Lub peev xwm ntawm Kev Tiv Thaiv Cov qog nqaij hlav los ntawm cov qog tshem tawm nrog Alpha hais, Protons, lossis Carbon Ion Radiation thiab nws txoj cai los ntawm kev sib xyaw nrog Immunoadjuvants lossis Inhibitors Ntawm Immune Suppressor Cells Thiab Checkpoint Molecules Part 1

Abstract:

Kev xa tawm ntawm kev kho hluav taws xob (RT) rau kev mob qog noj ntshav nrog lub hom phiaj kho tau raug kho kom zoo thiab ua raws li cov qauv hauv 80 xyoo dhau los. Ob qho kev ua haujlwm hauv tsev kho mob thiab chaw kho mob tau hais txog qhov kev soj ntsuam tias hluav taws xob ua rau cov qog thiab nthuav tawm nws cov khoom rau lub cev tiv thaiv kab mob hauv hom uas pab txhawb kev cuam tshuam ntawm kev tiv thaiv qog nqaij hlav los yog txhawb cov lus teb zoo li no.

Kev kho hluav taws xob tuaj yeem ua rau DNA ntawm cov qog nqaij hlav cancer puas tsuaj, tiv thaiv lawv kom tsis txhob loj hlob thiab kis mus ntxiv. Txawm li cas los xij, kev kho hluav taws xob tuaj yeem ua rau lub cev tsis zoo, ua rau muaj kev pheej hmoo kis mob. Qhov no tuaj yeem ua rau lub cev tsis muaj zog thiab ua rau muaj kev pheej hmoo kis mob. Yog li ntawd, cov neeg mob yuav tsum tau them nyiaj tshwj xeeb rau kev tswj hwm lub cev tiv thaiv kab mob kom noj qab haus huv thiab tswj kev noj qab haus huv thaum lub sijhawm thiab tom qab kev kho hluav taws xob.

Tsis tas li ntawd, cov kev tshawb fawb tau pom tias kev kho hluav taws xob tuaj yeem muaj qee qhov kev txhawb nqa thiab ntxiv dag zog rau lub cev tiv thaiv kab mob. Kev kho hluav taws xob ua kom lub cev tiv thaiv kab mob kom lub cev tiv thaiv kab mob tuaj yeem tua cov qog nqaij hlav cancer zoo dua. Cov txiaj ntsig no tuaj yeem yog vim kev kho hluav taws xob ua kom lub cev tiv thaiv kab mob thiab txhawb lawv kom tso cytokines, uas ua rau muaj peev xwm ntawm lub cev tiv thaiv kab mob los tua cov qog nqaij hlav cancer. Yog li ntawd, kev kho hluav taws xob tuaj yeem siv los ua ib feem ntawm kev siv tshuaj tiv thaiv kab mob, qee zaum los pab lub cev tiv thaiv kab mob qog noj ntshav zoo dua. Yog li ntawd, peb yuav tsum txhim kho peb txoj kev tiv thaiv. Cistanche tuaj yeem txhim kho peb cov tib neeg kev tiv thaiv, vim Cistanche muaj ntau yam tshuaj antioxidant, xws li vitamin C, carotenoids, thiab lwm yam. Cov khoom xyaw no tuaj yeem tshem tawm cov dawb radicals thiab txo oxidation. Kev ntxhov siab, txhim kho kev tiv thaiv ntawm lub cev.

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Nyem cistanche tubulosa cov txiaj ntsig

Sab nraud beam photon hluav taws xob yog qhov nthuav dav tshaj plaws hauv kev kho qhov chaw tshem tawm, thiab nws siv tau nthuav tawm "abscopal effect". Particle radiotherapy (PRT), uas tau nyob rau ntau theem ntawm kev tshawb fawb thiab kev loj hlob rau 70 xyoo, niaj hnub no muaj rau kev kho mob ntawm cov neeg mob nyob rau hauv daim ntawv ntawm alpha hais, proton, los yog carbon ion radiotherapy. Kev them nyiaj hluav taws xob hluav taws xob yog ua raws li kev nrawm ntawm cov tsiaj uas raug them, xws li protons lossis carbon-12, uas tso lawv lub zog rau hauv cov qog kho mob thiab muaj cov txiaj ntsig zoo ntawm cov tshuaj lom neeg zoo dua piv nrog cov hluav taws xob photon.

