Evolution And Progress Of MRNA Vaccines in The Treatment Of Melanoma: Yav Tom Ntej Prospects
Aug 08, 2023
Abstract: mRNA tshuaj tiv thaiv encoding qog antigens tuaj yeem ua rau lub cev tiv thaiv kab mob ntawm tus tswv tsev tiv thaiv kab mob qog noj ntshav, txhim kho kev nthuav qhia antigen thiab tiv thaiv kab mob. Txij li thaum muaj kev sib kis ntawm COVID-19 kev sib kis, kev txaus siab rau cov tshuaj tiv thaiv mRNA tau nrawm dua, vim tias kev txhaj tshuaj tiv thaiv tus kab mob no tau ua ib qho kev ntsuas los txwv kev kis tus kab mob. Muab hais tias kev txhaj tshuaj tiv thaiv kab mob yog lub hauv paus ntawm kev kho mob melanoma nyob rau ntau xyoo dhau los, kev tiv thaiv kab mob hauv lub cev ntxiv los ntawm cov tshuaj tiv thaiv mRNA tuaj yeem yog qhov tseem ceeb tom ntej hauv kev kho mob melanoma. Cov ntaub ntawv ua ntej los ntawm cov qauv qog nqaij hlav murine tau muab pov thawj ntawm cov tshuaj tiv thaiv mRNA 'muaj peev xwm ua rau tus tswv tsev tiv thaiv kab mob tiv thaiv kab mob. Ntxiv mus, cov tshuaj tiv thaiv kab mob tshwj xeeb tau pom nyob rau hauv cov neeg mob melanoma tau txais cov tshuaj tiv thaiv mRNA, thaum qhov kev sim KEYNOTE-942 tsis ntev los no tuaj yeem tsim kev koom ua ke ntawm mRNA-4157/V940 tshuaj tiv thaiv rau hauv kev kho mob melanoma algorithm, ua ke nrog kev tiv thaiv kab mob. checkpoint inhibition. Raws li cov ntaub ntawv uas twb muaj lawm tau sim thiab tshuaj xyuas ntxiv, cov neeg tshawb xyuas twb tau txais kev txaus siab txog qhov tshiab no, cog lus rau txoj hauv kev kho mob qog noj ntshav.
Ntsiab lus: mRNA; cov tshuaj tiv thaiv kab mob; melanoma; mob qog noj ntshav; tshuaj tiv thaiv kab mob
cistanche ntxiv cov txiaj ntsig-Antitumor
1. Taw qhia
Txij li thaum mRNA tau tshawb pom thiab lees paub tias yog ib qho tseem ceeb thiab muaj peev xwm ntawm cov noob transcription mediator [1], kev tsim cov protein qhia rau hauv cov kab lis kev cai ntawm tes thiab cov qauv murine tau siv dav hauv kev tshawb fawb mob qog noj ntshav [2–4]. Nyob rau xyoo 1990-2000 xyoo caum, ntau qhov kev sim ntawm mRNA-based tshuaj tiv thaiv kab mob qog noj ntshav tau tsim nyob rau hauv qib preclinical, siv kev qhia ntawm cov kab mob qog noj ntshav xws li carcinoembryonic antigen (CEA) thiab glycoprotein 100 (gp100). [5–7]. Txawm li cas los xij, cov tshuaj tiv thaiv mRNA-raws li tsis tau muab tso rau hauv kev kho mob kom txog rau thaum qhov kev tawm tsam ntawm COVID-19 kis thoob qhov txhia chaw, feem ntau yog vim tsis muaj kev tshawb fawb thiab kev siv txuj ci tsim nyog los ua pov thawj lawv cov tshuaj tiv thaiv kab mob nrog rau lawv txoj kev ruaj ntseg [8 ,9] ib. Tau ntau xyoo dhau los, kev txawj ntse txog kev tsim tshuaj tiv thaiv mRNA maj mam nce ntxiv, thaum kawg tso cai rau lawv los ua qhov tseem ceeb tiv thaiv tus kabmob kis tsis ntev los no [8,9]. Tseeb tiag, dhau xyoo 2020-2021, Pfifiser thiab Moderna mRNA cov tshuaj tiv thaiv tau kawm hauv kev sim tshuaj, tau raug pom zoo, thiab tau muab rau pej xeem hauv kev mob siab rau txwv tsis pub kis tus kab mob thiab txo qhov hnyav ntawm nws qhov kev kuaj mob tshwm sim hauv tus kab mob. tib neeg [10–12]. Hauv cov ntsiab lus no, kev txaus siab tshawb fawb hauv cov tshuaj tiv thaiv mRNA raws li kev kho mob antineoplastic tau rov ua dua. mRNA tshuaj tiv thaiv kab mob sib kis los ntawm kev nthuav qhia antigen, raws li lawv tau koom ua ke los ntawm cov hlwb dendritic, uas yog li nthuav tawm cov tshuaj tiv thaiv kab mob qog noj ntshav rau ntawm lawv qhov chaw, yog li inducing cytotoxic CD8 ntxiv nrog rau cov pab CD4 ntxiv rau kev ua haujlwm ntawm tes thaum nce kev tso tawm ntawm cov kab mob inflammatory [13] . Yog li ntawd, lawv sawv cev rau txoj kev cog lus ntawm kev xa cov ntaub ntawv caj ces rau lub cev tiv thaiv kab mob tsis cuam tshuam nrog cov qauv DNA DNA lossis cuam tshuam cov cellular protein qhia nyob rau hauv ib qho chaw ruaj khov, vim mRNA tsis nkag mus rau hauv lub cell nucleus, uas yuav ua rau muaj kev hloov pauv tsis zoo [8,9,14. , 15] ib. Tsis tas li ntawd, mRNA tuaj yeem raug xa mus yam tsis muaj kab mob lossis plasmid vectors, yog ib txwm yaj los ntawm tus tswv tsev cell, thiab tsis tshua muaj nqi los tsim piv rau DNA-txog kev kho mob, ua kom muaj kev nyab xeeb dua thiab kev tsim khoom loj [8,9,13, 16, 17] ib. tshuaj tiv thaiv mRNA tej zaum yuav raug txhaj tshuaj ex vivo; antigen-presenting cells-xws li dendritic cells-yog cais los ntawm tus neeg mob, incubated nrog mRNA tshuaj tiv thaiv kom induce qhia ntawm mRNA-encoded antigens, thiab thaum kawg rov qhia rau tus tswv tsev. Lwm txoj hauv kev muaj kev tswj hwm ncaj qha ntawm cov tshuaj tiv thaiv mRNA rau tus neeg mob thiab yuav tsum muaj cov qauv tshuaj tiv thaiv ruaj ntseg, ua tau los ntawm kev sib koom ua ke ntawm stabilizing cationic complexes xws li protamine (xws li resin-zoo li alkaline protein) thiab polymers xws li polyethyleneimine [8,9. , 18] ib. Kev nce qib thev naus laus zis tsis ntev los no tau ua rau muaj kev txhim kho lipid nanoparticles siv los ua mRNA vectors, thauj mRNA kom ruaj ntseg rau hauv cytoplasm, vim lawv yog ob qho tib si ruaj khov thiab nquag mus rau endocytosis, tsis cuam tshuam nrog cov loaded mRNA muaj nuj nqi [8,9,18]. Nyob rau xyoo tsis ntev los no, cov txheej txheem ntawm kev tsim tshuaj tiv thaiv mRNA tau tshawb nrhiav thiab ua kom zoo dua qub. Kev hloov pauv ntawm mRNA molecule koom nrog yog ua nyob rau hauv vitro, raws li DNA sib lawv liag encoding lub hom phiaj antigen, tom kawg tau muab tso rau hauv ib qho linearized