CAR T-Cell therapy ee kansarka sambabada unugyada aan yareyn

March 2024 : CAR T-cell therapy is a potential cancer treatment strategy, notably in hematological malignancies. However, its effectiveness in solid tumors, such as lung cancer, is limited due to the tumor microenvironment’s immunosuppressive nature. Researchers are developing next-generation CAR T cells to boost their infiltration, survival, and persistence inside malignancies. Clinical trials are underway to assess the safety and efficacy of CAR T-cell treatments in lung cancer, with some yielding promising results. Antigen escape, immunological barriers, and on-target off-tumor damage are among the challenges in CAR T-cell treatment for lung cancer. Engineering CAR constructs, altering the buro microenvironment, and employing off-the-shelf CAR T cells are some strategies for addressing these problems.

One of the leading hospitals in China has successfully conducted trials of CAR T-Cell therapy in kansarka sanbabada ee aan yareyn patients. CAR T-Cell on all these cancers is applicable for patients after some lines of treatment such as surgery, chemotherapy and radiotherapy but relapsed.

Of all malignancies, lung cancer has the greatest incidence and fatality rates worldwide. A growing variety of immunotherapeutic medicines, particularly those that target monoclonal antibodies, have been employed in the clinical treatment of malignancy in the current immunotherapy period, although it still has numerous drawbacks. In addition to being utilised successfully against haematological cancers, chimeric antigen receptor-modified T (CAR-T) cells have also created new opportunities for the immunotherapy of solid tumours, such as lung cancer. The lack of appropriate tumor-specific antigens, an immunosuppressive tumour microenvironment, a low level of CAR-T cell penetration into tumour tissues, together with off-target effects, etc. make it difficult to target kansarka sanbabada-specific antigens with modified CAR-T cells. Meanwhile, due to numerous difficulties such as tumor lysis syndrome, neurotoxicity syndrome, and cytokine sii daayo syndrome, the clinical usage of CAR-T cells is still restricted. With the goal of offering fresh perspectives and methods for pre-clinical studies and clinical trials of CAR-T cell therapy for lung cancer, we outline the fundamental structure and generation characteristics of CAR-T cells in this review, summarise the typical tumor-associated antigens, and highlight the current challenges.

Qaab dhismeedka BAABUURTA

Tan iyo markii la aasaasay, isticmaalka CARs ee daawaynta unugyada T-cell waxay soo martay afar jiil oo soo noqnoqda, kuwaas oo dhamaantood ku salaysan calaamada unugyada gudaha ee CAR. Jiilkii ugu horreeyay ee CAR-yadu waxay lahaayeen firfircooni daciif ah iyo waqti gaaban oo ku saabsan badbaadada vivo sababtoo ah waxay ka kooban yihiin oo keliya calaamadaha aqoonsiga antigen. Aagga gudbinta calaamadda ee jiilka labaad iyo saddexaad ee CARs, siday u kala horreeyaan, waxay ka koobnaayeen hal iyo laba unugyo-kharasheedka. Isbeddelladan ayaa la sameeyay si loo kordhiyo badbaadada unugga T, cytotoxicity, iyo kororka. Unugyada wada kicinta ee CAR-yada waa la wanaajiyey, kuwaas oo wanaajiyey waxqabadka unugga CAR-T. 4-1BB ama CD28 waa labada jiil labaad ee wada kicinta ee inta badan la isticmaalo. Intaa waxaa dheer, cytotoxicity, wax soo saarka cytokine, iyo firfircoonida unugyada T ayaa dhamaantood lagu muujiyay in la hagaajiyay borotiinka firfircoonida DNAX 10 (DAP10). Iyada oo ku saleysan khadadka unugyada unugyada aan yarayn ee kansarka sambabada (NSCLC), dib u dhaca korriinka kansarka sambabada ee bilawga ah iyo korodhka firfircoonida ka hortagga burooyinka ayaa lagu muujiyay noocyada xayawaanka ee vivo ee kansarka sambabada bini'aadamka xenotransplantation. Cytokines-ka-bararka iyo isku-xidhka kicinta ayaa lagu daray naqshadaynta jiilka afraad ee CAR-T si ay u caawiyaan unugyada T-yada inay soo dhex galaan oo ay uga gudbaan guryaha cadawga leh ee TME.

