CAR T-Cell terapiyasi nima?
CAR T-Cell terapiyasi, uning to'liq nomi Ximerik antigen retseptorlari T-hujayra immunoterapiyasi,. Bu hujayra terapiyasining yangi turi bo'lib, u ko'p yillar davomida qo'llanilgan, ammo so'nggi yillarda faqat yaxshilangan va klinik jihatdan qo'llanilgan. Boshqa immunoterapiya singari, uning asosiy printsipi saraton hujayralarini tozalash uchun bemorning o'z immunitet hujayralaridan foydalanishdir, ammo farq shundaki, bu dori emas, hujayra terapiyasi.
CAR T-Cell terapiyasining jarayoni
1: Saraton kasallaridan immunitetli T hujayralarini ajratib oling.
2: Using genetic engineering technology to add a chimeric antibody that recognizes shish 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 vitro madaniyatida ko'p sonli CAR-T hujayralari kengaytiriladi. Umuman olganda, bemorga milliardlab yoki hatto o'nlab milliardlab CAR-T hujayralari kerak (tana hajmi qanchalik katta bo'lsa, shuncha ko'p hujayralar talab qilinadi).
4: kengaytirilgan CAR-T hujayralari bemorga qaytariladi.
5: Bemorlarni, ayniqsa, bir necha kun oldin organizmning zo'ravon reaktsiyalarini diqqat bilan kuzatib boring (sababi keyinroq tavsiflanadi) va ishni bajaring.
Hujayra ishlab chiqarish jarayonini yaxshilang
Ishlab chiqarish xarajatlarini kamaytirish uchun universal CAR-T hujayralarini qanday ishlab chiqarish katta muammodir. Mumkin bo'lgan usullardan biri - donorlardan T hujayralarini olish, hujayralarning HLA genini nokaut qilish va klassik bo'lmagan HLA molekulalarini ifodalash, tabiiy qotil hujayralar vositachiligida hujayra tanib olish va hujayra lizisini oldini olish va shu bilan universal T hujayra mahsulotini ishlab chiqarishdir. Bundan tashqari, CAR genini T hujayralarining xromosomalariga integratsiya qilish kerak bo'lmasligi mumkin, chunki RNK bilan transfektsion CARning vaqtinchalik ifodasi hayvonlar modellarida ham ishlaydi. Qo'shimcha xavfsizlik uchun sarumsiz vositalar tavsiya etiladi.
Yaqinda FDA hujayra va gen terapiyasi mahsulotlari bo'yicha ko'rsatmalar loyihasini ishlab chiqdi va nashr etdi, ulardan biri ishlab chiqaruvchilardan ushbu hujayralar yoki gen terapiyasi mahsulotlarining faollik ko'rsatkichlarini aniqlashni talab qiladi. Genetik jihatdan o'zgartirilgan T hujayralari uchun faoliyat bilan bog'liq bo'lishi mumkin bo'lgan ko'plab omillar mavjud, ular orasida gen tashuvchisi, madaniyat sharoitlari, CAR tuzilishi, hujayra turi va hujayra turining nisbati. Hozirgi vaqtda faoliyatning eng oddiy ko'rsatkichi CAR + hujayralarining soni hisoblanadi. Biroq, hujayraning aniq turi ham faoliyat uchun bir xil ahamiyatga ega bo'lishi mumkin. Masalan, markaziy xotira hujayralari CD8 + hujayralarining uzoq muddat yashashi faollik ko'rsatkichi bo'lishi mumkin. Hozirgi kunda ko'pchilik tadqiqotchilar periferik qondan olingan T hujayralariga e'tibor berishadi. Ba'zi tadqiqotchilar tabiiy qotil hujayralarni o'tkazish uchun ikkinchi avlod CAR dan foydalanganlar.
Siz o'qishni xohlashingiz mumkin: Hindistonda CAR T-Cell terapiyasi
CAR T-Cell terapiyasining gematologik xavfli kasalliklarni davolash uchun afzalliklari
So'nggi besh yil ichida CAR-T ning ajoyib samaradorligi doimiy ravishda ba'zi tadqiqot institutlarining sarlavhalariga aylandi. Qon hujayralari membranalarida ko'plab ma'lum antigen ifodalari mavjud va tabiiy ravishda qon a'zolari (qon, suyak iligi va limfa tugunlari kabi) joylashgan leykotsitlar va T hujayralarini olish nisbatan oson bo'lgani uchun CAR-T hujayralari birinchi navbatda davolash uchun ishlatiladi. malign leykemiya. Hayratda.
