Kuyini ukwelashwa kwe-CAR T-Cell?
Ukwelashwa kwe-CAR T-Cell, whose full name is Chimeric Antigen Receptor T-Cell Immunotherapy,. This is a new type of cell therapy that has been used for many years, but has only been improved and used clinically in recent years. Similar to other immunotherapy, its basic principle is to use the patient’s own immune cells to clear cancer cells, but the difference is that this is a cell therapy, not a drug.
Inqubo yokwelashwa kwe-CAR T-Cell
1: Hlukanisa amaseli omzimba T ezigulini zomdlavuza.
2: Using genetic engineering technology to add a chimeric antibody that recognizes isisu cells and activates T cells to kill tumor cells at the same time, T cells instantly turn into tall CAR-T cells. It is no longer an ordinary T cell, it is a “terrorist” T cell with GPS navigation, ready to find cancer cells and launch suicide attacks at the same time!
3: In in vitro culture, a large number of CAR-T cells are expanded. Generally, a patient needs billions or even tens of billions of CAR-T cells (the larger the body size, the more cells are required).
4: Amaseli e-CAR-T anwetshiwe abuyiselwa esigulini.
5: Bhekisisa iziguli, ikakhulukazi ukusabela komzimba ngodlame ezinsukwini ezimbalwa ezedlule (isizathu sizokuchazwa ngokuhamba kwesikhathi), bese wenza umsebenzi.
Thuthukisa inqubo yokukhiqizwa kwamaseli
Indlela yokukhiqiza amaseli e-CAR-T jikelele ukunciphisa izindleko zokukhiqiza kuyinselele enkulu. Enye indlela engaba khona ukuthola amaseli e-T kubanikeli, ukhiphe isakhi sofuzo se-HLA samaseli, futhi uveze ama-molecule e-HLA angajwayelekile ukuze kuvinjelwe ukubonwa kwamaseli angumbulali wemvelo kanye nokuhlanganiswa kwamaseli, ngaleyo ndlela kukhiqizwe umkhiqizo wamaseli we-T wendawo yonke . Ukwengeza, kungase kungadingeki ukuhlanganisa isakhi sofuzo se-CAR kuma-chromosome ama-T cell, njengoba ukubonakaliswa kwesikhashana kwe-CAR edluliselwe nge-RNA nakho kusebenza kumamodeli ezilwane. Ukuze uthole ukuphepha okwengeziwe, imidiya engasebenzisi i-serum iyanconywa.
I-FDA isanda kuthuthukisa futhi yashicilela imihlahlandlela esalungiswa yemikhiqizo yokwelashwa kwamaseli nofuzo, enye yazo edinga abakhiqizi ukuthi banqume izinkomba zomsebenzi zala maseli noma imikhiqizo yokwelashwa kofuzo. Kumaseli we-T aguqulwe izakhi zofuzo, kunezinto eziningi ezingahlobene nomsebenzi, kufaka phakathi isakhi sofuzo, izimo zamasiko, ukwakheka kwe-CAR, uhlobo lweseli, kanye nenani lohlobo lweseli. Njengamanje, inkomba elula yomsebenzi yinombolo yamaseli e-CAR +. Noma kunjalo, uhlobo ngqo lweseli lungabaluleka ngokulinganayo emsebenzini. Isibonelo, ukusinda kwesikhathi eside kwamaseli wememori emaphakathi, amaseli e-CD8 +, kungaba yinkomba yomsebenzi. Iningi labaphenyi njengamanje ligxile kuma-T cell atholakala egazini lomngcele. Abanye abacwaningi basebenzise i-CAR yesizukulwane sesibili ukwengeza amaseli wemvelo.
Ungahle uthande ukufunda: Ukwelashwa kwe-CAR T-Cell eNdiya
Izinzuzo zokwelashwa kwe-CAR T-Cell ekwelapheni izifo ezimbi ze-hematological
Eminyakeni emihlanu edlule, ukusebenza kahle okuhle kwe-CAR-T kuqhubeke kwaba yizihloko zezikhungo ezithile zocwaningo. Ngenxa yokuthi kunezinkulumo eziningi ze-antigen ezaziwayo kulwelwesi lwamangqamuzana egazi, futhi kulula ukuthola ama-leukocyte nama-T cell ngokwemvelo ezithweni zegazi (njengegazi, umnkantsha, nama-lymph nodes), amangqamuzana e-CAR-T asetshenziselwa ukwelapha kuqala. i-leukemia eyingozi. Emangele.
CAR-T cells are also the most used clinical trials for hematological malignancies. The results of these clinical trials indicate several key factors that may affect the efficacy of CAR-T cell therapy. For example, although all diseases can express CD19, i-leukemia enamandla ye-lymphoblastic appears to have a higher response rate than chronic lymphocytic leukemia or indolent lymphoma. The reasons may include patients with lymphoma have T cell defects, tumor microenvironment inhibition, previous treatment, the patient’s age and T cell activity and components (such as the ratio of CD4: CD8, the content of regulatory T cells). The tumor microenvironment may also affect the function of CAR-T cells to dissolve tumor cells. By analyzing CAR-T cells isolated from tumor tissue, they found that they express PD-1, so the therapeutic effect may be affected by PD-L1. Checkpoint blocking technology can increase T cell viability. Application of lymphatic attrition and injection of lymphokines can support the in vivo expansion and survival of imported T cells.