plasmid [8,9,18]. Tau dim degradation los ntawm extracellular RNases (enzymes decomposing mRNA), ib feem ntawm kev tswj hwm mRNA nkag mus rau cytoplasm ntawm lub hom phiaj cell los ntawm endocytosis, muab txhais ua cov proteins los ntawm ribosomal machinery. Cov protein uas tau tshwm sim tuaj yeem raug tso tawm los yog thauj thiab nthuav tawm ntawm cov cell sab nraud, txuas nrog MHC (qhov loj histocompatibility complex) chav kawm I lossis II cov proteins [8,9,18]. Raws li twb tau hais lawm, kev ruaj ntseg yog qhov tseem ceeb rau kev txhaj tshuaj mRNA zoo, muab qhov tsis zoo ntawm mRNA thiab muaj ntau ntawm cov RNases extracellular. Tsim cov tshuaj tiv thaiv mRNA muaj zog tuaj yeem ua tiav los ntawm kev sib koom ua ke ntawm 50 thiab 30 thaj chaw tsis tau txhais, uas suav nrog thaj chaw encoding, tiv thaiv nws qhov kev puas tsuaj. Capping los ntawm methylation ntawm 50 cheeb tsam, thiab txuas ntawm poly (A) tail (ib theem ntawm ntau adenosine monophosphates) mus rau 30 cheeb tsam, yog ob qho tib si ua haujlwm kom ruaj khov mRNA ib ntus [8,9,18]. mRNA-raws li kev kho mob muaj peev xwm dav; Lawv tuaj yeem siv rau cov kab mob malignancies, kis kab mob, thiab kev ua xua. Hauv oncology, lub hom phiaj ntawm kev txhaj tshuaj mRNA, tsis hais txog ntawm txoj kev tswj hwm lossis cov txheej txheem encoded, yog txhawm rau ua kom lub cev tiv thaiv kab mob thiab txhawb nqa lub cev tiv thaiv kab mob tiv thaiv kab mob qog noj ntshav [8,9,16,18]. Target proteins encoded los ntawm mRNA tshuaj tiv thaiv ib ntus soj ntsuam hauv thaj tsam ntawm oncology yog ib qho ntawm peb pawg tseem ceeb: 1. Neoantigens lossis mutated protein cov ntaub ntawv tshwj xeeb tshaj tawm los ntawm cov qog, vim yog DNA hloov pauv, lwm yam mRNA splicing, lossis kev hloov pauv tom qab. Lawv yog tus cwj pwm los ntawm cov qog nqaij hlav thiab cov qog nqaij hlav tshwj xeeb thiab tuaj yeem cuam tshuam nrog hom qog lossis txawm tias yog tus kheej, tus neeg mob tshwj xeeb antigens [19]. 2. Cov qog nqaij hlav sib txuas, uas tuaj yeem pom ntawm cov ntaub so ntswg ib txwm muaj, lawv cov lus qhia sib txawv ntawm qhov ntau lossis cov qauv ntawm cov qauv ib txwm muaj, xws li MAGE-A3 (MAGE tsev neeg tus lej A3), NY-ESO-1 (New York esophageal squamous cell carcinoma 1), tyrosinase, TPTE (transmembrane phosphatase with tensin homology), thiab gp100 [20]. 3. Inflammatory mediators, chemokines extracellularly excreted xws li IL-12 (interleukin-12) thiab GM-CSF (granulocyte-macrophage colony-stimulating factor), los yog qhia rau ntawm lub cellular nto xws li TLR4 (tus xov tooj hu -zoo li receptor 4) [21]. Kev rho tawm ntawm cov proteins saum toj no thiab mRNA ib ntus, thiab kev lees paub ntawm cov tshuaj tiv thaiv kab mob neoantigens feem ntau thiab cov kev hloov pauv DNA sib raug, tau tso cai tsim cov qauv DNA tsim nyog uas yuav raug ua haujlwm hauv kev tsim ntau yam tshuaj tiv thaiv mRNA, uas tuaj yeem siv rau ntau hom tshuaj tiv thaiv. kev mob nkeeg [8,9,16,18,21]. Cov tshuaj tiv thaiv kab mob tiv thaiv kab mob yog cov tshuaj tiv thaiv monoclonal tsom rau cov receptors tshwj xeeb ntawm lub cev tiv thaiv kab mob lossis cov kab mob malignant, ua rau lub cev tsis ua haujlwm ntawm tus tswv cytotoxic T lymphocytes uas yuav raug ntxias los ntawm cov qog hlwb. Cov neeg ua haujlwm zoo li no (piv txwv li, pembrolizumab, nivolumab, ipilimumab) tau hloov kho kho mob qog noj ntshav txij li xyoo 2010, txhawb kev kho mob rau ntau yam neoplasms, ua rau cov lus teb lub hom phiaj ruaj khov, thiab ua rau cov neeg mob muaj sia nyob ntev [22]. Qhov tseem ceeb tshaj, kev siv tshuaj tiv thaiv kab mob tau dhau los ua kev kho mob tseem ceeb rau cov neeg mob uas tsis yog-chemosensitive neoplasms xws li melanoma, muab kev kho mob ntev thiab muaj txiaj ntsig [22]. Txawm li cas los xij, kev tiv thaiv kab mob tseem tuaj yeem tshwm sim; Raws li qhia los ntawm cov ntaub ntawv soj ntsuam, 50 feem pua thiab 64 feem pua ntawm cov neeg mob melanoma, txawm tias nyob rau hauv kev sib xyaw ua ke ntawm ipilimumab thiab nivolumab, yuav muaj kev mob tshwm sim ntawm 1 thiab ntawm 5 xyoo tom qab pib kho, feem [23]. Lub hauv paus tiv thaiv mechanisms rau immunotherapy yuav raug sau tseg raws li hauv qab no:
Txo kev qhia ntawm lub hom phiaj molecules, xws li PD-L1 (programmed death-ligand 1) los ntawm cov qog nqaij hlav cancer, cuam tshuam nrog kev ua haujlwm ntawm cov tshuaj tiv thaiv PD-1 (programmed cell death protein 1) antibodies. Anti-PD-1 cov neeg ua haujlwm, xws li nivolumab thiab pembrolizumab, yog tsim los tiv thaiv kev tiv thaiv kab mob ntawm lub cev tiv thaiv kab mob thiab cov kab mob malignant, uas yog kho los ntawm kev sib txuas ntawm PD-1, qhia los ntawm T lymphocytes, thiab PD -L1, qhia los ntawm malignant hlwb. Yog li ntawd, tsis tshua muaj PD-L1 qhia tau raug txiav txim siab los qhia thawj qhov tsis kam [24,25].
cistanche tshuaj ntsuab-Antitumor
2. Tsawg neoantigen lub nra ntawm malignant hlwb. Neoantigens yog cov neoplastic antigens tshwj xeeb, muab los ntawm kev hloov pauv caj ces nqa los ntawm cov qog; qhov siab dua cov qog mutational load, qhov ntau dua ntawm cov hloov pauv antigens nthuav tawm ntawm cov qog nqaij hlav cancer. Cov hloov kho mob qog noj ntshav no tau lees paub tias txawv teb chaws los ntawm lub cev tiv thaiv kab mob, txhim kho kev tiv thaiv kab mob thiab cytotoxicity. Cov qog uas nqa cov neoantigens txwv tsis pub tuaj yeem hla lub cev tiv thaiv kab mob, thiab tsis tshua teb rau cov tshuaj tiv thaiv kab mob tiv thaiv kab mob [26,27].
