona kunge aine inhibitory regulatory T cell (Treg) clone amplification. Mukuwedzera, huwandu hweTMB hunogona kusiyana nekukwanisa kweTMB neoantigens, sezvo nzvimbo chaiyo yekuchinja inobatawo basa rinokosha; Shanduko dzinoyananisa nzira dzakasiyana dzekuratidzwa kweantigen dzinogona kukanganisa kuratidzwa (kana kusaratidza) kwemaantigen matsva kune immune system, zvichiratidza kuti bundu remukati uye immunological hunhu hunofanirwa kuenderana kuitira kuburitsa yakakwana mhinduro dzeIC.

Parizvino, TMB inoyerwa kuburikidza nechizvarwa chinotevera sequencing (NGS), iyo inogona kusiyana pakati pemasangano akasiyana (mukati) kana mapuratifomu ekutengesa anoshandiswa. NGS inosanganisira yakazara exome sequencing (WES), yakazara genome sequencing, uye yakanangwa kutevedzana, iyo inogona kuwanikwa kubva kumota tishu uye kutenderera bundu DNA (ctDNA). Zvakakosha kucherechedza kuti mhando dzakasiyana dzemamota dzine huwandu hwakasiyana hweTMB, iine immunogenic tumors senge melanoma, NSCLC, uye squamous cell carcinoma ine mazinga epamusoro eTMB. Saizvozvo, nzira dzekuona dzakagadzirirwa mhando dzakasiyana dzebundu dzine tsananguro dzakasiyana dzeTMB threshold values. Muchidzidzo cheNSCLC, melanoma, urothelial carcinoma, uye kenza diki yemapapu, nzira dzekuongorora idzi dzinoshandisa nzira dzakasiyana dzekuongorora (senge WES kana PCR yekuona nhamba dzakati dzemajini ane hukama) uye zvikumbaridzo (TMB yakakwirira kana TMB yakaderera).

Microsatellites haina kugadzikana zvakanyanya. Microsatellite yakanyanya kusagadzikana (MSI-H), sepan cancer biomarker yeICI mhinduro, ine hunyanzvi hwekuita mukufanotaura kushanda kweICI mumakenza akasiyana siyana. MSI-H inokonzerwa nekusawirirana kwekugadzirisa kukanganisa (dMMR), zvichiita kuti pave nepamusoro-soro mutation rate, kunyanya munzvimbo dze microsatellite, zvichiita kuti pave nekugadzirwa kwenhamba yakawanda yemaantigens matsva uye pakupedzisira kukonzera clonal immune response. Nekuda kwekuremerwa kukuru kwekuchinja kunokonzerwa nedMMR, MSI-H tumors inogona kutariswa semhando yepamusoro mutation mutoro (TMB) bundu. Zvichienderana nemhedzisiro yekuyedzwa kwekiriniki yeKEYNOTE-164 uye KEYNOTE-158, FDA yakabvumidza pembrolizumab kurapwa kweMSI-H kana dMMR tumors. Iyi ndeimwe yemishonga yekutanga yegomarara repani yakatenderwa neFDA inotungamirwa nebundu biology kwete histology.

Pasinei nekubudirira kwakakosha, pane zvakare nyaya dzinofanirwa kuziva kana uchishandisa MSI mamiriro. Semuenzaniso, kusvika ku50% yedMMR colorectal cancer varwere havana mhinduro kuICI kurapwa, kuratidza kukosha kwezvimwe zvinhu mukufanotaura mhinduro. Zvimwe zvinhu zvemukati zvemamota zvisingagone kuongororwa nemapuratifomu ekuona aripo anogona kunge ari kupa zvinhu. Semuyenzaniso, kwave nemishumo yekuti varwere vane shanduko mumajeni encoding akakosha catalytic subunits epolymerase delta (POLD) kana polymerase ε (POLE) mudunhu reDNA vanoshaya kuvimbika kwekudzokorora uye vanoratidza "super mutation" phenotype mumamota avo. Mamwe emamota aya akawedzera zvakanyanya kusagadzikana kwema microsatellite (saka ari eMSI-H), asi kusawirirana kugadzirisa mapuroteni haashaikwe (saka kwete dMMR).