Hauv kev tshuaj xyuas no, peb yuav coj cov pov thawj tias alpha hais, proton, lossis carbon ion hluav taws xob tuaj yeem rhuav tshem cov qog thiab ua kom muaj cov tshuaj tiv thaiv qog noj ntshav. Radiation kuj tseem tuaj yeem cuam tshuam ncaj qha rau kev faib tawm thiab kev ua haujlwm ntawm lub cev tiv thaiv kab mob xws li T hlwb, tswj T hlwb, thiab mononuclear phagocytes. Cov qog tshem tawm los ntawm hluav taws xob tuaj yeem ua rau lub cev tiv thaiv kab mob. Txawm li cas los xij, kev tshem tawm ib leeg tsis tshua ua rau muaj kev tiv thaiv qog noj qab haus huv uas ua rau lub cev tsis kam lees. Immunotherapy tuaj yeem ntxiv kev tshem tawm los txhawb kev tiv thaiv qog noj ntshav kom zoo dua tshem tawm cov kab mob hauv zos thiab cov qog metastatic. Ntau txoj hauv kev thiab cov neeg ua haujlwm xws li immunoadjuvants, suppressor cell inhibitors, lossis checkpoint inhibitors tau siv los tswj lub cev tiv thaiv kab mob ua ke nrog hluav taws xob. Qhov kev tshuaj xyuas no hais txog qhov tshwm sim ntawm cov kab mob sib kis ntawm cov xov tooj cua thiab nws qhov kev sib raug zoo nrog kev tiv thaiv kab mob qog noj ntshav.

Ntsiab lus:

alpha hluav taws xob; proton hluav taws xob; carbon ion; immunotherapy; immunoadjuvants; checkpoint inhibitors; tiv thaiv kab mob hlwb; hu xov tooj zoo li receptors; qog abolition; tiv thaiv qog noj ntshav.

1. Taw qhia

Mob qog noj ntshav yog qhov thib ob ua rau tuag thoob ntiaj teb, cuam tshuam rau 19 lab tus neeg mob tshiab txhua xyoo. Kwv yees li ntawm ib ntawm rau tus neeg tuag yog vim mob qog noj ntshav, thiab nws yog lub luag haujlwm rau kwv yees li 9.6 lab tus neeg tuag hauv 2018 [1].

Cov neeg mob feem ntau raug kho los ntawm kev phais, kws khomob, tshuaj lom neeg (immunotherapy, angiogenesis inhibitors, qog noj ntshav inhibitors), thiab kev kho hluav taws xob. Kev phais thiab kev kho hluav taws xob feem ntau yog siv rau kev tshem tawm cov qog thawj zaug, thaum kws khomob thiab tshuaj tiv thaiv kab mob yog siv rau kev tswj cov qog hauv zos thiab kev kho mob antimetastatic.

Kev kho mob qog noj ntshav yog tsom feem ntau txhawm rau tshem tawm cov metastases nyob deb, uas yog lub luag haujlwm rau kev tuag tsawg kawg 67 feem pua thiab txog li 90 feem pua ntawm cov neeg mob qog noj ntshav, nyob ntawm seb hom qog nqaij hlav [2].

Qhov tseem ceeb ntawm kev kho mob antitimetastatic, chemotherapy, tsis yog tshwj xeeb thiab cuam tshuam rau feem ntau cov cell replicating, thaum so cov qog nqaij hlav cancer yuav tsis raug puas tsuaj. Yuav kom tswj tau tus mob qog noj ntshav kom zoo dua qub, tus tswv tsev tiv thaiv kab mob yuav tsum tau txhawb nqa. Txawm li cas los xij, kev ua tiav tshwj xeeb ntawm kev tiv thaiv kab mob tiv thaiv cov qog los ntawm kev txhaj tshuaj tiv thaiv kab mob tsis tshua tau ua tiav, txawm tias nyob rau hauv cov qog nqaij hlav antigenic. Raws li lwm txoj hauv kev, sim ua kom koom nrog lub cev tiv thaiv kab mob hauv qhov chaw los tiv thaiv qog nqaij hlav nrog antigens los ntawm kev ua cov qog nws cov tshuaj tiv thaiv, tsis tas yuav tsum tau cais cov qog-0 txuam nrog antigens [3].

Txoj hauv kev no muaj nws cov hauv paus hauv qhov tshwm sim thawj zaug tau piav qhia tias yog "abscopal effect" [4,5]. Nws tau raug pom tias kev txhoj puab heev hauv cov qog nqaij hlav puas tsuaj (kev tshem tawm) tuaj yeem ua rau kev tso tawm ntawm cov qog antigens, uas tuaj yeem ua rau cov qog nqaij hlav tiv thaiv kab mob, thiab yuav rhuav tshem cov qog nqaij hlav hauv thawj cov qog thiab nyob deb ntawm metastases [6].