3. Kev tiv thaiv kab mob. Nws tau pom tias cov qog nqaij hlav cancer, tab sis kuj yog cov hlwb los ntawm myeloid, qog stroma hlwb, thiab CD4 ntxiv rau kev tswj hwm T lymphocytes, tuaj yeem ua rau lub cev tsis muaj zog los ntawm kev txhawb nqa tawm ntawm kev tawm tsam cytokines xws li IL-10 (interleukin{{ 4}}) thiab lwm yam tshuaj kho mob xws li TGF-beta (cov qog loj hlob beta), uas inhibit lub cev tiv thaiv kab mob hauv lub cev thiab kev nthuav dav, thiab tsim cov inflammatory cytokines [28–30]. Hauv cov ntsiab lus no, kev txhaj tshuaj mRNA aspires los ua ib qho tseem ceeb ntxiv rau cov tshuaj tiv thaiv kab mob tiv thaiv kab mob, thim rov qab txoj hauv kev (Daim duab 1). Antigens tseem ceeb heev rau kev tiv thaiv kab mob (xws li ob tus neeg mob- lossis qog-hom tshwj xeeb neoantigens thiab qog-nrog rau cov tshuaj tiv thaiv kab mob) encoded los ntawm mRNA cov tshuaj tiv thaiv tuaj yeem nthuav tawm rau ntawm cov cellular nto ntawm cov tshuaj tiv thaiv kab mob, txhawb kev paub txog cov qog zes los ntawm tus tswv tsev tiv thaiv kab mob. qhov system, tsis hais txog ntawm lub hauv paus qog neoantigen ntau lawm lossis PD-L1 qhia [8,9,16]. Nyob rau tib lub sijhawm, cov tshuaj tiv thaiv mRNA encoding immune-activation-associated molecules, xws li IL-12, IFN (interferon-alpha), GM-CSF, thiab TLR4, tej zaum yuav muaj peev xwm tiv thaiv kab mob qog noj ntshav-xws li kev tiv thaiv kab mob. los ntawm kev rov ua kom lub cev tiv thaiv kab mob ua haujlwm thiab inflammatory mediator ntau lawm [8,9,16]. Tseeb tiag, hauv qhov kev sim tshaj tawm tsis ntev los no, ib qho tshuaj tiv thaiv mRNA encoding rau ib leeg-chain IL-12 (fusion ntawm IL-12p40 thiab IL12p35 subunits), IFN- , GM-CSF, thiab IL{{39 }}sushi (fusion ntawm IL-15 mus rau sushi domain ntawm IL-15 receptor), tswj kom kov yeej kev tiv thaiv tiv thaiv PD-1 kev kho mob hauv txoj hnyuv adenocarcinoma murine qauv, inducing qog shrinkage thiab ntev ciaj sia taus ntawm cov nas kho [31] Tom qab ntawd, kev sib koom ua ke ntawm cov tshuaj tiv thaiv mRNA thiab cov tshuaj tiv thaiv kab mob tiv thaiv kab mob tau dhau los ua qhov kev xav zoo rau yav tom ntej kho lub tswv yim [8,9,16]. Targeted immunotherapy tau ua tiav siv rau melanoma, neoplasm nrog kev sib raug zoo nrog lub cev tiv thaiv kab mob [32]. Txawm li cas los xij, metastatic melanoma tseem yog kab mob tuag taus rau ib feem tseem ceeb ntawm cov neeg mob, ua rau muaj kev xav tau kev tshawb fawb ntxiv rau kev txiav txim siab kho mob. Kev txhaj tshuaj tiv thaiv kab mob mRNA tuaj yeem dhau los ua cov kauj ruam tseem ceeb ntxiv mus rau lub hom phiaj no. Hauv kev tshuaj xyuas tam sim no, peb sim piav qhia txog cov ntaub ntawv kho mob thiab kho mob tsis ntev los no hais txog cov tshuaj tiv thaiv mRNA hauv kev kho mob melanoma, nrog rau cov kev cia siab yav tom ntej thiab cov ntawv thov muaj peev xwm.
Daim duab 1. Schematic sawv cev ntawm cov tshuaj tiv thaiv mRNA cuam tshuam nrog lub cev tiv thaiv kab mob, txhawm rau txhim kho lub cev tiv thaiv kab mob tiv thaiv kab mob. TMB: Tumor mutational nra, ICIs: Immune checkpoint inhibitors.
2. Cov pov thawj Preclinical
Cov tshuaj tiv thaiv mRNA tau raug tshuaj xyuas hauv cov qauv mob qog noj ntshav murine hauv ntau qhov kev sim (Table 1). Stabilization los ntawm lipid calcium phosphate nanoparticles (LCPs) tau pom tias txhim kho kev ua haujlwm ntawm mRNA tshuaj tiv thaiv encoding gp100 thiab tyrosinase-related protein 2 (TRP-2) uas tau tswj hwm rau immunocompetent murine B16F10 melanoma qauv. Kev txhaj tshuaj tiv thaiv ua rau cov qog nqaij hlav loj zuj zus, thaum ua kom muaj sia nyob ntawm cov nas kho [33].
Table 1. tshuaj tiv thaiv mRNA raws li kev kho mob melanoma: cov ntaub ntawv kho mob.
Xyoo 2018, Wang et al. [34] tau tshaj tawm ua tiav hauv vitro hloov pauv ntawm cov hlwb dendritic los ntawm LCP-raws li cov tshuaj tiv thaiv uas muaj mRNA encoding tyrosinase-related protein 2 (TRP-2) thiab silencing RNA (siRNA) tsom PD-L1 qhia. TRP-2 yog ib qho protein mediating melanin synthesis nyob rau hauv melanocytes thiab tau tshaj tawm hais tias yuav ua rau melanoma cell tsis kam tiv thaiv DNA-damaging agents thaum overexpressed [38]. Thaum cov qauv murine melanoma tau txhaj tshuaj tiv thaiv ncaj qha, CD8 ntxiv rau T lymphocyte tsim nyob rau hauv cov qog nqaij hlav, qog loj, thiab tus po tau nce ntxiv piv rau cov tsiaj tsis kho. T lymphocyte-tshwj xeeb cov tshuaj tiv thaiv rau TRP-2 tau txhim kho, thaum PD-L1 (programmed death- ligand 1) qhia tau zoo khob. Cov qog loj hlob tau qeeb qeeb hauv cov tsiaj kho, nrog rau kev loj hlob ntawm cov qog nqaij hlav cancer. Qhov zoo siab, kev txhaj tshuaj tiv thaiv los ntawm kev sib xyaw ntawm TRP-2-encoding mRNA thiab siRNA tau pom tias muaj qhov cuam tshuam loj dua ntawm cov qog hlav loj hlob piv rau kev sib koom ua ke ntawm TRP-2 tshuaj tiv thaiv mRNA thiab tshuaj tiv thaiv PD{{22} } (programmed cell death protein 1) monoclonal antibody. Nws kuj tau sau tseg tias LCP tsim zoo li txhawb kev loj hlob ntawm dendritic cell, los ntawm kev txhim kho cov calcium hauv cov cell. Lwm LCP-raws li cov tshuaj tiv thaiv mRNA, kuj encoding TRP-2, tswj infiltrate antigen-presenting cells (APCs) los ntawm phagocytosis, inducing vigorous T cell activation, thiab txhawb kev hu xov tooj zoo li receptor 4 (TLR4)-kho teeb liab thiab inflammatory cytokine tso tawm thaum subcutaneously txhaj nyob rau hauv melanoma murine qauv. Yog li ntawd, cov qog loj hlob tau qeeb qeeb hauv cov nas uas tau txhaj tshuaj tiv thaiv kev sib piv rau kev tswj tsis tau kho [35]. Kev txhaj tshuaj intratumoral ntawm cov tshuaj tiv thaiv ua ke uas muaj cov khoom siv hluavtaws phosphorothioate-hloov CpG oligodeoxynucleotides (CpG-ODNs) tau pom tias txhim kho lub cev tiv thaiv kab mob thiab mRNA encoding rau cov melanoma neoantigens tshwj xeeb hauv cov qauv syngeneic murine, inhibiting melanoma loj hlob thaum txhawb cov qog thiab cov kab mob CD4. Ntxiv rau lymphocytes [36]. Hauv kev sim uas nyuam qhuav luam tawm, mRNA encoding TRP-2 thiab ovalbumin, lub qe dawb cov protein tau pom los txhim kho kev paub txog neoantigen los ntawm cytotoxic lymphocytes [39], xa mus rau cov qog nqaij hlav ntawm syngeneic melanoma murine qauv, tswj los txhawb cov lus teb cytotoxic cell. los ntawm CD8 plus T cells. Nyob rau tib lub sijhawm, ua ke nrog cov tshuaj tiv thaiv PD-1 inhibitor, cov lus teb ua tiav tau pom hauv 40 feem pua ntawm cov nas kho. Kev txhaj tshuaj tiv thaiv tau pom tias ua rau lub cev tiv thaiv kab mob ntev ntev hauv kev sim rov ua dua tshiab, qhov twg metastatic qog loj hlob tau cuam tshuam hauv cov tsiaj txhaj tshuaj [37].