Mukuwedzera, yakafanana neTMB, MSI-H inobatwawo nemhando itsva dzeantigen dzakagadzirwa nekusagadzikana kwe microsatellite, kugamuchirwa kwevaenzi vemarudzi matsva eantigen, uye kugadzirisa maitiro ekudzivirira zvirwere. Kunyangwe mumamota emhando yeMSI-H, huwandu hukuru hwekuchinjisa nucleotide humwechete hwakaonekwa semufambi wekuchinja (asiri mutyairi mutations). Nokudaro, kuvimba chete nenhamba ye microsatellites yakaonekwa mubundu haina kukwana; Iyo chaiyo mhando yekuchinja (inozivikanwa kuburikidza neakananga mutation profiles) inogona kuvandudza kufungidzira kuita kweiyo biomarker. Pamusoro pezvo, chikamu chidiki chete chevarwere vegomarara ndeveMSI-H tumors, zvichiratidza kudiwa kwazvino kweakawanda anoshanda biomarkers. Naizvozvo, kuziva mamwe ma biomarkers anoshanda kufanotaura kushanda uye kutungamira kutungamira kwevarwere kunoramba kuri kwakakosha nzvimbo yekutsvagisa.

Sangano rakavakirwa biomarker research

Tichifunga kuti maitiro ekuita kweICI ndeyekudzoreredza immune cell kudzvanywa kwete kunanga zvakananga nzira dzemukati dzema tumor cell, kumwe kutsvagisa kunofanirwa kutarisisa kuongorora kwakarongeka mamiriro ekukura kwebundu uye kupindirana pakati pebundu masero nemaseru edziviriro, izvo zvinogona kubatsira kujekesa zvinhu zvinokanganisa ICI mhinduro. Mapoka mazhinji ekutsvagisa akadzidza bundu kana maitiro ekudzivirira emhando dzakasiyana dzematishu, senge bundu uye immune gene mutation maficha, tumor antigen mharidzo yekushomeka, kana multicellular immune system kana aggregates (senge tertiary lymphoid zvimiro), izvo zvinogona kufanotaura mhinduro kune immunotherapy.

Vatsvagiri vakashandisa NGS kuteedzera bundu uye immune exome uye transcriptome yevarwere tishu pamberi uye mushure meICI kurapwa, uye vakaita ongororo yekufungidzira. Nekushandisa akawanda akabatanidzwa modhi, akasanganiswa nehunyanzvi hwakadai sesero-sero sequencing uye spatial imaging, kana akawanda omics modhi, kugona kufanotaura kweICI kurapwa kwakagadziridzwa. Uye zvakare, nzira yakazara yekuongorora tumor immune masaini uye mukati memukati bundu hunhu yakaratidzawo kwakasimba kufungidzira kugona. Semuenzaniso, yakazara batch yekuteedzera nzira iyo panguva imwe chete inoyera bundu uye maitiro ekudzivirira ekudzivirira epamusoro kune imwechete yekuongorora shanduko. Mhedzisiro iyi inosimbisa kukosha kwekufananidza kushanda kweICI nenzira yakazara, kusanganisira kubatanidza mhedzisiro yekugona immune immune, mukati memukati tumor maitiro, uye tumor immune components mumurwere wega wega kufanotaura zviri nani varwere vachapindura immunotherapy.

Tichifunga kuomarara kwekubatanidza bundu uye zvinhu zvinotambira mukutsvagisa biomarker, pamwe nekudikanwa kwekureba kwekubatanidzwa kwe immune microenvironment maficha, vanhu vatanga kuongorora biomarkers vachishandisa komputa modelling uye muchina kudzidza. Parizvino, zvimwe zvinokatyamadza zvakawanikwa zvekutsvaga zvakabuda mundima iyi, zvichiratidza remangwana remunhu oncology achibatsirwa nekudzidza muchina.