Kubalulekile ukuqonda izici ezibalulekile zomsebenzi weseli ye-CAR-T. Ukuvezwa kweCAR endaweni yeseli akungabazeki ukuthi kubalulekile. Okwesibili, amangqamuzana e-CAR-T anele kufanele abonakale egazini ngemva kokufakelwa. Amaseli e-CAR-T angatholwa nge-polymerase chain reaction kanye ne-flow cytometry. Akukacaci ukuthi ingakanani umthamo omncane wamaseli e-CAR-T odingekayo ukuze usebenze. Uma amaseli e-CAR-T anganwetshwa ngokuphumelelayo ku-vivo, khona-ke inani elincane lamaseli e-CAR-T lisengakwazi ukukhiqiza imiphumela emihle. Uma kubhekwa inkimbinkimbi yokukhiqiza amaseli e-CAR-T, kuyathandeka kakhulu ukukwazi ukufeza imiphumela yokwelapha ngesilinganiso esiphansi samaseli. Akungabazeki ukuthi amaseli angenisiwe kumele aphile isikhathi esanele. Ngokusekelwe ku-kinetics ye-tumor cell clearance eye yabonwa, amaseli atshaliwe adinga ukuphila ku-vivo okungenani izinyanga ezimbalwa. Ngakolunye uhlangothi, uma amangqamuzana e-CAR-T esetshenziswa kuphela njengendlela yokwelapha yesikhashana yokufakelwa komnkantsha wamathambo, angadinga kuphela ukuhlala amasonto ambalwa. Alukho ucwaningo lomtholampilo olungahleliwe lokufakazela ukuthi amaseli e-CAR-T angangena esikhundleni sokufakelwa komnkantsha wamathambo. Kodwa okungenani iziguli ezingafanele ukufakelwa umnkantsha wamathambo zingathola ukufakelwa kweseli ye-CAR-T.
Toxicity and adverse reactions mainly include cytokine release syndrome, macrophage activation syndrome, hemophilic i-lymphoma and B cell hypoplasia. I-Cytokine release syndrome is often accompanied by high levels of IL-6 secretion and leads to macrophage activation syndrome. Although it can be clearly assumed that CAR-T cells can directly kill tumor cells, it is not completely clear which cells produce a large number of cytokines, especially IL-6 (a key factor for toxic response). It is also unclear whether general immunosuppression of anti-cytokine antibodies or steroid hormones can affect anti-tumor responses. IL-6 may be produced by dead B cells, dead tumor cells, or macrophages recruited to lyse tumor cells. It is still unclear whether the severity of cytokine release syndrome or macrophage activation syndrome is related to the anti-tumor effect. The relatively rare adverse reactions include slow response, epilepsy, aphasia, changes in mental state, etc. These are reversible. Macrophage activation syndrome is often associated with neurological toxicity. B cell hypoplasia is the expected result of CD-19 ukwelashwa okubhekiswe and can be used as an indicator of the survival and effectiveness of CD-19 targeted CAR-T cells in vivo. B cell hypoplas
ia ingajovwa nge-glycinin njengokwelashwa okwengeziwe. Ukuphikelela kwe-B-cell hypoplasia, noma ngabe kunezinye izindlela zokwelapha ezingashintsha, kungaholela engozini yokutheleleka. Amaseli we-B angalulama ngemuva kokunyamalala kwamaseli we-CAR-T emzimbeni, ngakho iziguli zingathola amaseli we-CAR-T futhi. Njengoba iziguli eziningi zithola ukwelashwa kwamaseli e-CAR-T, ucwaningo lomtholampilo kufanele lubheke ekutadisheni ukuphendula okunobuthi kanye nezindlela zabo zokuphatha, kufaka phakathi i-cytokine blockade, i-steroids, nesikhathi esifanele kanye nomthamo we-immune protein supplementation.
Ngenxa yobuthi obubalulekile bamaseli e-CAR-T, abacwaningi baphinde bazama amasu okuhlanganisa izakhi zofuzo kumaseli noma bavale ukukhuluma kwezakhi zofuzo. Kodwa-ke, kusenzima ukuhlanganisa uhlelo lofuzo lokuzibulala kuwo wonke amangqamuzana e-CAR-T, ngoba izinhlelo eziningi zokuzibulala zinama-immunogenic (ngokwesibonelo, i-herpes simplex virus eveza i-thymus kinase) noma ama-prodrugs abangela ukuzibulala kufanele afakwe ngaphakathi. Ngaphezu kwalokho, i-T-cell homing ingaguqulwa yinkulumo yesikhashana yama-chemokine receptors noma ukuvinjelwa kwemithi kwama-chemokine receptors kungasetshenziswa njengecebo lokuthuthukisa ukusebenza kahle nokunciphisa ubuthi.
Amathemba ajabulisayo okwelashwa kwe-CAR T-Cell
There are two main obstacles in expanding the application of CAR-T cells beyond B-cell malignancies: finding new targets and mass production. Potentially promising targets include CD30 (for the treatment of Hodgkin’s disease and i-mycosis fungoides), immunoglobulin Gκ light chain (for the treatment of B-cell leukocytes), CD33 and Lewis-Y (acute myeloid leukemia), CD123 and CD44v6 (Acute myeloid leukemia and myeloma), CD19 (B cells), CD23, and ROR1 (chronic lymphocytic leukemia). New targets under study include BCMA, CD70, CD74, CD138 and CS1 (see table below). Currently, pharmaceutical companies, biotechnology companies, universities, and cooperative organizations are conducting CAR-T cell research. This is an exciting period for the treatment of all hematological malignancies; ten years ago, few people expected that the hope of modifying gene therapy would be realized by CAR-T cells for the treatment of hematological malignancies.
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