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, o'tkir limfoblastik leykemiya 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.
CAR-T hujayralari faoliyatining asosiy xususiyatlarini tushunish muhimdir. Hujayra yuzasida CAR ifodasi, shubhasiz, muhim ahamiyatga ega. Ikkinchidan, transplantatsiya qilinganidan keyin qonda etarli miqdorda CAR-T hujayralari aniqlanishi kerak. CAR-T hujayralarini polimeraza zanjiri reaktsiyasi va oqim sitometriyasi yordamida aniqlash mumkin. Samarali bo'lishi uchun CAR-T hujayralarining minimal dozasi qancha talab qilinishi aniq emas. Agar CAR-T hujayralari in vivo jonli ravishda kengaytirilishi mumkin bo'lsa, unda oz miqdordagi CAR-T hujayralari hali ham yaxshi ta'sir ko'rsatishi mumkin. CAR-T hujayralarini ishlab chiqarishning murakkabligini hisobga olgan holda, hujayralarning past dozasida terapevtik ta'sirga erishish juda jozibali. Import qilingan hujayralar etarlicha vaqt omon qolishi kerakligiga shubha yo'q. Kuzatilgan o'simta hujayralari klirensining kinetikasiga asoslanib, transplantatsiya qilingan hujayralar in vivo jonli ravishda kamida bir necha oy yashashi kerak. Boshqa tomondan, agar CAR-T hujayralari faqat suyak iligi transplantatsiyasi uchun o'tish davri terapiyasi sifatida ishlatilsa, ular faqat bir necha hafta davom etishi mumkin. CAR-T hujayralari suyak iligi transplantatsiyasi o'rnini bosishi mumkinligini isbotlovchi tasodifiy klinik tadqiqotlar yo'q. Ammo hech bo'lmaganda suyak iligi transplantatsiyasi uchun mos bo'lmagan bemorlar CAR-T hujayra transplantatsiyasini olishlari mumkin.
Toxicity and adverse reactions mainly include cytokine release syndrome, macrophage activation syndrome, hemophilic limfoma and B cell hypoplasia. Sitokinni chiqarish sindromi 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 maqsadli terapiya 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 qo'shimcha davolash sifatida glitsininni AOK qilish mumkin. Doimiy B-hujayrali gipoplaziya, hatto almashtirish terapiyasi bilan ham, infektsiya xavfini oshirishi mumkin. B hujayralari tanada CAR-T hujayralari yo'qolganidan keyin tiklanishi mumkin, shuning uchun bemorlar yana CAR-T hujayralarini olishlari mumkin. Ko'proq bemorlar CAR-T hujayra terapiyasini olganligi sababli, klinik tadqiqotlar toksik reaktsiyalarni va ularni boshqarish usullarini, shu jumladan sitokin blokadasini, steroidlarni va immun protein qo'shimchasining optimal vaqti va dozasini o'rganishga qaratilishi kerak.
CAR-T hujayralarining sezilarli toksikligi tufayli tadqiqotchilar hujayralardagi o'z joniga qasd qilish genlarini birlashtirish yoki gen ekspressionini o'chirish strategiyasini ham sinab ko'rishdi. Ammo o'z joniga qasd qilish gen tizimini barcha CAR-T hujayralariga birlashtirish hali ham qiyin, chunki ko'plab o'z joniga qasd qilish gen tizimlari immunogen (masalan, timus kinazani ifodalaydigan herpes simplex virusi) yoki o'z joniga qasd qilishga olib keladigan oldingi dorilar tomir ichiga yuborilishi kerak. Bundan tashqari, T-xujayrasining homingini ximokin retseptorlarining vaqtinchalik ekspressioni bilan o'zgartirish mumkin yoki ximokin retseptorlarining farmakologik blokadasi samaradorlikni oshirish va toksikani kamaytirish strategiyasi sifatida ishlatilishi mumkin.
CAR T-Cell terapiyasining ajoyib istiqbollari
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 mikoz qo'ziqorinlari), 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.
Saraton kasalligi global saraton diagnostikasi va davolash bo'yicha maslahatlarni amalga oshiradigan birinchi mahalliy veb-sayt. U 30 dan ortiq global saraton diagnostikasi va davolash muassasalari va 300 dan ortiq ekspertlar bilan mahalliy bemorlarga onkologiya bo'yicha mutaxassislar maslahati va maslahatlarini berish uchun bemorlarga eng ilg'or genetik testlar, dori-darmonlar, texnologiya va klinik sinovlarni davolashda yordam beradi. standartlashtirilgan va individuallashtirilgan.