Matambudziko anosanganikwa nawo nematissue based biomarkers

Mipimo yenzira dzekuongorora. Mamwe ane chinangwa biomarkers anoita zvakanaka mune mamwe mabundu marudzi, asi kwete hazvo mune mamwe marudzi ebundu. Kunyangwe bundu rakanangana nemajini maficha ane simba rekufungidzira kupfuura TMB nevamwe, haagone kushandiswa kuongororwa kwemamota ese. Muchidzidzo chakanangana nevarwere veNSCLC, gene mutation features zvakawanikwa zvichinyanya kufanotaura nezveICI efficacy pane yakakwirira TMB (≥ 10), asi vanopfuura hafu yevarwere havana kukwanisa kuona gene mutation features.

Tumor heterogeneity. Iyo tishu yakavakirwa biomarker nzira inongotora sampuli pane imwechete bundu saiti, izvo zvinoreva kuti kuongororwa kweakananga mabundu zvikamu zvinogona kusanyatso ratidza kuratidzwa kwese kwese kwemurwere. Semuyenzaniso, zvidzidzo zvakawana heterogeneity muPD-L1 kutaura pakati nepakati pemamota, uye nyaya dzakafanana dziripo nemamwe mavanga ematishu.

Nekuda kwekuoma kwemasisitimu ebhayoloji, akawanda aimbomboshandiswa matishu biomarkers anogona kunge akarerutswa. Pamusoro pezvo, maseru ari mu tumor microenvironment (TME) anowanzo famba, saka kudyidzana kunoratidzwa mukuongororwa kwenzvimbo kungasamiririre kudyidzana kwechokwadi pakati pebundu maseru nemasero ekudzivirira. Kunyangwe kana ma biomarker achigona kumiririra iyo yese bundu nharaunda panguva yakatarwa, izvi zvibodzwa zvinogona kuramba zvichikurudzirwa uye nekuchinja zvine simba nekufamba kwenguva, zvichiratidza kuti imwe snapshot pane imwe nguva inogona kusamiririra shanduko ine simba zvakanaka.

Mwoyo murefu heterogeneity. Kunyangwe kana shanduko dzinozivikanwa dzemajini dzine chekuita neICI kuramba dzichionekwa, vamwe varwere vakatakura vanozivikanwa kuramba biomarkers vanogona kuramba vachibatsirwa, pamwe nekuda kwemamorekuru uye/kana immune heterogeneity mukati mebundu uye munzvimbo dzakasiyana dzebundu. Semuenzaniso, β 2-microglobulin (B2M) inoshaya inogona kuratidza kutsva kana kuwanikwa kwemishonga yemishonga, asi nekuda kwehterogeneity yekushayikwa kweB2M pakati pevanhu uye mukati memakumbo, pamwe chete nekubatana kwemaitiro ekuzivikanwa kwekudzivirira kwekudzivirira zvirwere muvarwere ava, kushayikwa kweB2M hakugoni kufanotaura zvakasimba kuti munhu mumwe nomumwe anoramba zvinodhaka. Naizvozvo, kunyangwe kuvepo kwekushomeka kweB2M, varwere vanogona kuramba vachibatsirwa neICI kurapwa.

Sangano rakavakirwa longitudinal biomarkers
Kutaura kwema biomarkers kunogona kuchinja nekufamba kwenguva uye nekukanganisa kwekurapa. Kuongororwa kwakasimba uye kumwe chete kwemamota uye immunobiology inogona kufuratira shanduko idzi, uye shanduko yebundu TME uye kutambira immune immune mazinga anogonawo kufuratirwa. Zvidzidzo zvakawanda zvakaratidza kuti kuwana sampuli pamberi uye panguva yekurapa kunogona kunyatsoona shanduko dzine chekuita neICI kurapwa. Izvi zvinosimbisa kukosha kweiyo dynamic biomarker ongororo.

