Umdlavuza wesibindi
Liver cancer is currently the fifth most common cause of cancer-related death in the world. The current first-line systemic treatment drug is mainly sorafenib, but usually only prolongs the overall survival of 3 months, and has serious side effects.
In 2010, immunotherapy was first successful in melanoma. Since then, it has targeted the immunosuppressive molecule PD-1, programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte-associated antigen 4 (CTLA -4) Monoclonal antibodies have been approved for listing one after another, breaking through the fortress of various solid tumors and bringing huge survival benefits to patients with advanced cancer, including hepatocellular carcinoma.
For example, data from stage I / II immune checkpoint inhibitors of advanced hepatocellular carcinoma show that the durable objective response rate for first-line and second-line use is about 20%. Clinical studies of anti-PD-1 / anti-PD-L1 in combination with other checkpoint molecules are also underway. In addition to immune checkpoint inhibitors, other strategies for using the immune system, including CAR-T cell NK cell therapy and peptide vaccines against hepatocellular carcinoma antigens, have also entered Phase I / II studies. Below we will systematically take stock for everyone.
Isithiyo sokuhlola izivikeli mzimba
I-PD-1 ne-PD-L1 / PD-L2
Izindawo zokuhlola izivikeli mzimba zingama-T cell surface molecule angacindezela noma avuselele amasosha omzimba. Okubaluleke kakhulu, banesibopho sokugcina ukubekezelelana kwabo nokuvimbela izimpendulo zomzimba ezingadingekile noma ezeqile.
On September 22, 2017, based on a 214-person Phase 2 clinical trial Checkmate-040, the US FDA approved the PD-1 antibody Opdivo for patients with advanced umdlavuza wesibindi abamelana ne-NEXAVAR.
On November 9, 2018, the US FDA approved the immunotherapy drug pembrolizumab (Pembrolizumab, Keytruda) to treat patients with advanced liver cancer (hepatocellular carcinoma). It is suitable for patients with hepatocellular carcinoma who have previously been treated with too much Gemira (Sorafenib).
Several clinical trials of other anti-PD-1 / anti-PD-L1 immunotherapy are currently underway. (Keynote-240, NCT02702401 and Keynote-394, NCT03062358) are two phase III clinical trials comparing keytruda as a second-line treatment for advanced HCC patients with placebo.
Ngaphezu kwalokho, ama-inhibitors ama-immune checkpoint inhibitors amasha iTislelizumab (anti-PD-1), camrelizumab (anti-PD-1) kanye ne-durvalumab (anti-PD-L1) njengamanje ahlolwa njengamazinga okuphendula kokwelashwa komugqa wesibili.
I-CTLA-4
I-CTLA-4 i-homologue ye-CD28 evezwe kumaseli we-T acushiwe. Icindezela ukusebenza kwe-T cell ngokuncintisana ne-CD7 yayo ye-ligand B1-28, edlulisa isiginali yokuzivikela, bese yona iletha isignali evimbela ama-T cell.
tremelimumab (tisimumab) is the only anti-CTLA-4 antibody tested as monotherapy or combination therapy in the treatment of advanced HCC. A small pilot clinical trial of 20 viremia patients with hepatitis C virus (HCV) -related HCC showed that not only the partial response rate of antitumor activity was 17.6%, but also showed antiviral activity and significant viral load Down.
Ezinye izindawo zokuhlola ezivimbela kanye nezindawo zokuhlola izivikeli mzimba
Ngaphezu kwe-PD-1 / PD-L1 ne-CTLA-4, kunamanye ama-receptors avimbelayo, afaka i-T cell immunoglobulin mucin 3 (TIM-3) ne-lymphocyte activation gene 3 (LAG-3). Izilingo ezihlanganisa ukwelashwa kwe-anti-PD-1 / anti-PD-L1 nezidakamizwa ezibhekiswe ku-TIM-3 (NCT03099109) kanye ne-LAG-3 (NCT03005782 ne-NCT01968109) seziqalile.
Isu elihlanganisiwe le-immunotherapy lomdlavuza wesibindi osezingeni eliphakeme
Yize inani lokuphendula lokwelashwa kwe-agent eyodwa ngama-immune checkpoint inhibitors selidlule kakhulu izinga lokuphendula le-sorafenib, kepha lilonke liphansi kakhulu (<20%). Ngakho-ke, emtholampilo, siyaqhubeka nokuhlola amasu okukhulisa impendulo yesiguli. Isibonelo, inhlanganisela yama-immune checkpoint inhibitors namanye ama-inhibitors okuhlola, ama-molecule amancane kinase inhibitors, ezinye izindlela zokwelapha ezihlelekile nezendawo.
Isivivinyo sesigaba I / II sokuhlanganiswa kwe-devarumab (durvalumab) ne-temlimumab (tremelimumab) yomdlavuza wesibindi esithuthukile sakhombisa isilinganiso sokuphendula esingu-20% ngaphandle kwemicimbi emibi kakhulu. Ucwaningo lwesigaba III (NCT03298451) lwale nhlanganisela yokwelashwa komugqa wokuqala njengamanje luyaqashwa.
The synergy between immune checkpoint inhibitors and local therapies (including ablation, radiation therapy and transarterial chemoembolization (TACE)) is also being investigated. Tumors with low mutation load and fewer new antigens are generally less immunogenic and have no / low response (or primary resistance) to checkpoint inhibitors. Local treatment and radiation therapy induce inflammation and produce new antigens that are released into the bloodstream. Therefore, the combination of checkpoint inhibitors and local area therapy is expected to increase sensitivity to checkpoint inhibitors.
In a preliminary study of 32 patients, temlimumab (tremelimumab) was used in combination with radiofrequency ablation or TACE. Partial reactions are observed in up to 25% of patients.