Kordhinta iyo waxtarka ka-hortagga buro ee unugyada CAR-T ayaa la muujiyay in la wanaajiyey iyada oo la wanaajinayo qaab-dhismeedka moduleka ka-baxsan marka lagu daro qaybaha gudbinta calaamadaha unugyada gudaha. Sida laga soo xigtay Qin et al., jajabka isbeddelka hal-silsiladda ah (scFv), kaas oo ku xidhan oo dhiirigeliya balaadhinta, socdaalka, iyo duulaanka kooxda kala-duwanaanta 4 (CD4) + CAR-T unugyada, ayaa la sameeyay mid dabacsan marka lagu daro. ee qaab-dhismeedka jilbiska. In kasta oo jiilka labaad ee CAR-T unugyadu ay sii ahaanayaan habka caadiga ah ee codsiga daawaynta, qaab dhismeedka qaab dhismeedka CAR-yada ayaa si joogto ah loo wanaajinayaa waxayna muhiim u tahay waxtarka CAR. T ayaa

CAR T-Cell therapy kansarka sanbabada iyo bartilmaameedka antigen

Marka bartilmaameedka-antigen-ku si gaar ah loogu muujiyo unugyada kansarka ama si xad dhaaf ah loogu muujiyo dhammaan ama badi unugyada kansarka sanbabada marka la barbardhigo unugyada caadiga ah, tani waa bartilmaameedka ugu fiican ee daaweynta unugyada CAR-T. Inkasta oo tiro badan oo antigens-ku-xiran buro (TAA) laga helay kansarka sambabada unugyada aan-yarayn (NSCLCs), kaliya dhowr ka mid ah antigen-yada ayaa si gaar ah loogu bartilmaameedsaday unugyada CAR-T (8). Intaa waxaa dheer, qaar ka mid ah bartilmaameedyada-antigen-yada ayaa sidoo kale si daciif ah loogu muujiyay unugyo caafimaad qaba, taasoo siinaya qaar ka mid ah unugyada CAR-T inay weeraraan unugyada caafimaadka qaba.

Epidermal factor factor reseptor (EGFR), reseptor factor koritaanka epidermal aadanaha 2 (HER2), mesothelin (MSLN), prostate stem cell antigen (PSCA), mucin 1 (MUC1), carcinoembryonic antigen (CEA), tyrosine kinase-sida agoonta receptor. ROR1), barnaamijka dhimashada ligand 1 (PD-L1), iyo CD80/CD86 ayaa ka mid ah bartilmaameedyada hadda lagu baranayo CAR.

Bukaanka kansarka sanbabada oo maraya daawaynta CAR T-Cell

Noofambar 2009, bukaanku wuxuu helay cufnaanta sambabada bidix waxaana lagu sameeyay qalliin xagjir ah oo kansarka sambabada bidix ah. Pathology: adenocarcinoma sambabada;
Laga soo bilaabo Jannaayo 2013 ilaa Jan 2017, saddex metastases oo maskaxda ah ayaa dhacay, qalliin iyo daawaynta shucaaca ayaa si isdaba joog ah loo siiyay kontorool xumo;
Laga soo bilaabo Maarso 2017 illaa Sebtember 2017, metastases maskaxda, unugyada mesoCAR-αPD1 oo muujinaya PD-1 antibody ayaa la siiyay 6 koorso oo daaweyn ah. Daaweynta ka dib, PR ayaa la qiimeeyay burooyinkana si weyn ayey u foorareen iyadoo qadar yar oo haraaga ah.

CAR T-Cell daaweynta Shiinaha

Daaweynta unugyada CAR-T ee Shiinaha waxa uu ku korayaa xawli aad u xowli badan. Natiijooyinka Daaweynta CAR T-cell ee Shiinaha iyo guud ahaan heerka daawadu waa mid ka mid ah kuwa ugu fiican adduunka xilligan. Waxaa jira in ka badan 300 oo tijaabo caafimaad ah oo ka dhacaya gudaha Shiinaha loogu talagalay daaweynta unugyada CAR T. Shiinaha ayaa ka mid ah wadamada ugu horreeya ee bixiya daaweynta unugyada CAR T ka dib USA & UK. Marka la eego tirada tijaabooyinka caafimaad ee CAR-T, Shiinaha ayaa ku xiga USA, isaga oo diiwaangelinaya ku dhawaad ​​33% tijaabooyinka adduunka oo dhan. Tirada daawaynta CAR T-cell ee horumarinta kiliinikada ayaa gariirtay sannadihii la soo dhaafay. Waqtigan xaadirka ah, gudaha Shiinaha, waxaa jira in ka badan 300 oo tijaabo caafimaad ah oo socda oo ku saabsan cudurrada dhiig-baxa iyo sidoo kale burooyinka adag.

China’s extensive explorations and breakthroughs in the search of novel target antigens, optimization of CAR structure, cocktail CAR-T therapy, combination therapy, and extension of CAR-T cell applications, imply that we are currently on the verge of a revolution in CAR-T therapy. US FDA has approved CAR T Daaweynta unugyada for relapsed B Acute lymphoblastic leukemia, lymphoma & multiple myeloma. Shiinaha waxay dhawaan ansixisay daaweynta CAR T-cell ee qaar ka mid ah kansarrada adag. Bukaannada ka kala socda adduunka oo dhan waxay u badan tahay inay ka faa'iidaysan doonaan horumarkan.

