Kolorektální karcinom je značně heterogenní onemocnění. Pokroky v molekulární biologii nádorů nám umožnily definovat specifické subtypy onemocnění. Pro řadu z nich je k dispozici cílená terapie v rámci tzv. personalizované (precizní) onkologie. Jedním z těchto subtypů je dMMR/MSI-H CRC, kdy se ukazuje, že imunoterapie v léčbě těchto nádorů je spojena s velmi dobrou a dlouhou dobou odpovědi. Tento článek má za cíl podat přehled aktuálních možností v terapii dMMR/MSI-H CRC.
Colorectal carcinoma is a heterogenous disease. Advancements in molecular biology of tumors lead to definition of specific subtypes. For many of them targeted therapy known as personalized (precision) treatment is available. dMMR/MSI-H CRC is one of these subtypes, where immunotherapy leads to significant and long lasting response. This review summarizes current options in treatment of dMMR/MSI-H CRC.
- Klíčová slova
- dMMR/MSI-H CRC,
- MeSH
- imunoterapie metody MeSH
- kolorektální nádory * farmakoterapie imunologie MeSH
- lidé MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Anti-CD133 monoclonal antibody (Ab)-conjugated poly(lactide-co-glycolide) (PLGA) nanocarriers, for the targeted delivery of oxaliplatin (OXA) and superparamagnetic nanoparticles (IO-OA) to colorectal cancer cells (CaCo-2), were designed, synthesized, characterized, and evaluated in this study. The co-encapsulation of OXA and IO-OA was achieved in two types of polymeric carriers, namely, PLGA and poly(lactide-co-glycolide)-poly(ethylene glycol) (PLGA-PEG) by double emulsion. PLGA_IO-OA_OXA and PEGylated PLGA_IO-OA_OXA nanoparticles displayed a comparable mean diameter of 207 ± 70 nm and 185 ± 119 nm, respectively. The concentration of the released OXA from the PEGylated PLGA_IO-OA_OXA increased very rapidly, reaching ~100% release after only 2 h, while the PLGA_IO-OA_OXA displayed a slower and sustained drug release. Therefore, for a controlled OXA release, non-PEGylated PLGA nanoparticles were more convenient. Interestingly, preservation of the superparamagnetic behavior of the IO-OA, without magnetic hysteresis all along the dissolution process, was observed. The non-PEGylated nanoparticles (PLGA_OXA, PLGA_IO-OA_OXA) were selected for the anti-CD133 Ab conjugation. The affinity of Ab-coated nanoparticles for CD133-positive cells was examined using fluorescence microscopy in CaCo-2 cells, which was followed by a viability assay.
- MeSH
- antigen AC133 imunologie MeSH
- antitumorózní látky chemie MeSH
- imunokonjugáty farmakologie MeSH
- kolorektální nádory farmakoterapie imunologie patologie MeSH
- kopolymer kyseliny glykolové a mléčné chemie MeSH
- lidé MeSH
- monoklonální protilátky chemie MeSH
- nanočástice aplikace a dávkování chemie MeSH
- nosiče léků chemie MeSH
- oxaliplatin chemie MeSH
- systémy cílené aplikace léků * MeSH
- uvolňování léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Colorectal cancer (CRC) is one of the leading cancers in both genders. TNM staging system is still the most commonly used tumor classification and prognostic system. The disadvantage of TNM is that the prognostic information it provides is incomplete, and patients with the same histological tumor stages may differ significantly in the clinical outcome. Therefore, the identification of new prognostic parameters is crucial. The carcinogenic process that gives rise to an individual tumor is unique and tumor microenviroment should be taken into consideration. In CRC, T-cell infiltration is not homogenous, and recent studies are mostly focusing on memory T-cells and CD8 cells in predicting disease-free survival (DFS) and overall survival (OS). It seems that DFS and OS are not only dependent on microsatellite instable or stable status but mostly on the levels of expression of the immune signatures. Also, patients with high infiltration of cytotoxic and memory cells have significantly better outcome. This review consolidates current knowledge and recent research about importance of immune-cell-associated proteins, specific gene profiles of immune cells and immunotherapy in CRC. We also discussed cell-specific signatures in cancer treatment.