2. Tumor Immunology thiab Immunotherapy of Cancer

Immunotherapy ntawm mob qog noj ntshav yog lub hom phiaj tseem ceeb txij li xyoo 1891 thaum William Coley pib sim kev kho mob qog noj ntshav ntawm cov neeg mob qog noj ntshav nrog cov khoom siv los ntawm cov kab mob, qhia txog kev kho mob thawj zaug txaus ntshai, thov tias cov txiaj ntsig zoo yog los ntawm kev ua kom muaj kev tiv thaiv qog noj ntshav [ 7]. Qhov kev siv zog no tau nce mus tas li hauv 130 xyoo dhau los, thiab tus naj npawb ntawm cov tshuaj tiv thaiv kab mob oncology nyob rau hauv kev tshawb nrhiav hauv 2020 tau nce 233 feem pua txog cov xyoo 2017 [8].

Lub luag haujlwm ntawm lub cev tiv thaiv kab mob hauv kev txhim kho qog thiab kev kho mob yog qhov teeb meem nyuaj heev. Muaj ntau lub ntsiab lus koom nrog, xws li ntau hom qog nqaij hlav, kab mob hauv cov caj ces, qhov nyuaj ntawm kev tiv thaiv kab mob, cov metabolism, hnub nyoog, thiab microbiome, rau npe ob peb. Qhov loj ntawm daim teb no tuaj yeem nkag siab tau los ntawm cov xov tooj ntawm cov ntawv tshaj tawm rau hnub tim (Pubmed tshawb ntawm "Tumor immunology" yuav tawm ntau dua 300,000 cov ntaub ntawv nrog ntau dua 45,000 tshuaj xyuas; "Immunotherapy" 95 ,000 kab lus, thiab 29,000 tshuaj xyuas). Kev tshuaj xyuas dav dav tsis ntev los no tau muab cov ntsiab lus zoo ntawm daim teb [9].

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3. Charged Particle Beam Radiotherapy

Nrog rau kev phais thiab kws khomob, kev kho hluav taws xob yog ib txoj hauv kev tseem ceeb tshaj plaws ntawm kev kho mob qog noj ntshav, thiab kwv yees li 50-70 feem pua ntawm cov neeg mob qog noj ntshav yuav tau txais kev kho hluav taws xob rau kev kho mob lossis palliative lub hom phiaj. Kev xa hluav taws xob kho mob (RT) rau kev mob qog noj ntshav, yos rov qab mus rau qhov kev tshawb pom ntawm X-rays hauv xyoo 1895, nrog rau lub hom phiaj los kho tau raug kho kom zoo thiab ua qauv zoo rau 80 xyoo dhau los.

Kev kho hluav taws xob muaj xws li photons (xws li gamma-rays thiab X-rays) los yog cov khoom (xws li, protons, neutrons, alpha hais, hnyav ions, thiab electrons). Kev kho hluav taws xob ntau tshaj plaws yog kev kho hluav taws xob sab nraud (EBRT) siv gamma- lossis x-rays hluav taws xob. Cov hluav taws xob muaj txiaj ntsig zoo rau kev kho mob ntawm cov chaw kab mob hauv cheeb tsam thiab cheeb tsam, lossis qhov chaw phais ntawm cov qog tsis ua tau vim qhov loj thiab qhov chaw ntawm cov qog, lossis tus neeg mob qhov mob. Qhov ua tau zoo ntawm photon hluav taws xob tsuas yog txwv vim yog hypoxia hauv cov qog.

Radiation induces ob peb lub xov tooj puas teb, suav nrog apoptotic cell tuag, mitotic kev puas tsuaj, necroptosis, ferroptosis, thiab senescence [10], ib txhia ntawm lawv pib los ntawm DNA ob-strand so (DSBs), uas paub tias yog cov feem ntau lom thiab hem. ntau hom kev tawg uas yuav tshwm sim rau DNA [11].

3.1. Proton thiab Carbon Ion Radiotherapy

Particle radiotherapy (PRT) yog lwm txoj hauv kev uas tau siv ntau theem ntawm kev tshawb fawb thiab kev loj hlob rau 70 xyoo. Niaj hnub no, kev kho mob muaj nyob rau hauv daim ntawv ntawm proton los yog carbon ion radiotherapy. Kev them nyiaj hluav taws xob hluav taws xob yog ua raws li qhov nrawm ntawm cov tsiaj uas raug them, xws li protons lossis carbon-12, uas tso lawv lub zog rau hauv cov qog kho mob.