Umnyango wezokwelapha we-Global Oncologist Network ubala izivivinyo zomtholampilo zamanje ze-immunotherapy checkpoint inhibitor monotherapy kanye nokwelashwa okuhlanganisiwe etafuleni elilandelayo ukuze uthole inkomba yakho. Labo abafuna ukubamba iqhaza bangashayela umnyango wezokwelapha ukuhlolwa kokuqala.
Ukwelashwa kwamaseli omzimba
UKWELASHWA KWEZIMOTO
T cells engineered with chimeric antigen receptors (CAR) gain the ability to recognize certain antigens, which allows specific cells (including isisu cells) to be targeted. CAR-T-based therapy has successfully treated CD19-positive hematological malignancies, which paved the way for its application in solid tumors. In HCC, Glypican-3 (GPC3) is most commonly used as a target for CAR-T therapy and has significant antitumor activity both in vitro and in vivo. Second, alpha-fetoprotein (AFP), which is usually overexpressed in HCC, is also used as a target and has a potent anti-tumor response. There are currently at least 10 phase I / II clinical trials (almost all conducted in China) to study the application of CAR-T cells in advanced HCC.
Ukwelashwa kwamaseli we-NK
I-NK (cell killer cell, NK) yiseli lomzimba elinamandla amakhulu okulwa nomdlavuza. Indawo enamandla kunazo zonke ukuthi ingakwazi ngqo futhi ngokushesha imizimba yabokufika engaphandle (ukutheleleka ngegciwane kanye namagciwane) ngaphandle kwenqubo yokwethulwa kwe-antigen futhi ngaphandle kwabanye abantu ababikayo. Amaseli, amangqamuzana omdlavuza, amaseli wokuqina, njll.)
Amaseli we-NK, njenge- "Molecular Patrol", ahamba egazini. Lapho nje sebethole amaseli angaphandle noma amaseli aguqukile alahlekelwe wukuzazisa kwawo (abizwa nge-MHC), i-receptor yeseli le-NK ngokushesha ithumela isignali bese ishesha iye kulwelwesi lweseli okuqondiswe kulo. Okusho ukuthi, amaseli e-NK kumele abe semgqeni wangaphambili wempi. Idedela izinhlayiya ezinobuthi kuyo, isheshe incibilikise amangqamuzana abhekiswe kuwo, futhi ibangele ukuthi amangqamuzana omdlavuza afe kungakapheli imizuzu emihlanu.
Kumele kuqashelwe ukuthi amangqamuzana e-NK, njengengxenye eyinhloko yesistimu yomzimba yokuzivikela, angamaseli omzimba abaluleke kakhulu emzimbeni womuntu, kepha aqabuke kakhulu egazini lomzimba lomuntu, elibala kuphela ama-lymphocyte ayi-5% -10%. Amaseli enza i-30-50% yama-lymphocyte esibindi sesibindi somuntu. Uma kuqhathaniswa nokujikeleza kwamaseli e-NK, amaseli we-NK esibindi anezici ezihlukile ze-phenotypic nezici zokusebenza, okukhombisa ukuphakama kwe-cytotoxicity kumaseli we-tumor. Ngesikhathi sokuvela komdlavuza wesibindi, inani lamaseli e-NK nomsebenzi wokukhiqiza we-cytokine (interferon-γ) nomsebenzi we-cytotoxic wehlisiwe. Ngakho-ke, izindlela zokwelapha ezisebenzisa kabusha amaseli e-NK futhi zizisebenzise ukuhlasela izicubu incl
ude chemoimmunotherapy kanye nokufakelwa kabusha kwamaseli we-NK. Njengamanje kunezivivinyo zomtholampilo zesigaba se-7 / II eziphenya i-NK cell-based immunotherapy ezigulini ze-HCC, iningi lazo ezamukela ukudluliswa kokutholwa kwamaseli we-autologous noma allogeneic NK.
Umuthi wokugoma we-Peptide
Cancer peptide vaccine is the same as CAR-T cell immunotherapy. The most studied peptide vaccine for hepatocellular carcinoma is GPC3, because it is overexpressed in up to 80% of liver cancers (including early tumors), but not in normal tissues. It is very specific Target. In addition, its expression is associated with a poor prognosis.
Isigaba sokuqala ngicwaninga ngeziguli ezingama-33 ezine-HCC ethuthukile zisebenzisa umuthi wokugomela i-GPC3 peptide ikhombise ukuthi umuthi wokugoma ubekezeleleke kahle, isiguli esisodwa sathola ukuxolelwa okuncane (1%), kanti iziguli eziyi-3 zinezifo ezizinzile ezinyangeni ezi-19 (2%). Amaphesenti angama-58 eziguli athuthukise impendulo ye-cytotoxic T lymphocyte ngemuva kokungeniswa ngomuthi othize we-GPC3, obehambisana nokuphila konke. Ukusetshenziswa okuhlanganisiwe komuthi wokugoma i-GPC3 peptide nezinye izindlela zokwelapha njengamanje kusacutshungulwa.
Amagama eziguli ezinomdlavuza wesibindi
Singene enkathini entsha ekwelapheni i-hepatocellular carcinoma, lapho amasu asekelwe kuma-immune checkpoint inhibitors azoba yisisekelo maduzane, njenge-monotherapy noma ngokuhambisana namanye ama-checkpoint inhibitors nama-kinase inhibitors. Ngaphezu kwalokho, ucwaningo olusha lwe-Immunotherapy kanye nentuthuko nayo ilethe ithemba nezinketho zokwelashwa ezigulini ezithuthukile. Ngenxa yokuthi ziningi kakhulu izivivinyo zemitholampilo, akunakwenzeka ukuba uzethule ngakunye kulesi sihloko.