- MeSH
- imunoterapie MeSH
- inhibitory kontrolních bodů terapeutické užití MeSH
- kolorektální nádory genetika imunologie patologie MeSH
- lidé MeSH
- nádorové mikroprostředí MeSH
- prognóza MeSH
- sekvenční analýza RNA MeSH
- staging nádorů MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
- Klíčová slova
- pembrolizumab,
- MeSH
- endometroidní karcinom farmakoterapie genetika imunologie MeSH
- inhibitory kontrolních bodů * terapeutické užití MeSH
- kolorektální nádory farmakoterapie genetika imunologie MeSH
- lidé MeSH
- mikrosatelitní nestabilita * účinky léků MeSH
- nádory dělohy farmakoterapie genetika imunologie MeSH
- přežití po terapii bez příznaků nemoci MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
Léčba generalizovaného kolorektálního karcinomu je bohužel stále většinou s paliativním záměrem. Do léčebného algoritmu paliativní systémové léčby se postupně dostaly nové molekuly, a to jednak ze skupiny imunoterapie: pembrolizumab, nivolumab či kombinace nivolumabu s ipilimumabem byly schváleny Food and Drug Administration (FDA) pro předléčený kolorektální karcinom s defektem v mismatch repair genech / vysokou mikrosatelitovou instabilitou (dMMR/MSI-H) a pembrolizumab získal schválení FDA do první linie paliativní léčby těchto pacientů. V České republice jsou bohužel tyto molekuly v indikaci kolorektálního karcinomu bez registrace a samozřejmě bez úhrady. Současně se do klinické praxe dostala kombinace cetuximabu a encorafenibu u předléčených pacientů s BRAF V600E mutací, bohužel zatím také bez úhrady.
The treatment of the metastatic colorectal cancer is unfortunately mostly palliative. There are new molecules which have entered the treatment algorithm of the colorectal cancer. From the immunotherapy pembrolizumab, nivolumab or combination of nivolumab with ipilimumab have been approved by the Food and Drug Administration (FDA) for the previously treated colorectal cancer with mismatch repair deficiency / high microsatellite instability (dMMR/MSI-H) and also pembrolizumab has gained approval FDA in the first line palliative treatment. In the Czech Republic unfortunately there are all these molecules in the diagnosis of colorectal cancer without registration and without reimbursement. At the same time there is new combination of cetuximab with encorafenib in previously treated patients with BRAF V600E mutation unfortunately without reimbursement.
- Klíčová slova
- pembrolizumab, encorafenib, binimetinib,
- MeSH
- cetuximab aplikace a dávkování terapeutické užití MeSH
- kolorektální nádory * farmakoterapie imunologie terapie MeSH
- lidé MeSH
- metastázy nádorů imunologie MeSH
- monoklonální protilátky terapeutické užití účinky léků MeSH
- nivolumab MeSH
- Check Tag
- lidé MeSH
There is a growing corpus of evidence indicating that anti-VEGF therapy may normalize the abnormal tumor vasculature with the potential to re-program the tumor immune microenvironment to a more immunosupportive profile. Tumor vessel normalization increases tumor perfusion, and, consequently, oxygen and nutrient supply, and thus can be assumed to improve the general response to anticancer immunotherapy. The increased antitumor immunity responses seen following anti-VEGF therapy may also be associated with the inhibition of the immunosuppressive action deployed by VEGF on effector T cells. Bearing in mind the recent advances of combination immunotherapy, combinations of anti-VEGF therapy with immune checkpoint inhibitors now appear to represent an attractive strategy. Key to the successful implementation of a combination strategy for treating cancer is understanding the interaction of these two therapeutic interventions, particularly in regards to appropriate reprogramming of the tumor immune microenvironment to improve antitumor immunity.