Qhov tshwj xeeb tshwj xeeb uas ua rau qhov kev ua tau zoo no yog qhov kev vam khom ntawm lub zog poob ntawm lub zog particle. Raws li cov nqi them qeeb qeeb hauv qhov teeb meem, lub zog poob ntawm ib chav tsev ntev nce ntxiv thiab lub zog loj ceev ncov (lub Bragg ncov) yog tsim thaum kawg ntawm txoj kev [12]. Lub zog deposited ceev ntawm Bragg ncov yog feem ntau siab dua los ntawm ib qho ntawm 3-5 tshaj li nws nyob rau ntawm qhov seem ntawm cov nqi particle txoj kev. Tsis tas li ntawd, tus txheeb ze lom neeg muaj txiaj ntsig zoo (RBE) ntawm cov khoom siv hluav taws xob cuam tshuam nrog photons lossis electrons ua rau qhov kev hloov pauv no muaj txiaj ntsig zoo.

Cov kev pab them nqi ntawm ib tug zoo-txhais ntim ntawm qog loj yog attained los ntawm yooj yim manipulation ntawm tus nqi particle beam. Lub ntim yog qhov tseem ceeb muab faib ua voxels, uas yog peb-dimensional cubes nrog cov kev tswj xyuas. Kev tswj ntawm txoj haujlwm lateral nyob rau hauv lub hom phiaj yog ua los ntawm electromagnetic steering ntawm lub nqaj. Qhov tob ntawm kev nkag mus yog ua tiav los ntawm kev sib txawv ntawm cov nqaj zog kom lub ncov Bragg tshwm sim ntawm qhov xav tau voxel. Kev siv passive shielding raws li ib tug txhais tau tias kom zoo dua raws li qhov kho ntim yog tseem siv rau qee yam.

Txhawm rau txo qis qhov tsis xav tau ntawm cov ntaub so ntswg noj qab haus huv, irradiation yog ua los ntawm cov lus qhia sib txawv, zoo li cov kev cai ntawm kev siv sab nraud photon kho; cov nyhuv tshuaj lom tau muab faib ua ntau qhov ntim ntawm cov ntaub so ntswg noj qab haus huv, thaum cov tshuaj kho mob yog concentrated nyob rau hauv lub hom phiaj ntim. Raws li nrog rau kev kho photon sab nraud, nws yog ib qho kev cai los faib cov kev kho rau hauv ob peb feem, kom tso cai rau cov ntaub so ntswg noj qab haus huv irradiated kom rov zoo los ntawm qhov tsis muaj kev cuam tshuam ntawm hluav taws xob. Cov ntaub so ntswg noj qab nyob zoo yog khaws cia zoo dua nrog cov nqi hluav taws xob hluav taws xob ntau dua li kev kho photon.

Tus neeg sib tw zoo tshaj plaws rau PRT yog qhov zoo-txhais, cov qog nqaij hlav nyob hauv qhov chaw uas nws tuaj yeem khaws cia tsis muaj zog thaum lub sij hawm irradiation thiab nws ib puag ncig tsis hloov ntawm kev kho mob. Cov qog nqaij hlav hauv hlwb yog thawj zaug tau kho rau cov laj thawj no, thiab tau txais txiaj ntsig zoo heev [13]. Yog li ntawd, tus naj npawb ntawm cov chaw tau loj hlob ntau xyoo dhau los, nrog txog 100 proton chaw thiab txog 10 cov chaw carbon thoob ntiaj teb.

PRT muaj qee qhov kev sib tw uas yuav tsum tau ua. Kev kho mob ntawm cov qog tsis ua haujlwm, xws li mob ntsws ntsws, yuav tsum muaj peev xwm hloov kho kev tswj ntawm lub nqaj kom ua raws li cov khoom siv hauv nruab nrog cev. Kev hloov pauv hauv lub cev ib puag ncig ntawm cov feem ntau yuav tsum tau ua kom lub zog ntawm lub zog rov ua kom zoo dua kom tsis txhob muaj kev hloov pauv tsis zoo ntawm Bragg ncov. Cov tshuaj tiv thaiv raws txoj kab teeb yuav ua rau muaj kev phom sij thib ob, uas nws yuav tsum tau txiav txim siab. Thaum kawg, ib qho yuav tsum nco ntsoov tias tus naj npawb ntawm cov neeg mob uas tuaj yeem kho tau los ntawm cov chaw tseem ceeb no muaj tsawg heev.