Waxaa laga yaabaa inaad jeceshahay inaad akhriso: CAR T-Cell daaweynta Shiinaha

Waa maxay daaweynta CAR T-Cell (Chimeric antigen receptors)?

CAR T-Cell therapy waa nooc ka mid ah daaweynta difaaca jirka oo adeegsata unugyada T-unugyada si gaar ah loo hagaajiyay kuwaas oo qayb ka ah habdhiska difaaca si loola dagaallamo kansarka. Muunad ka mid ah unugyada T ee bukaannada ayaa laga soo ururiyaa dhiigga, ka dibna waa la beddelaa si ay u soo saaraan dhismayaal gaar ah oo loo yaqaan 'chimeric antigen receptors' (CAR) oo korkooda ah. Marka unugyada CAR ee la beddelay dib loogu celiyo bukaanka, unugyadan cusub waxay weeraraan antigen-ka gaarka ah waxayna dilaan unugyada burooyinka.

Sidee ayuu u shaqeeyaa CAR T-Cell therapy?

Daaweynta CAR T-cell waxay caawimo ka qaadataa habka difaaca jirka si uu u weeraro loona dilo unugyada kansarka. Tan waxaa lagu sameeyaa iyadoo laga saarayo qaar ka mid ah unugyada la cayimay ee dhiigga bukaanka, wax ka beddelka shaybaarka oo dib loogu duraa bukaanka. Daaweynta CAR T-cell waxay soo saartay natiijooyin aad u dhiirigelinaya Liin-dhiska non-Hodgkin sidaasna ay ku ansixisay FDA.

Waa kuwee musharixiinta saxda ah ee daaweynta CAR T-Cell?

At present FDA has approved CAR T-Cell therapy for some forms of aggressive and refractory Non-Hodgkin lymphoma and relapsed and refractory Lymphoblastic lymphoblastic leukemia. Bukaanku wuxuu u baahan yahay inuu soo diro warbixinno caafimaad oo buuxa si uu u hubiyo isticmaalka daawaynta CAR T-Cell ee daawaynta.

Shuruudaha ka mid noqoshada CAR T-cell therapy:

1. Bukaanada qaba CD19+ B-cell Lymphoma (Ugu yaraan 2 nidaamyadii hore ee kiimoteraabiga ee la isku daray)

2. Inaad gaarto 3 ilaa 75 sano

3. Dhibcaha ECOG ≤2

4. Haweenka awoodda dhalmada leh waa in laga qaado shaybaadh uur kaadi ah oo la caddeeyey in aan lahayn daawaynta ka hor. Dhammaan bukaannadu waxay ku heshiiyaan inay isticmaalaan habab la isku halayn karo oo ka hortagga uurka inta lagu jiro muddada tijaabada iyo ilaa la socodka wakhtiga ugu dambeeya.

Shuruudaha ka-saarista ee daaweynta CAR T-cell:

1. Dhiig-kar gudaha ah ama miyir-beel

2. Neefsashada oo xumaata

3. Xinjirowga xididdada dhiigga ku faafa

4. Hematosepsis ama Infekshan firfircoon oo aan la xakamayn

5. Sonkorowga oo aan la xakamayn

Faa'iidooyinka daaweynta CAR T-Cell

1. > 5000 kiisaska CAR T oo ay sameeyeen dhakhaatiir xirfad sare leh.
2. Isbitaalada Shiinaha waxay soo saareen noocyo badan oo CAR T Cell ah oo ay kujiraan CD19 & CD 22 kadibna wadan kale oo aduunka ah.
3. Shiinaha wuxuu ku socdaa in kabadan 300 tijaabooyin caafimaad oo ku saabsan daaweynta CAR T Cell. In ka badan waddammada kale ee meeraha ka jira.
4. Saamaynta caafimaad ee CAR T Cell waxay la mid tahay ta USA ama waddan kale oo mararka qaarkood way ka fiicantahay.

Nidaamka daaweynta ee daaweynta CAR T-Cell

• Qiimeyn dhameystiran ee bukaanka
• Ururinta unugyada jirka
• T-unugyada ayaa markaa lagu farsameeyaa shaybaarka
• T-Unugyada hida-wadaha ayaa markaa lagu dhuftaa iyadoo la adeegsanayo iyaga oo ku koraya shaybaarka. Unugyadan waa la qaboojiyey ka dibna waxaa loo diraa xarumaha daaweynta.
• Buugga kahor, bukaanka waxaa lasiin karaa kiimiko ku daaweynta kansarkooda. Tani waxay ka caawineysaa daaweynta inay u shaqeyso si ka wanaagsan.
• Waxyar kadib daaweynta kemotherabi CAR T-Unugyada waxaa lagu shubaa nidaam u eg faleebada dhiigga.
• Bukaanka waxaa u jira 2-3 bilood oo soo kabasho ah.