cistanche tubulosa- txhim kho lub cev tiv thaiv kab mob
3. Cov ntaub ntawv pov thawj kho mob
Cov tshuaj tiv thaiv mRNA tau muab rau cov neeg mob melanoma siab heev nyob rau hauv cov ntsiab lus ntawm ntau theem I/II kev sim tshuaj (Table 2). Raws li thaum ntxov xyoo 2006, ib qho tshuaj tiv thaiv uas muaj cov autologous monocyte-derived dendritic hlwb, ex vivo loaded nrog autologous qog mRNA, tau intranodal los yog intradermally txhaj rau 22 malignant melanoma cov neeg mob. Cov tshuaj tiv thaiv kab mob tshwj xeeb, tshwj xeeb los ntawm T lymphocyte nthuav dav thiab interferon- ntau lawm yog, qhov tseeb, pom nyob rau cuaj tawm ntawm 19 tus neeg mob, ntsuas los ntawm T cell proliferation / interferon- ELISPOT kev soj ntsuam, nrog rau hauv 8/18 ntsuas los ntawm kev ncua sij hawm tsis txaus siab. [40]. Intradermal lossis intranodal tswj tau ua rau lub cev tiv thaiv kab mob hauv 70 feem pua (7/10) thiab 25 feem pua (3/12) ntawm cov neeg mob kho, feem [40]. Tom qab ntawd ntawm [41], cov tshuaj tiv thaiv kab mob CD4 ntxiv thiab CD8 ntxiv rau T cell teb tawm tsam neoantigens encoded los ntawm cov tshuaj tiv thaiv mRNA tau tshaj tawm ntawm cuaj tus neeg teb; Cov neeg mob 'T cells cais tawm tom qab txhaj tshuaj tiv thaiv tuaj yeem tsim ntau yam T cell clones tshwj xeeb ua rau cov hlwb dendritic, thaum muaj ntau yam T cell receptors cuam tshuam txog cov tshuaj tiv thaiv neoantigen spectrum tau sau tseg. Direct intradermal kev tswj hwm ntawm protamine-stabilized mRNA encoding rau melanoma antigens (Melan-A, Tyrosinase, gp100, MAGE-A1, MAGE-A3, Survivin) rau 21 tus neeg mob metastatic melanoma [42] tau txais txiaj ntsig zoo, ua rau tsis muaj qhov tshwm sim tsis zoo ntawm qib. 3 los yog siab dua. Markedly, kev tswj hwm thiab myeloid suppressor cell ncig tau txwv hauv cov neeg mob txhaj tshuaj. Cov tshuaj tiv thaiv T lymphocyte tshwj xeeb tiv thaiv cov tshuaj tiv thaiv antigens tau sau tseg hauv ob ntawm plaub tus neeg mob uas ntsuas tau, thiab cov lus teb tiav tau pom nyob rau hauv ib ntawm xya tus neeg mob uas ntsuas tau.
Table 2. cov tshuaj tiv thaiv mRNA hauv kev kho mob melanoma: cov ntaub ntawv kho mob.
Cov tshuaj tiv thaiv TriMix mRNA, muaj xws li mRNA encoding rau CD40 ligand (T helper cell nto protein, mediating antigen-specific reaction), constitutively active hu-like receptor 4 (hematopoietic and nonhematopoietic cell surface antigen mediating recognition of exogenous and endogenous antigens), thiab CD70 (cov qog nqaij hlav tiv thaiv kab mob antigen), tau raug sim hauv ntau qhov kev sim. Hauv kev tshawb nrhiav kev sim [43], autologous TriMix-electroporated dendritic cells tau kis los ntawm mRNA encoding rau melanoma-associated antigen (MAGE-A3, MAGE-C2, tyrosinase, lossis gp100), conjugated nrog HLA chav kawm II teeb liab. Transfected dendritic cells raug tswj xyuas kom zoo rau 35 theem III / IV cov neeg mob melanoma tsis tuaj yeem, tab sis tsis muaj lub hom phiaj teb raws li RECIST cov txheej txheem tau pom. Tom qab ntxiv IFN- -2b kev tswj hwm, 1/17 cov neeg mob soj ntsuam tau ntsib cov lus teb ib nrab, thaum 5/17 qhia txog kab mob ruaj khov. Daim tawv nqaij biopsies ua nyob rau hauv 21 cov neeg mob tom qab ib tug thib plaub TriMix-DCs txhaj tshuaj pom infiltration los ntawm cov tshuaj tiv thaiv neoantigen-specific T lymphocytes nyob rau hauv 12 ntawm lawv. Qhov tseem ceeb, kev txhaj tshuaj tiv thaiv kab mob autologous nrog TriMix-DCs thawed nrog melanoma-txuas nrog antigens (MAGE-A3, MAGE-C2, tyrosinase, gp100) tau pom tias ua rau muaj kev nthuav dav ntawm cov tshuaj tiv thaiv neoantigen-directed T lymphocytes, pom muaj ob qho tib si hauv peripheral ntshav kuaj. /14 thiab hauv daim tawv nqaij biopsies hauv 12/14 ntawm cov neeg mob kho tau zoo [44]. Ntawm 14 tus neeg mob uas ntsuas tau, ob qhov ua tiav thiab ib feem lub hom phiaj teb tau raug sau tseg, nrog rau lwm tus neeg mob 4/14 uas qhia txog kev tiv thaiv kab mob. PFS thiab OS txawv ntawm 1.8 mus rau 51 lub hlis, thiab 6.4 mus rau 51 lub hlis, feem; tab sis tsis muaj kev sib koom ua ke ntawm cov txiaj ntsig kev kho mob thiab cov lus teb tiv thaiv kab mob hauv qhov kev tshawb fawb [44]. Cov tshuaj tiv thaiv TriMix tau raug tshaj tawm los ua kom muaj kev ntsuas lub cev tiv thaiv kab mob hauv 4/10 cov neeg mob uas muaj theem siab melanoma tau txais koob tshuaj ntau, thiab hauv 3/9 cov neeg mob tau txais koob tshuaj tsawg, hauv ASCO 2019 [47].