BACKGROUND/AIM: Tumour-infiltrating lymphocytes (TILs) and Granzyme B play crucial roles in immune reactions against colorectal carcinoma (CRCa). The inhibitor of Granzyme B is Serpin B9. The aim of this study was to evaluate the effect of immunohistological parameters of TILs on the prognosis of CRCa and presence of lymph node metastasis. PATIENTS AND METHODS: A total of 152 patients who underwent surgery for CRCa were analyzed, including 63 patients in cohort stage II, according to the Union for International Cancer Control (UICC), and 89 patients in cohort UICC stage III. The TIL pattern was classified as peritumoural (PTL), intratumoural (ITL), intrastromal (ISL) or Crohn-like, and immunohistological staining of TIL and cancer cells was also performed. RESULTS: A significantly higher density of CD8+ and CD4+ TILs was observed in the UICC II group, and significantly higher densities of CD4+ TILs were observed in the UICC II group in all distinguished patterns. In the same cohort, higher numbers of CD57+ cells and FoxP3+ TILs and Granzyme B levels were observed. In cohort UICC III, there was a higher density of ISL, PTL CD8+, CD25+ TILs and cancer cells showed staining for Serpin B9. CD57, Granzyme B and CD8 were demonstrated as positive prognostic factors of overall survival, and CD57 and CD4+ TILs were demonstrated as positive prognostic factors of recurrence. CONCLUSION: TILs and CD57 are promising prognostic factors of CRCa. The association of Serpin B9 with lymph node metastasis reveals a potential mechanism for tumour resistance to immune reaction.
- MeSH
- kolorektální nádory imunologie patologie MeSH
- lidé MeSH
- lymfatické metastázy imunologie patologie MeSH
- nádorové biomarkery imunologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- tumor infiltrující lymfocyty imunologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: The objective of this study was to investigate serum levels of immunosuppressive cytokines TGF beta 1 and VEGF and count of immune cells in peripheral blood in stage II and III colorectal cancer patients. METHODS: Blood samples were collected from 22 colorectal patients and 25 healthy controls before the start of treatment. All patients were examined by a clinical immunologist to exclude patients with immune disorders and autoimmune diseases. TGF beta 1 and VEGF were measured by ELISA, and anti-tumor cellular immunity cells (CD4, CD8, B cells, NK cells) were measured by flow cytometry. RESULTS: TGF beta 1 and VEGF plasma levels were significantly increased in stage II and III colorectal patients compared with control group (both p < 0.0001). A decrease in the cellular immunity was shown in the absolute numbers of cytotoxic T lymphocytes (CD8+ ; p = 0.0240), helper T lymphocytes (CD4+ ; p = 0.0019), and natural killer cells (CD16 + CD56+; p < 0.0001) in both stage II and stage III patients. On the contrary, B lymphocyte (CD19+) serum levels were increased in colon cancer patients (p < 0.0001) compared to the control group. CONCLUSIONS: Our results show peripheral blood levels of TGF beta and VEGF were significantly increased in colorectal patients and changes in cellular anticancer immunity in comparison to control group. These results will be compared with results from Immunoscore.
- MeSH
- adenokarcinom imunologie MeSH
- B-lymfocyty imunologie MeSH
- buněčná imunita MeSH
- buňky NK imunologie MeSH
- CD4-pozitivní T-lymfocyty imunologie MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- kolorektální nádory imunologie MeSH
- krevní oběh MeSH
- lidé středního věku MeSH
- lidé MeSH
- počet lymfocytů MeSH
- staging nádorů MeSH
- transformující růstový faktor beta1 krev MeSH
- vaskulární endoteliální růstový faktor A krev MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- Bacteroides genetika izolace a purifikace metabolismus MeSH
- Bifidobacterium genetika izolace a purifikace metabolismus MeSH
- Enterobacteriaceae genetika izolace a purifikace metabolismus MeSH
- idiopatické střevní záněty metabolismus mikrobiologie MeSH
- kolorektální nádory imunologie metabolismus mikrobiologie MeSH
- lidé MeSH
- metabolický syndrom imunologie metabolismus mikrobiologie MeSH
- metody výživy klasifikace MeSH
- mikrobiota * fyziologie genetika imunologie MeSH
- parenterální výživa úplná metody normy MeSH
- střevní mikroflóra * fyziologie imunologie fyziologie genetika imunologie MeSH
- syndrom dráždivého tračníku metabolismus mikrobiologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
