Immunotherapy uses drugs to help the body’s own immune system better recognize and destroy cancer cells. Immunotherapy can be used to treat patients with advanced colorectal cancer.
Immunitet tekshiruvi inhibitori
Immunitet tizimining muhim qismi bu organizmning normal hujayralariga hujum qilishdan o'zini himoya qilish qobiliyatidir. Buning uchun u immunitet hujayralarida "tekshiruv punkti" oqsillaridan foydalanadi, ular immun javobini boshlash uchun yoqilishi kerak (yoki o'chirilishi kerak).
Saraton hujayralari ba'zida immunitet tizimining ularga hujum qilishini to'xtatish uchun ushbu tekshiruv punktlaridan foydalanadi. Biroq, ushbu tekshiruv punktlariga yo'naltirilgan dorilar saraton kasalligini davolash usullari sifatida katta istiqbollarga ega.
Tekshirish nuqtasi inhibitörleri deb nomlangan giyohvand moddalarni kolorektal saraton hujayralari yuqori darajadagi mikrosatellit beqarorligi (MSI-H) kabi o'ziga xos genetik o'zgarishlar yoki ijobiy o'zgarishlarni (MMR) genetik o'zgarishlarga ijobiy ta'sir ko'rsatgan odamlarda qo'llash mumkin.
These drugs are used in people whose cancer is still growing after chemotherapy. They may also be used to treat people whose cancer cannot be removed surgically, relapses after treatment (relapse) or has spread to other parts of the body (metastasis).
Tasdiqlandi immunoterapiya dorilar
PD-1 inhibitor approved
Pembrolizumab (Pembrolizumab, Keytruda) and nivolumab (Nivolumab, Opdivo) are drugs that target PD-1, a protein on cells of the immune system called T cells that usually helps Prevent these cells from attacking other cells in the body. By blocking PD-1, these drugs can enhance the immune response to cancer cells.
On May 24, 2017, the US FDA approved the PD-1 inhibitor pembrolizumab (Pembrolizumab, Keytruda) for the treatment of solid shish patients with microsatellite highly unstable (MSI-H) / mismatch repair defects (dMMR), The tumor types cover 15 different malignant tumors, including colorectal cancer, small cell lung cancer, and cervical cancer.
2 yil 2017 avgustda AQSh oziq-ovqat va farmatsevtika idorasi (FDA) ftorurasil, oksaliplatin va irinotekanni davolash uchun nivolumab (Navumab, Opdivo) ni ma'qulladi. Kattalardagi yoki bolalardagi (-12 yosh) metastatik kolorektal saraton kasalligini davolash uchun juda beqaror (MSI -H) davolovchi mikrosatelit yoki mos kelmaydigan ta'mirlash nuqsonlari (dMMR).
CTLA-4 inhibitori tasdiqlangan
Ipilimumab (Yervoy) - bu immunitetni kuchaytiradigan boshqa dori. Uni yolg'iz ishlatish mumkin emas. Uni T hujayralarida yana bir protein bo'lgan CTLA-4 blokirovkasini ta'minlovchi nivolumab bilan birlashtirish kerak.
MSI-High (MSI-High) mCRC-ning muvaffaqiyatli holati nivolumab va ipilimumabning birgalikda ishlatilishi bo'lib, bu II bosqich CheckMate142 tadqiqotida baholangan. Kombinatsiyalangan terapiya ORR ni (ob'ektiv javob darajasi) 49% ni ko'rsatdi va 5 bemorning 119 nafarida CR (to'liq javob) va 53 PR (qisman javob) mavjud edi. Ko'pgina bemorlar (n = 82) ilgari ftorurasil, oksaliplatin va irinotekanni qabul qilishgan. Ushbu bemorlarda ORR 46%, 3 CR va 35 PR ni tashkil etdi.
CheckMate-142 ma'lumotlariga ko'ra, FDA 12 yosh va undan katta bo'lgan kattalar va pediatrik bemorlarni davolash uchun kombinatsiyani (Nivolumab + Ipilimumab) tasdiqladi, shu jumladan MSI-H yoki mos kelmaydigan ta'mirlash nuqsonlari (dMMR) bo'lgan mCRC bemorlari, bu bemorlar oldinga siljishdi ftoruratsil, oksaliplatin va irinotekan bilan davolashdan keyin.
Kolorektal terapiyada MSI / dMMR qo'llanilishini talqin qilish
MSI DNK metilatsiyasi yoki gen mutatsiyalari natijasida hosil bo'lgan mos kelmaydigan ta'mirlash genlarining yo'qolishini anglatadi, natijada mikrosatellit takroriy ketma-ketliklari uzunligi o'zgaradi. Tadqiqot natijasida MSI-H immunoterapiya uchun mos keladigan o'smalar uchun muhim biomarker ekanligi aniqlandi.
MSI - bu mikrosatellitning beqarorligi, MMR (mos kelmaslik tuzatish) genlarning mos kelmasligini tiklash funktsiyasiga tegishli. Inson nomuvofiqligini tiklash geni (MMR geni) transkripsiyadan va tarjimadan so'ng mos kelmaydigan ta'mirlash oqsilini ifoda etishi mumkin. Agar biron bir MMR oqsilining ekspressioni yo'qolishi hujayraning mos kelmaydigan ta'mirlash funktsiyasida nuqsonlarni keltirib chiqarishi mumkin bo'lsa, DNKning replikatsiyasi jarayonida bazaning mos kelmasligi tuzatish funktsiyasining yo'qolishi to'planishga olib keladi, bu esa mikrosatellit beqarorligi (MSI) paydo bo'lishiga olib keladi. Kolorektal saraton kasalligining taxminan 15% MSI yo'lidan kelib chiqadi.