Superman tshuaj ntsuab cistanche-Antitumor
Tib yam tshuaj tiv thaiv TriMix-DC-MEL, raws li mRNA coding rau plaub melanoma-txuas nrog antigens (tyrosinase, gp100, MAGE-A3, thiab MAGE-C2), kuj tau ua ke nrog kev tswj hwm ipilimumab hauv 30 qib siab. Cov neeg mob melanoma [46] Tshaj tawm tsib xyoos tag nrho thiab kev muaj sia nyob tsis muaj kev vam meej yog 28 feem pua thiab 18 feem pua. Kev ntsuam xyuas lub cev tiv thaiv kab mob los ntawm peripheral ntshav mononuclear cell (PBMC) retrieval thiab ntsuam xyuas rau melanoma tshuaj tiv thaiv antigen enrichment yog ua tau rau 15/30 cov neeg mob (4/15, 4/15, thiab 2/15 nrog CR, PR, thiab SD, feem). Lub cev tiv thaiv kab mob rau cov tshuaj tiv thaiv tau sau tseg hauv 12/15 cov neeg mob thiab tau cuam tshuam nrog cov lus teb lub hom phiaj kho mob, ua kom muaj zog ntau dua hauv cov neeg mob uas muaj cov lus teb ib nrab thiab ua tiav piv rau cov neeg mob uas muaj tus kab mob ruaj khov los yog kev loj hlob. Qhov tseem ceeb, kev muaj sia nyob tag nrho tau pom tias muaj feem cuam tshuam nrog feem pua ntawm CD8 ntxiv rau T cell ua rau cov neeg tiv thaiv kab mob [46]. Kev txhaj tshuaj nrog autologous dendritic cells loaded nrog mRNA encoding rau melanoma-specific antigens (MAGE-A1, -A3, -C2, tyrosinase, MelanA/MART-1, lossis gp100), thiab HLA class II-targeting sequence, muaj kuj tau raug soj ntsuam nyob rau hauv 30 resected theem III/IV melanoma cov neeg mob [45]. Tshaj tawm qhov nruab nrab ntawm kev rov qab tsis muaj sia nyob yuav luag ob xyoos (22 lub hlis; 95 feem pua CI 12-32 lub hlis). Thaum lub sijhawm tshaj tawm, kaum ob tus neeg mob tau tuag, thiab plaub xyoos tag nrho cov ciaj sia taus yog 70 feem pua. Qhov nruab nrab tag nrho cov ciaj sia tsis tau mus txog. Hauv kev sim ua kom nthuav dav melanoma-txuas nrog neoantigen spectrum siv rau cov tshuaj tiv thaiv mRNA, Ping li al. [48] piv 471 melanoma cov ntaub so ntswg mus rau 812 cov qauv ntawm daim tawv nqaij. Tag nrho ntawm tsib lub hom phiaj qog nqaij hlav qog nqaij hlav tau txheeb xyuas (PTPRC, SIGLEC10, CARD11, LILRB1, ADAMDEC1); siab antigen qhia tau txuam nrog ntev OS thiab DFS, nrog rau ntau dua qog infiltration los ntawm antigen-tam sim no hlwb. Kev qhia muaj zog ntawm tsib antigens los ntawm cov qog nqaij hlav qog noj ntshav tau cuam tshuam nrog cov qog nqaij hlav tiv thaiv kab mob ntau dua thiab txhim kho tus neeg mob kom muaj sia nyob, qhov qis qis thiab lub sijhawm muaj sia nyob luv dua tau cuam tshuam nrog immunogenically 'txias' melanomas. Cov kev tshawb fawb soj ntsuam no tuaj yeem ua rau muaj kev lees paub ntawm cov tshuaj tiv thaiv kab mob tiv thaiv kab mob siab heev, uas tuaj yeem ua lub hauv paus rau kev tsim tshuaj tiv thaiv mRNA tshiab. Tam sim no, kev txhaj tshuaj mRNA tau raug tshuaj xyuas hauv rau rau qhov kev sim tshuaj kho mob melanoma, uas twb tau pom cov txiaj ntsig tau zoo [49,50]. KEYNOTE-942 (NCT03897881) [33,34], ib qho kev sim qhib-label theem IIb txuas ntxiv, twb tau qhia tshwj xeeb txhawb cov txiaj ntsig txog kev kho mob ntxiv. Hauv txoj kev tshawb no, kev sib xyaw ua ke ntawm tus kheej cov tshuaj tiv thaiv mRNA encoding 20 qhov sib txawv ntawm qhov sib txawv neoantigens thiab anti-PD-1 inhibitor pembrolizumab tau muab rau cov neeg mob uas tau raug tshem tawm tag nrho theem III / IV melanoma, piv rau ib tus neeg sawv cev pembrolizumab kho. Raws li kev tshaj tawm xov xwm tsis ntev los no los ntawm cov tuam txhab tsim khoom [51], cov neeg mob tau txais kev kho mob ntxiv nrog pembrolizumab ua ke nrog cov tshuaj tiv thaiv mRNA-4157/V940 zoo li muaj 44 feem pua ntawm cov kab mob rov qab los yog tuag, piv rau cov neeg mob hauv qab no. ib leeg-tus neeg saib xyuas pembrolizumab kev kho mob (HR=0.56, 95 feem pua CI, 0.31–1.08; one-sided p-value=0.0266). Kev kho mob hnyav txog cov xwm txheej tsis zoo tau tshaj tawm ntawm tus nqi ntawm 14.4 feem pua thiab 10 feem pua , hauv kev sib xyaw ua ke thiab ib leeg-tus neeg sawv cev pembrolizumab caj npab, feem [51]. Kev xav txog cov neeg tshawb nrhiav qhov kev txaus siab txog KEYNOTE-942 qhov tshwm sim thaum ntxov, xibfwb Georgina Long ntawm Melanoma Institute of Australia tau hais tias qhov kev sim no tuaj yeem tsim "penicillin moment" txog kev kho mob melanoma [52]. Tsis tas li ntawd, qhov kev sim theem III tseem tab tom npaj txhawm rau pib ua cov kauj ruam tom ntej [53]. Kev nyab xeeb thiab kev ua siab ntev ntawm BNT111 mRNA tshuaj tiv thaiv, uas encodes plaub melanoma antigens: NY-ESO-1, tyrosinase, MAGE-A3, thiab TPTE, yog nyob rau hauv kev ntsuam xyuas nyob rau hauv ib theem kuv sim (NCT02410733). Tib yam tshuaj tiv thaiv no tau koom nrog lwm tus PD-1 inhibitor, ceiplimab, nyob rau hauv peb lub caj npab sib piv theem II (NCT04526899) [50]. Cov kws tshawb fawb yuav tau sim los sib piv monotherapy nrog BNT111 tshuaj tiv thaiv los yog ceiplimab rau kev sib xyaw ntawm ob tus neeg ua haujlwm, raws li kev kho thib ob tiv thaiv kab mob tiv thaiv kab mob inhibitor refractory, tsis tuaj yeem kho melanoma [50]. Kev sim Memorial Sloan Kettering Cancer Center theem I yog tam sim no soj ntsuam kev tswj hwm ntawm autologous human Langerhans-type dendritic cells, electroporated nrog mRNA tshuaj tiv thaiv encoding rau TRP{105}}, rau cov neeg mob IIB mus rau IV theem melanoma, tom qab kev kho mob phais kom tsim nyog. (NCT01456104) [50]. Ib qho tshuaj tiv thaiv mRNA autologous raws li gp100, tyrosinase, PRAME, MAGE-A3, IDO, thiab lwm yam kev hloov pauv ntawm cov qog nqaij hlav, thauj khoom ntawm cov hlwb dendritic, yuav tsum tau muab tshuaj rau hauv cov neeg mob uveal melanoma, ua ke nrog kev kho mob, hauv theem kuv sim ( NCT04335890) [33]. Ntxiv mus, ib theem kuv qhib-label sim (NCT05264974) [50], teem rau pib nrhiav neeg mob nyob rau hauv 2023, lub hom phiaj los tshawb txog qhov tolerability ntawm autologous qog mRNA nanoparticle tshuaj tiv thaiv nyob rau hauv theem IIIB mus rau theem IV melanoma cov neeg mob, tom qab tus kab mob relapse txawm adjuvant. tshuaj tiv thaiv kab mob. Txoj kev tshawb no yuav tsum ua kom tiav hauv 2027 [50].