Ropa rakavakirwa biomarkers
Kubatsira kwekuongorora ropa kuri mukukwanisa kwayo kuongorora biologically maronda ega ega ega, kuratidza kuverenga kweavhareji kwete kuverengerwa kwesaiti chaiyo, zvichiita kuti ive yakakodzera kuongorora shanduko ine simba ine chekuita nekurapa. Mhedzisiro yetsvakiridzo yakawanda yakaratidza kuti kushandisa kutenderera bundu DNA (ctDNA) kana kutenderedza bundu masero (CTC) kuongorora kushoma residual chirwere (MRD) kunogona kutungamira sarudzo dzekurapa, asi bvunzo idzi dzine ruzivo rushoma pakufanotaura kana varwere vachigona kubatsirwa kubva kune immunotherapies senge ICI. Naizvozvo, ctDNA yekuongorora inofanirwa kusanganiswa nedzimwe nzira dzekuyera immune activation kana kugamuchira immune immune. Panyaya iyi, kufambira mberi kwakaitwa mu immunophenotyping yeperipheral blood mononuclear cells (PBMCs) uye proteomic kuongororwa kweextracellular vesicles uye plasma. Semuyenzaniso, peripheral immune cell subtypes (senge CD8 + T masero), kutaura kwakakwirira kwemamolekemu ekudzivirira ekudzivirira (akadai sePD1 pane peripheral CD8 + T masero), uye mazinga akakwirisa emapuroteni akasiyana muplasma (akadai seCXCL8, CXCL10, IL-6, IL-10, PRAP1, uye VEGD dynamics yekuwedzera kune ese biodynamics ekuwedzera biofas). Chakanakira nzira nyowani idzi ndechekuti vanogona kuongorora shanduko mukati mebundu (zvakafanana neshanduko dzakaonekwa nectDNA) uye dzinogona kuratidza shanduko mukudzivirira kwemurwere.

Radiomics
Izvo zvinofanotaura zvinhu zve data yemufananidzo zvinogona kunyatso kunda zvipimo zvetishu biomarker sampling uye biopsy, uye inogona kuona bundu rose uye zvichibvira dzimwe metastatic nzvimbo chero nguva. Naizvozvo, ivo vanogona kuve chikamu chakakosha cheasina-invasive ane simba biomarkers mune ramangwana. Delta radiomics inogona kuverengera shanduko mune akawanda bundu maficha (senge bundu saizi) panguva dzakasiyana dzenguva, senge pamberi uye mushure meICI kurapwa, panguva yekurapa, uye inotevera yekutevera. Delta radiomics haingofanofembera yekutanga kana kusaita mhinduro yekurapwa kwekutanga, asi zvakare kuona yakawana kuramba ICI munguva chaiyo uye kutarisa chero kudzokorora mushure mekuregererwa kwakakwana. Iyo yekufungidzira modhi yakagadziridzwa kuburikidza nemichina yekudzidza tekinoroji yakatonaka kupfuura yechinyakare RECIST chiyero mukufanotaura mhinduro yekurapa uye zvinogona kuitika zvakaipa. Tsvagiridzo yazvino inoratidza kuti aya mamodhiyo eradiomics ane nzvimbo iri pasi pe curve (AUC) inosvika 0.8 kusvika 0.92 mukufanotaura mhinduro ye immune therapy.

Imwe mukana weradiomics kugona kwayo kunyatsoona kufambira mberi kwepseudo. Iyo radiomics modhi yakagadzirwa kuburikidza nemuchina kudzidza inogona kunyatsosiyanisa pakati pechokwadi nenhema kufambira mberi nekuyera zvakare CT kana PET data yebundu rega rega, kusanganisira zvinhu zvakaita sechimiro, kusimba, uye magadzirirwo, ine AUC ye0.79. Aya mamodhiyo eradiomic anogona kushandiswa mune ramangwana kudzivirira kupera nguva isati yakwana yekurapa nekuda kwekusafungira kuenderera kwechirwere.

Intestinal microbiota
Iwo ma biomarkers egut microbiota anotarisirwa kufanotaura maitiro ekurapa kweICI. Ongororo dzakawanda dzakaratidza kuti chaiyo gut microbiota ine hukama nemhinduro yemhando dzakasiyana dzegomarara kuICI kurapwa. Semuenzaniso, mune varwere vane melanoma uye kenza yechiropa, kuwanda kweRuminococcaceae mabhakitiriya anosanganiswa nePD-1 immunotherapy mhinduro. Akkermansia muciniphila hupfumi hwakajairika muvarwere vane kenza yechiropa, kenza yemapapu, kana renal cell carcinoma, vanopindura zvakanaka kuICI kurapwa.