PCR can be used to detect the length of microsatellite sites (microsatellites are tandem repeats of short DNA sequences in the genome of eukaryotes) in tumor cell DNA, and then compared with the corresponding normal cell DNA. With the popularization and application of NGS (Second Generation Sequencing), in addition to traditional immunohistochemistry and PCR detection, microsatellite status can also be detected on the NGS platform. To understand the authoritative NGS genetic testing institutions at home and abroad, please consult 400-626-9916.
Bundan tashqari, o'sma namunalari (shu jumladan jarrohlik namunalari va ponksiyon namunalari) to'rtta mos kelmaydigan genlarni immunohistokimyoviy aniqlash uchun ishlatilishi mumkin, jumladan: MLH1, MSH2, MSH6 va PMS2. Ushbu to'rtta oqsildan birortasi etishmayotgan ekan, o'sma dMMR ga tegishli bo'lib, bu mos kelmaydiganlarni tiklash funktsiyasining nuqsonidir. Agar to'rtta oqsil ijobiy ifoda etilsa va o'sma pMMR bo'lsa, mos kelmaslikni tiklash funktsiyasi tugallangan.
Genetik sinov MSI hisobotini tahlil qilish
Quyidagi rasmda Global Onkologlar Tarmoqidagi bemor, MSI testidan so'ng, mahalliy genetik tekshiruv kompaniyasi (400-626-9916) tomonidan MSI-H kasalligi aniqlangan. Ushbu bemor juda omadli va immunoterapiya uchun javob beradi.
Global Onkologlar Tarmoqidagi yana bir bemor AQSh Keruis Gen (400-626-9916) tomonidan ijobiy sinovdan o'tkazildi va to'rtta oqsilning hammasi ijobiy (musbat), demak, bemor pMMR bo'lgan va yuqorida tasdiqlangan Immunoterapiya uchun mos emas. .
Sinovning yakuniy natijalarini talqin qilish MSS (mikrosatellitning barqarorligi), MSI-L (mikrosatellening past beqarorligi) va MSI-H (mikrosatellening yuqori beqarorligi) ga bo'linishi mumkin. Odatda, dMMR MSI-H ga, pMMR esa MSS va MSI-L ga teng.
PD-1 inhibitorlaridan foydalanish bo'yicha choralar
- Ushbu dorilar har 2 yoki 3 xaftada vena ichiga (IV) tomchilab yuboriladi.
- Ushbu dorilarning yon ta'siriga charchoq, yo'tal, ko'ngil aynish, qichishish, toshma, ishtahani yo'qotish, ich qotishi, og'riyotgan og'riqlar va diareya kiradi.
- Boshqa jiddiy yon ta'sirlar kamroq uchraydi. Ba'zida immunitet tizimi boshqa qismlarga hujum qilishi mumkin, ehtimol o'pkada, ichakda, jigarda, gormon ishlab chiqaruvchi bezlarda, buyrakda yoki boshqa organlarda jiddiy yoki hayot uchun xavfli muammolar bo'lishi mumkin.
- Infuzion paytida bemorning jismoniy holatini real vaqtda kuzatib borish kerak.
Ipilimumab dori-darmonlariga qarshi ehtiyot choralari
- Ushbu dori kolorektal saraton kasalligini davolash uchun nivolumab (Opdivo) bilan ishlatiladi, ammo uni yakka o'zi qo'llash mumkin emas. Vena ichiga (IV) infuziya bilan yuboriladi, odatda har 3 haftada 4 tsikl davolanadi.
- Ushbu dorining eng keng tarqalgan yon ta'siriga charchoq, diareya, toshma va qichishish kiradi.
- Ushbu preparatni qo'llashda jiddiy yon ta'sirlar PD-1 inhibitörlerine qaraganda tez-tez uchraydi. PD-1 inhibitörleri kabi, bu dori ham immunitet tizimining tananing boshqa qismlariga hujum qilishiga olib kelishi mumkin, bu esa ichak, jigar, gormon ishlab chiqaradigan bezlar, asab, teri, ko'zlar yoki boshqa organlar bilan bog'liq jiddiy muammolarga olib kelishi mumkin. Ba'zi odamlarda ushbu yon ta'sirlar hayot uchun xavfli bo'lishi mumkin.
- Infuzion paytida bemorning jismoniy holatini real vaqtda kuzatib borish kerak.
Kolorektal saraton kasalligida immunoterapiya preparatlarini qanday tanlash mumkin?
Amerikalik kolorektal saraton mutaxassisi doktor Chiorean “MSI-H bilan kasallangan bemorlar uchun Pembrolizumab yoki nivolumab ko'proq afzaldir. Nivolumab ipilimumab bilan birgalikda (CTLA-4 inhibitori) kamdan kam qo'llaniladi. Menimcha, farq i
s very small. Similarly, some people may argue that CTLA-4 may be better tolerated by the inhibitory response, but I also feel that the toxicity is significantly higher. ”
Dr. Messersmith said that when he needed to quickly obtain therapeutic effects, he used nivolumab and ipilimumab combination therapy. Adding ipilimumab can get an additional 15%–20% response rate. If the patient is symptomatic, it can be added. Even though this may increase adverse reactions, the treatment effect is even greater. This requires an assessment of the patient’s physical condition.
If patients and their families have difficulty in choosing an immunotherapy drug, they can seek domestic authoritative colorectal cancer experts for consultation through the Global Oncologist Network (+91 96 1588 1588) to determine the final, more suitable treatment plan.