4. Cov lus xaus thiab lub zeem muag yav tom ntej
cistanche ntxiv cov txiaj ntsig-yuav ua li cas ntxiv dag zog rau lub cev
Nyem qhov no mus saib Cistanche Enhance Immunity khoom
【Nug ntxiv】 Email: cindy.xue@wecistanche.com / Whats App: 0086 18599088692 / Wechat: 18599088692
Thaum lub sijhawm COVID-19 muaj thoob qhov txhia chaw, cov tshuaj tiv thaiv mRNA tau kawm nruj heev, qhia txog lub peev xwm ntawm cov thev naus laus zis thev naus laus zis no los tsim kho kev kho mob melanoma. Tsiaj cov qauv kev sim thiab kev sim tshuaj ntsuam xyuas tau pom cov txiaj ntsig tau zoo, teeb tsa keeb kwm yav dhau los rau kev tshawb fawb ntau dua hauv xyoo tom ntej. KEYNOTE-942 kev sim tshwj xeeb, sib txuas cov tshuaj tiv thaiv mRNA nrog cov tshuaj tiv thaiv kab mob tiv thaiv kab mob, aspires kom ua tiav qhov tseem ceeb tom ntej hauv kev kho mob melanoma. Cov ntsiab lus tseem ceeb rau kev kuaj mob yav tom ntej thiab kev tshawb fawb soj ntsuam tshawb xyuas mRNA-raws li kev kho mob qog noj ntshav yuav muaj xws li:
1. Kev txheeb xyuas cov tshuaj tiv thaiv kab mob siab heev, xws li cov tshuaj chemokines lossis cov qog muaj feem cuam tshuam nrog cov tshuaj tiv thaiv kab mob, uas yuav ua rau muaj txiaj ntsig zoo thiab muaj kev tiv thaiv kab mob tshwj xeeb, tsis muaj kev cuam tshuam rau lub cev ib txwm muaj.
2. Kev tsim kho cov kws tshaj lij txog kev paub thiab kev tsim kho kom tsim tau cov tshuaj tiv thaiv mRNA ruaj khov uas muaj peev xwm dim ntawm kev puas tsuaj thaum ntxov, ua kom muaj kev nyab xeeb, raug tsim tawm raws sijhawm, thiab muab faib rau hauv qhov loj.
3. Kev ua siab ntev ntawm qhov ua tau ua ke ntawm kev txhaj tshuaj mRNA nrog cov tshuaj tiv thaiv kab mob tiv thaiv kab mob thiab txawm tias tshuaj tua kab mob lossis kev kho mob hluav taws xob; tab sis kuj lawv cov txiaj ntsig ntawm lub hom phiaj teb, kab mob rov qab los yog kev tiv thaiv kev loj hlob, kev ciaj sia tag nrho, thiab lub neej zoo rau cov neeg mob.
4. Cov txiaj ntsig kho mob ntawm kev txhaj tshuaj mRNA-raws li nyob rau hauv qhov chaw kho mob metastatic, adjuvant, thiab neoadjuvant, nrog rau kev kho thawj zaug lossis thib ob thiab lwm yam.
Raws li cov lus nug saum toj no tseem yuav tsum tau teb, cov kws kho mob yuav tsum paub txog kev nrhiav neeg ua haujlwm nyob rau hauv thiaj li yuav qhia rau cov neeg mob, muab sijhawm rau lawv rau npe thiab tau txais cov tshuaj raws li kev siv tshuab tam sim no.
Cov ntaub ntawv
1. Brenner, S.; Jacob, F.; Meselson, M. Ib qho nruab nrab tsis ruaj khov nqa cov ntaub ntawv los ntawm cov noob mus rau ribosomes rau protein synthesis. Xwm Txheej 1961, 190, 576–581. [CrossRef] [PubMed]
2. Wolff, JA; Malone, RW; Williams, P.; Chaw, W.; Acsadi, G.; Jani, ib.; Felgner, PL Direct gene hloov mus rau hauv cov leeg nas hauv vivo. Science 1990, 247 Pt 1, 1465–1468. [CrossRef]
3. Baklausev, VP; Kilpeläinen, A.; Petkov, S.; Abakumov, MA; Grinenko, NF; Yusubalieva, GM; Latanova, UA; Gubskiy, IL; Zabozlaev, FG; Starodubova, ES; ua al. Luciferase Expression tso cai rau Bioluminescence Imaging Tab sis Imposes txwv ntawm Orthotopic Mouse (4T1) Model of Cancer Cancer. Sci. Rep. 2017, 7, 7715. [CrossRef] [PubMed]
4. Jenkins, DE; Hornig, YS; Aw, Y.; Dusich, J.; Purchio, T. Bioluminescent tib neeg mob qog noj ntshav cov kab mob qog noj ntshav uas tso cai nrawm thiab nkag siab hauv vivo tshawb pom cov qog mammary thiab ntau yam metastases hauv cov nas tsis muaj zog tiv thaiv kab mob. Lub mis Cancer Res. Xyoo 2005, 7, R444–R454. [CrossRef] [PubMed]
5. Conry, RM; LoBuglio, AF; Wright, M.; Sumerel, L.; ib. Pike, MJ; Johanning, F.; Benjamin, R. Lu, D.; Curiel, DT Tus cwj pwm ntawm tus tub txib RNA polynucleotide tshuaj tiv thaiv vector. Cancer Res. 1995, 55, 1397–1400.
6. Zhou, WJ; Hoon, DS; Huang, SK; Fujii, S.; Hashimoto, K.; Morishita, R.; Kaneda, Y. RNA tshuaj tiv thaiv melanoma: Induction ntawm antitumor tiv thaiv los ntawm tib neeg glycoprotein 100 mRNA txhaj tshuaj. Hum. Gene Ther. 1999, 10, 2719–2724. [CrossRef]
7. Boczkowski, D.; Nair, SK; Snyder, D.; Gilboa, E. Dendritic hlwb pulsed nrog RNA yog cov muaj zog antigen-tam sim no hlwb hauv vitro thiab hauv vivo. J. Exp. Med. Xyoo 1996, 184, 465–472. [CrossRef]
8. Sahin, UA; Karikó, K.; Türeci, UA. mRNA-based therapeutics-Tsim ib chav kawm tshiab ntawm cov tshuaj. Nat. Rev. Drug Discov. 2014, 13, 759–780. [CrossRef]
9. Pardi, N.; Hogan, MJ; Porter, FW; Weissman, D. mRNA tshuaj tiv thaiv—Ib lub sijhawm tshiab hauv kev txhaj tshuaj tiv thaiv. Nat. Rev. Drug Discov. 2018, 17, 261–279. [CrossRef]
10. Polack, FP; Thomas, SJ; Kitchin, N.; Absalon, J.; Gurtman, UA; Lockhart, S.; ib. Perez, JL; Pérez Marc, G.; Moreira, ED; Zerbini, C.; ua al. Kev nyab xeeb thiab kev ua tau zoo ntawm BNT162b2 mRNA COVID-19 tshuaj tiv thaiv. N. Engl. J. Med. 2020, 383, 2603–2615. [CrossRef]
11. Shroff, RT; Chalasani, P.; Wei, R.; Pennington, D.; Quir, G.; Schoenle, MV; Peyton, KL; Uhrlaub, JL; Ripperger, TJ; Jergov'c, M.; ua al. Cov tshuaj tiv thaiv kab mob rau ob thiab peb koob tshuaj BNT162b2 mRNA rau cov neeg laus uas muaj cov qog nqaij hlav. Nat. Med. 2021, 27, 2002–2011. [CrossRef]
12. Jackson, LA; Anderson, EJ; Rouphael, NG; Roberts, PC; Mas, M.; Coler, RN; McCullough, MP; Chappell, JD; Denison, MR. Stevens, LJ; ua al. Ib qho tshuaj tiv thaiv mRNA tiv thaiv SARS-CoV2d daim ntawv qhia ua ntej. N. Engl. J. Med. Xyoo 2020, 383, 1920–1931. [CrossRef]
13. Iavarone, C.; O'hagan, DT; Yus, D.; Delahaye, NF; Ulmer, JB Mechanism of action of mRNA-based vaccines. Kws Tshuaj Tiv Thaiv Kab Mob 2017, 16, 871–881. [CrossRef]
14. Tomba'cz, I.; Weissman, D.; Pardi, N. Kev txhaj tshuaj nrog tus xa xov RNA: Ib qho kev cog lus rau kev txhaj tshuaj DNA. Txoj kev Mol. Biol. 2021, 2197, 13–31.