Uye zvakare, iyo nyowani yemuchina yekudzidza modhi inogona kuzvimiririra yemhando dzebundu uye kubatanidza chaiyo gut bhakitiriya genera nemhinduro yekurapa ye immunotherapy. Zvimwe zvidzidzo zvakaratidzawo basa chairo rinoitwa nemapoka emabhakitiriya ega mukudzora immune system, achienderera mberi nekuongorora nzira yekudzivirira kana kukurudzira kupukunyuka kwemasero egomarara.

Neoadjuvant therapy
Dynamic ongororo ye tumor biology inogona kutungamira inotevera kiriniki yekurapa nzira. Iyo neoadjuvant therapy kuyedza inogona kuongorora maitiro ekurapa kuburikidza nekuregererwa kwepathological mune zvienzaniso zvekuvhiya. Mukurapa melanoma, iyo yekutanga pathological mhinduro (MPR) inosanganiswa nekudzokorora kwemahara ekurarama. Mukuedza kwePRADO, vatsvakurudzi vanotarisa matanho anotevera ekupindira kwekliniki, akadai sekuvhiyiwa uye / kana adjuvant therapy, zvichienderana nemurwere chaiwo data rekuregererwa.

Pakati pemhando dzakasiyana dzegomarara, akati wandei matsva ekurapa adjuvant nzira achiri kushaya musoro kuenda kumusoro. Naizvozvo, sarudzo pakati pe immunotherapy monotherapy kana musanganiswa kurapa kazhinji inosarudzwa pamwe chete nachiremba ari kuenda uye murwere. Parizvino, vatsvakurudzi vakagadzira inonzi interferon gamma (IFN gamma) ine 10 genes sebiomarker yekufanotaura kuregererwa kwechirwere mu melanoma mushure mekurapa neoadjuvant. Ivo vakawedzera kubatanidza zvinhu izvi mu algorithm yekusarudza varwere vane simba kana kushaya simba mhinduro kune neoadjuvant therapy. Muchidzidzo chekutevera chinonzi DONIMI, vatsvakurudzi vakashandisa chibodzwa ichi, chakabatanidzwa nekuongorora kwakaoma, kwete kungofanotaura mhinduro yekurapa, asiwo kuti vaone kuti ndeipi nhanho yechitatu yevarwere ve melanoma inoda kuwedzerwa kwe histone deacetylase inhibitors (HDACi) kuwedzera mhinduro kune neoadjuvant ICI kurapwa.

Tumor modhi inotorwa kubva kuvarwere
In vitro tumor modhi ine mukana wekufungidzira mhinduro dzakanangana nemurwere. Kusiyana neiyo in vitro papuratifomu inoshandiswa pakupindura zvinodhaka spectrum ongororo yehematological malignancies, mabundu akasimba anotarisana nematambudziko makuru nekuda kweakasarudzika bundu microstructure uye tumor immune kudyidzana. Yakareruka tumor cell tsika haigone kutevedzera zviri nyore izvi zvakaomarara maficha. Muchiitiko ichi, bundu senge nhengo kana nhengo dzenhengo dzinobva kuvarwere dzinogona kutsiva zvimiro izvi, sezvo vachigona kuchengetedza iyo yekutanga bundu sero chimiro uye kutevedzera kupindirana nelymphoid uye myeloid immune masero kuti aongorore mhinduro dzeICI nenzira yemurwere, nekudaro vachinyatso kuburitsa zvipenyu munzvimbo ine chokwadi chetatu-dimensional nharaunda.

Zvidzidzo zvakati wandei muChina neUnited States zvakatora iyi nyowani yepamusoro-soro yekuvimbika matatu-dimensional in vitro tumor modhi. Mhedzisiro yacho inoratidza kuti mamodheru aya anogona kunyatsofanotaura mhinduro yekenza yemapapu, kenza yekoloni, kenza yemazamu, melanoma uye mamwe mamota kuICI. Izvi zvinoisa hwaro hwekuenderera mberi nekusimbisa uye kuenzanisa kuita kwekufungidzira kwemhando idzi.