Heavy-ion beams muaj cov kab hluav taws xob siab hloov hluav taws xob (LET), uas yog, ntau dua ntawm lub zog ntawm cov khoom xa mus rau ib chav nyob deb. Qhov no nce tus naj npawb ntawm ionization txheej xwm xa nyob rau hauv ib tug luv luv ncua sij hawm yields ib tug txhim khu kev qha tshwm sim rau ob-strand DNA so ntawm lwm yam teebmeem nyob rau hauv lub qog cell; Qhov no muaj feem xyuam rau kev puas tsuaj lom neeg xa mus rau ib chav tsev koob tshuaj los ntawm kev suav kev sib piv rau qhov sib npaug photon koob thiab yog hu ua tus txheeb ze kev ua tau zoo (RBE) [14].

Tsis tas li ntawd, cov hluav taws xob hnyav ionizing tuaj yeem muaj txiaj ntsig zoo rau kev noj qab haus huv, vim muaj ntau txoj hauv kev tuag ntawm tes thiab tso tawm cytokine mediators ntawm o. Mitotic catastrophe (ib txoj hauv kev ua ntej kev tuag ntawm tes uas tshwm sim hauv mitosis los yog qhov tshwm sim ntawm kev tsis txaus ntseeg mitotic kev loj hlob) yog thawj hom ntawm hluav taws xob vim yog cell tuag hauv cov qog nqaij hlav. High-linear-zog-hloov (LET) hluav taws xob xws li alpha hais tau pom tias ua rau muaj kev txhim kho chromosome rearrangements thiab kev ua me nyuam tuag [15], vim yog ob qho tib si complexity thiab tag nrho cov DNA puas pawg [16,17].

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3.2. Alpha Particle-Based Radiotherapy

High-LET alpha hais yog cov neeg sib tw zoo rau kev tua cov qog hlwb. Alpha-particle-emitting atoms yog siv nyob rau hauv lub hom phiaj alpha () particle therapy (TAT), ua kom zoo dua ntawm txoj kev luv luv thiab ionizing heev ntawm -particle emissions. Common -emitters, suav nrog 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At, thiab 149Tb, tau siv [18]. TAT yog ib feem ntawm qhov dav dav ntawm radiopharmaceutical therapy (RPT), uas tau nthuav dav hauv xyoo tas los no [19].

Txawm li cas los xij, kev nkag mus luv luv ntawm alpha hais hauv cov ntaub so ntswg (50-90 microns) txwv lawv siv rau kev kho cov qog nqaij hlav.

Peb tau tsim kev kho mob qog nqaij hlav intratumoral zoo thiab nyab xeeb rau cov qog nqaij hlav, siv alpha-emitting atoms los ntawm Ra-224 qhov chaw hauv cov qog. Kev kho mob tau hu ua "diffusing alpha-emitters radiation therapy (DaRT)". Cov thev naus laus zis yog los ntawm kev nkag mus rau hauv intratumoral ntawm Radium-224-cov noob coated (224Ra, 3.66 hnub ib nrab-lub neej), tso tawm alpha-emitting atoms uas tawg mus rau hauv cov qog thiab tso cov khoom ua kom puas alpha heev [20].

Kev ua haujlwm luv luv ntawm alpha hais hauv cov ntaub so ntswg ua kom zoo dua vim qhov tso tawm hauv zos ntawm lub zog tsom rau cov qog nqaij hlav cancer, sparing ib puag ncig cov ntaub so ntswg noj qab haus huv. Cov kev tshawb fawb hauv paus thiab kev txhais lus tau nthuav tawm tias DaRT modality ncua kev loj hlob ntawm cov qog nqaij hlav, ncua kev ciaj sia, thiab txo cov kab mob metastatic hauv cov nas uas muaj ntau yam nas- thiab cov qog nqaij hlav los ntawm tib neeg [21,22]. Qhov tseem ceeb tshaj, raws li kev kho mob monotherapy, DaRT tau pom tias yuav ua rau muaj kev tiv thaiv kab mob qog noj ntshav tom qab tshem tawm cov qog. Tsis ntev los no, kev sim tshuaj ntsuam xyuas ntawm cov neeg mob squamous cell carcinoma (SCC) ntawm lub taub hau, caj dab, thiab tawv nqaij ua tiav cov lus teb ntawm ntau dua 70 feem pua ntawm cov qog [23,24].

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