15. Miao, L.; Zhang, YJ; Huang, L. mRNA tshuaj tiv thaiv kab mob qog noj ntshav. Mol. Cancer 2021, 20, 41. [CrossRef]
16. Barbier, AJ; Jiang, UA; Zhang, P. Wooster, R.; Anderson, DG Kev kho mob ntawm mRNA tshuaj tiv thaiv thiab kev tiv thaiv kab mob. Nat. Biotechnol. 2022, 40, 840–854. [CrossRef] [PubMed]
17. Van Nuffel, AM; Wilgenhof, S.; Thielemans, K.; Bonehill, A. Hla kev txwv HLA hauv kev sim tshuaj kho mob: Kev tiv thaiv kab mob ntawm mRNA-loaded DC therapy. Oncoimmunology 2012, 1, 1392–1394. [CrossRef]
18. Xu, S.; Yang, K.; Li, R.; Zhang, L. mRNA Vaccine Era-Mechanisms, Drug Platform thiab Clinical Prospection. Int. J. Mol. Sci. 2020, 21, 6582. [CrossRef] [PubMed]
19. Xie, N.; Shen, G.; Gao, W.; Huang, Z.; Huang, C.; Fu, L. Neoantigens: Kev cog lus lub hom phiaj rau kev kho mob qog noj ntshav. Teeb liab Transduct. Target Ther. 2023, 8, 9. [CrossRef]
20. Liu, CC; Yang, H.; Zhang, R. Zhao, JJ; Hao, DJ Tumour-associated antigens thiab lawv cov kev siv tshuaj tiv thaiv kab mob. Eur. J. Cancer Care 2017, 26, e12446. [CrossRef] [PubMed]
21. Cosentino, M.; Marino, F. Nkag siab txog Pharmacology ntawm COVID-19 mRNA Cov Tshuaj Tiv Thaiv: Ua Si Dice nrog Spike? Int. J. Mol. Sci. 2022, 23, 10881. [CrossRef] [PubMed] 22. Bagchi, S.; Yuan, R.; Engleman, EG Immune Checkpoint Inhibitors rau Kev Kho Mob Cancer: Clinical Impact thiab Mechanisms of Response and Resistance. Ann. Rev. Pathol. 2021, 16, 223–249. [CrossRef] [PubMed]
23. Larkin, J.; Chiarion-Sileni, V.; Gonzalez, R. Grob, JJ; Rutkowski, P. Lao, CD; Cowey, CL; Schadendorf, D.; Wagstaff, J.; Dummer, R.; ua al. Tsib-xyoo Ciaj sia nyob nrog kev sib xyaw Nivolumab thiab Ipilimumab hauv Advanced Melanoma. N. Engl. J. Med. 2019, 381, 1535–1546. [CrossRef] [PubMed]
24. Patel, SP; Kurzrock, R. PD-L1 Kev Tshaj Tawm raws li Kev Tshawb Fawb Biomarker hauv Cancer Immunotherapy. Mol. Cancer Ther. Xyoo 2015, 14, 847–856. [CrossRef]
25. Fundytus, A.; Lub rooj muag khoom, CM; Tannock, IF Koj tuaj yeem mus qis npaum li cas? PD-L1 qhia ua biomarker hauv kev sim tshuaj tiv thaiv kab mob qog noj ntshav. Ann. Oncol. 2021, 32, 833–836. [CrossRef] 26. Jardim, DL; Goodman, A.; de Melo Gagliato, D.; Kurzrock, R. Cov Kev Sib Tw ntawm Tumor Mutational Burden ua ib qho Immunotherapy Biomarker. Cancer Cell 2021, 39, 154–173. [CrossRef]
27. Chan, TA; Yarchoan, M.; Jaffee, E.; Swanton, C.; Quezada, SA; Stenzinger, A.; Peters, S. Kev loj hlob ntawm qog mutation lub nra raws li ib tug immunotherapy biomarker: Utility rau lub chaw kho mob oncology. Ann. Oncol. Xyoo 2019, 30, 44–56. [CrossRef]
28. Ntev, H.; Jia, Q. Vaj, L.; Fang, W.; Wang, Z.; Jiang, T.; Zhou, F.; Jin, Z.; Huang, J.; Zhou, L.; ua al. Cov qog nqaij hlav-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression thiab curtail anti-PD-1/PD-L1 kev kho mob. Cancer Cell 2022, 40, 674–693.e7. [CrossRef]
29. Garcia Garcia, CJ; Huang, Y.; Fuentes, NR; Turner, MC; Monberg, ME; Lin, D.; Nguyen, ND; Fujimoto, TN; Zhao, J.; Li, JJ; ua al. Stromal HIF2 tswj kev tiv thaiv kab mob hauv Pancreatic Cancer Microenvironment. Gastroenterology 2022, 162, 2018–2031. [CrossRef]
30. Wu, Y.; Yim, M.; Nia, M.; mav, q.; Wu, K. Myeloid-derived suppressor hlwb: Ib lub hom phiaj tshiab rau kev tiv thaiv kab mob qog noj ntshav. Mol. Cancer 2022, 21, 184. [CrossRef]
31. Bernardo, M.; Tolstykh, T. Zhang, YA; Bangari, DS; Cai, H.; Heyl, KA; Li, JS; Malkova, NV; Malley, K.; Marquez, E.; ua al. Ib qho kev sim qauv ntawm kev tiv thaiv PD-1 tsis kam ua kom pom kev ua kom TGFß thiab Notch txoj hauv kev thiab muaj kev nkag siab rau mRNA immunotherapy hauv zos. Oncoimmunology 2021, 10, 1881268. [CrossRef] [PubMed]
32. TUG, M.; Passarelli, UA; Mannavola, F.; Felici, C.; ib. Stucci, LS; Civ, M.; Silvestris, F. Immune System Evasion as Hallmark of Melanoma Progression: Lub luag hauj lwm ntawm Dendritic Cells. Pem hauv ntej. Oncol. 2019, 9, 1148. [CrossRef] [PubMed]
33. Oberli, MA; Reichmuth, AM; Dorkin, JR; Mitchell, MJ; Fenton, OS; Jaklenec, UA; Anderson, DG; Langer, R.; Blankschtein, D. Lipid Nanoparticle Assisted mRNA Xa rau Kev Kho Mob Cancer Immunotherapy. Nano Let. 2017, 17, 1326–1335. [CrossRef] [PubMed]
34. Vaj, Y.; Zhang, L. Xu, Z.; Miao, L.; Huang, L. mRNA Tshuaj tiv thaiv nrog Antigen-Specifific Checkpoint Blockade Induces ib qho kev tiv thaiv tiv thaiv kab mob tiv thaiv tsim Melanoma. Mol. Ther. Xyoo 2018, 26, 420–434. [CrossRef]
35. Zhang, H.; koj, X.; Wang, X.; Koj, L.; Wang, Z.; Xu, F.; Li, M.; Yaj, Z.; Liu, J.; Huang, P. ua al. Kev xa cov tshuaj tiv thaiv mRNA nrog cov khoom siv lipid zoo li potentiates antitumor kev ua tau zoo los ntawm kev hu xov tooj zoo li receptor 4 signaling. Proc. Natl. Acad. Sci. USA 2021, 118, e2005191118. [CrossRef]
36. Li, Q.; Rau, J.; Li, W.; Jiang, G.; Hu, R. CpG Oligodeoxynucleotide Tsim los ua kom muaj zog tiv thaiv kab mob tiv thaiv kab mob tiv thaiv kab mob hauv kev sib xyaw nrog Neoantigen-Based mRNA Tshuaj Tiv Thaiv Kab Mob. Drug Des. Dev. Ther. 2021, 15, 3953–3963. [CrossRef]