Waqtiga daaweynta CAR T-Cell

1. Imtixaan & imtixaan: hal toddobaad

2. Daaweynta ka hor & T-Cell Ururinta: hal toddobaad

3. T-cell diyaarinta & soo noqoshada: laba-saddex toddobaad

4. Falanqaynta Waxtarka 1aad: saddex toddobaad

5. Falanqaynta Waxtarka 2aad: saddex toddobaad.

Dhibaatooyinka ay keento CAR T-Cell therapy

Saameynaha guud ee CAR T-cell therapy waxaa ka mid ah:

• Calaamadaha sii deynta Cytokine
  Xaaladaha qaarkood, bukaanada waxaa laga yaabaa inay yeeshaan astaamo u eg hargab sida qandho, qarqaryo, madax-xanuun, lallabbo, matag, saxaro dabacsan, iyo murqo ama xanuun kalagoysyo ah. Waxa kale oo laga yaabaa inay keento cadaadis dhiig oo hooseeya, neefsashada oo ku adkaata, iyo garaaca wadnaha oo degdeg ah. Dhibaatooyinkan soo raaca waxaa sabab u ah sii daynta cytokines ee unugyada difaaca jirka inta lagu jiro daawaynta CAR T-cell. Calaamadahani badanaa waa kuwo fudud, laakiin waxay noqon karaan kuwo halis ah oo nafta halis gelinaya bukaanada qaarkood.
• Dhacdooyinka neerfaha
  Dhacdooyinka neerfaha ayaa dhici kara waxayna ku noqon karaan bukaanada qaarkood qatar. Dhacdooyinka noocan oo kale ah waxaa ka mid ah maskaxda maskaxda (cillad maskaxeed iyo cillad), jahwareer, hadalka oo adkaada, kacsiga, suuxdinta, lulmo, xaalad miyir doorsoon iyo isu dheelitirnaan la'aan.
• Neutropaenia iyo Dhiigyaraan
  Bukaanjiifka qaarkood waxaa laga yaabaa inay yeeshaan neutropenia ama tirada unugyada cad oo hooseeya. Sidoo kale, dhiig-yaraan ama hoos u dhaca tirada unugyada dhiigga cas ayaa sidoo kale dhici karta daawadaan awgeed.
  .
  Nasiib wanaag, inta badan dhibaatooyinkan soo raaca sida caadiga ah waxay xalliyaan iskood ama waxaa lagu maareyn karaa isticmaalka daawooyinka.

Sidee waxtar u leedahay daaweynta CAR T-Cell?

Daaweynta CAR T-cell ee daaweynta qanjiro iyo kansarrada kale ee dhiigga waxay muujiyeen natiijooyin rajo leh. Tan iyo daawaynta CAR T-cell, bukaanno badan oo hore u soo noqday burooyinka dhiigga waxay lahaayeen natiijooyin rajo leh mana jirin wax caddayn ah oo kansar ah. Waxa kale oo ay ka caawisay baxnaaninta bukaanada hore ugu guul daraystay in ay wax ka qabtaan badi daawaynta caadiga ah ee kansarka.

Si kastaba ha noqotee, daraasadaha muddada-dheer ee loogu talagalay bukaanka ballaaran ee bukaanka ah ayaa loo baahan yahay si loo xaqiijiyo waxtarka daaweyntan. Tijaabooyin ballaaran ayaa sidoo kale gacan ka geysan doona go'aaminta suurtagalnimada dhibaatooyinka soo raaca iyo dariiqooyinka saxda ah ee lagula macaamilo.

Immisa ayay ku kacaysaa daawaynta CAR T-cell?

Shiinaha waa hogaamiyaha adduunka ee daaweynta unugyada CAR-T & BMT. Ilaa hadda waxa jira in ka badan 300 oo tijaabo unugyada CAR-T ah oo socda. Daaweynta CAR-T ee Shiinaha ayaa ah tan ugu miisaaniyad badan adduunka oo dhan. Sababtoo ah diyaarinta unugga CAR-T hadda waa bilaash! Bukaanku waa inay bixiyaan kharashka daawaynta iyo adeegyada. Wadarta kharashka daawaynta ayaa noqon doona ilaa $60,000 -$80,000.

Sidoo kale akhri sidan: Daaweynta CAR T Cell ee Hindiya 

Sideen ku qaadan karaa daawaynta CAR T-cell gudaha Shiinaha?

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