37. Chen, J.; yog, z;. Huang, C.; Qiu, M.; Nkauj, D.; Li, Y.; Xu, Q. Lipid nanoparticle-mediated lymph node-targeting xa cov tshuaj tiv thaiv kab mob qog noj ntshav mRNA elicits robust CD8 ntxiv rau T cell teb. Proc. Natl. Acad. Sci. USA 2022, 119, e2207841119. [CrossRef] [PubMed]
38. Chu, W.; Pak, BJ; Bani, MR; Kapoor, M.; Lu, SJ; Tamir, A.; Kerbel, RS; Ben-David, Y. Tyrosinase-related protein 2 raws li tus neeg nruab nrab ntawm melanoma tshwj xeeb tsis kam rau cis-diamminedichloroplatinum(II): Kev kho mob cuam tshuam. Oncogene 2000, 19, 395–402. [CrossRef]
39. Nws, M.; Huang, L.; Hu, X.; Zhou, C.; Bachir, ZA; Lan, M.; Chen, R.; Gao, F. Ua tau zoo ovalbumin tus me nyuam siv ib tug tshiab multifunctional micellar platform rau tsom melanoma immunotherapy. Int. J. Pharm. Xyoo 2019, 560, 1-10. [CrossRef]
40. Kyte, JA; Mus, L.; Aamdal, S.; Kev, G.; Dualand, S.; Hauser, M.; Gullestad, HP; Ryder, T.; Lislerud, K.; Hammerstad, H.; ua al. Theem I / II sim ntawm kev kho melanoma nrog cov hlwb dendritic hloov nrog autologous qog-mRNA. Cancer Gene Ther. 2006, 13, 905–918. [CrossRef]
41. Kyte, JA; Kev, G.; Lislerud, K.; Thor Straten, P. Dualand, S.; Aamdal, S.; Gaudernack, G. T cell teb nyob rau hauv cov neeg mob melanoma tom qab txhaj tshuaj tiv thaiv qog-mRNA transfected dendritic hlwb. Cancer Immunol. Immunother. 2007, 56, 659–675. [CrossRef]
42. Weide, IB; Pascolo, S.; Scheel, IB; Derhovanessian, E.; Pfllugfelder, A.; Eigentler, TK; Pawelec, G.; Hoerr, ib.; Rammensee, HG; Garbe, C. Direct txhaj ntawm protamine-tiv thaiv mRNA: Cov txiaj ntsig ntawm kev sim tshuaj tiv thaiv theem 1/2 hauv cov neeg mob metastatic melanoma. J. Immunother. Xyoo 2009, 32, 498–507. [CrossRef] [PubMed]
43. Wilgenhof, S.; Van Nuffel, AM; Corthals, J.; Heirman, C.; Tuyaerts, S.; Benteyn, D.; De Coninck, A.; Van Riet, I.; Verfaillie, G.; Vandeloo, J.; ua al. Kev txhaj tshuaj tiv thaiv kab mob nrog autologous mRNA electroporated dendritic cell vaccine hauv cov neeg mob uas muaj mob melanoma. J. Immunother. 2011, 34, 448–456. [CrossRef] [PubMed]
44. Benteyn, D.; Van Nuffel, AM; Wilgenhof, S.; Corthals, J.; Herman, C.; Neeb, B.; Thielemans, K.; Bonehill, A. Cwj pwm ntawm CD8 ntxiv rau T-cell cov lus teb hauv cov ntshav peripheral thiab cov tawv nqaij txhaj tshuaj ntawm cov neeg mob melanoma kho nrog mRNA electroporated autologous dendritic cells (TriMixDC-MEL). Biomed Res Int. 2013, 2013, 976383. [CrossRef]
45. Wilgenhof, S.; Corthals, J.; Van Nuffel, AM; Benteyn, D.; Heirman, C.; Bonehill, ib.; Thielemans, K.; Neyns, B. Cov txiaj ntsig kev kho mob ntev ntev ntawm cov neeg mob melanoma kho nrog tus xa xov RNA-electroporated dendritic cell kho tom qab ua tiav kev txiav tawm ntawm metastases. Cancer Immunol. Immunother. 2015, 64, 381–388. [CrossRef] [PubMed]
46. De Keersmaecker, B.; Claerhout, S.; Carrasco, J.; ib. Bar, ib.; Corthals, J.; Wilgenhof, S.; Neeb, B.; Thielemans, K. TriMix thiab qog antigen mRNA electroporated dendritic cell txhaj tshuaj tiv thaiv ntxiv rau ipilimumab: Txuas ntawm T-cell ua kom thiab cov lus teb hauv chaw kho mob hauv cov melanoma siab heev. J. Immunother. Cancer 2020, 8, e000329. [CrossRef]
47. Arance Fernandez, AM; Baurain, J.-F.; Vulsteke, C.; Raut, A.; Soria, A.; Carrasco, J.; ib. Neeb, B.; De Keersmaecker, B.; Van Assche, T.; Lindmark, B. Ib theem kuv kawm (E011-MEL) ntawm TriMix-based mRNA immunotherapy (ECI-006) hauv cov neeg mob melanoma resected: Kev tshuaj xyuas kev nyab xeeb thiab kev tiv thaiv kab mob. J. Clin. Oncol. 2019, 37, 2641. [CrossRef]
48. Ping, H.; Yus, W.; Gong, X.; Tug, X.; Lin, C.; Chen, Z.; Cai, C.; Guo, K.; Ke, H. Kev tshuaj xyuas melanoma qog antigens thiab cov kab mob tiv thaiv kab mob rau kev tsim cov tshuaj tiv thaiv mRNA. Tshawb xyuas. Cov Tshuaj Tshiab 2022, 40, 1173–1184. [CrossRef]
49. Lorentzen, CL; Haanen, JB; Met, Ö.; Svane, IM Clinical nce qib thiab kev sim tsis tu ncua ntawm cov tshuaj tiv thaiv mRNA rau kev kho mob qog noj ntshav. Lancet Oncol. 2022, 23, e450–e458. [CrossRef]
50. ClinicalTrials.gov. Muaj nyob online: https://www.clinicaltrials.gov/ ( nkag mus rau 10 Lub Ib Hlis 2023).
51. Moderna thiab Merck Tshaj Tawm mRNA-4157/V940, Kev Tshawb Fawb Txog Tus Kheej mRNA Tshuaj Tiv Thaiv Kab Mob, hauv Kev Sib Txuas Nrog KEYTRUDA®(Pembrolizumab), Tau Txais Cov Ntsiab Lus Tseem Ceeb Txog Qhov Kawg nyob rau theem 2b KEYNOTE-942 Kev sim. Muaj nyob online: https://www.merck.com/news/moderna-and-merck-announce-mrna-4157-v940-an-investigational-personalized-mrna cancer-vaccine-in-combination- with-keytruda-pembrolizumab-met-primary-efficacy-endpoint-in-phase-2b-keynote-94/ ( nkag mus rau 13 Kaum Ob Hlis 2022).
52. Kev tawg hauv mRNA Tshuaj Tiv Thaiv Melanoma. Muaj nyob online: https://www1.racgp.org.au/newsgp/clinical/breakthrough in-mrna-vaccines-for-melanoma ( nkag mus rau 10 Lub Ib Hlis 2023).
53. mRNA Vaccine Plus KEYTRUDA® Txhim kho Melanoma Survival. Muaj nyob online: https://www.europeanpharmaceuticalreview. com/news/177505/mrna-vaccine-plus-keytruda-improve-melanoma-survival/ ( nkag mus rau 10 Lub Ib Hlis 2023).
