"NU21-03-00539" Dotaz Zobrazit nápovědu
BACKGROUND: Immune checkpoint inhibitors (ICIs), including those targeting PD-1, are currently used in a wide range of tumors, but only 20-40% of patients achieve clinical benefit. The objective of our study was to find predictive peripheral blood-based biomarkers for ICI treatment. METHODS: In 41 patients with advanced malignant melanoma (MM) and NSCLC treated with PD-1 inhibitors, we analyzed peripheral blood-based immune subsets by flow cytometry before treatment initialization and the second therapy dose. Specifically, we assessed basic blood differential count, overall T cells and their subgroups, B cells, and myeloid-derived suppressor cells (MDSC). In detail, CD4 + and CD8 + T cells were assessed according to their subtypes, such as central memory T cells (TCM), effector memory T cells (TEM), and naïve T cells (TN). Furthermore, we also evaluated the predictive value of CD28 and ICOS/CD278 co-expression on T cells. RESULTS: Patients who achieved disease control on ICIs had a significantly lower baseline proportion of CD4 + TEM (p = 0.013) and tended to have a higher baseline proportion of CD4 + TCM (p = 0.059). ICI therapy-induced increase in Treg count (p = 0.012) and the proportion of CD4 + TN (p = 0.008) and CD28 + ICOS- T cells (p = 0.012) was associated with disease control. Patients with a high baseline proportion of CD4 + TCM and a low baseline proportion of CD4 + TEM showed significantly longer PFS (p = 0.011, HR 2.6 and p ˂ 0.001, HR 0.23, respectively) and longer OS (p = 0.002, HR 3.75 and p ˂ 0.001, HR 0.15, respectively). Before the second dose, the high proportion of CD28 + ICOS- T cells after ICI therapy initiation was significantly associated with prolonged PFS (p = 0.017, HR 2.51) and OS (p = 0.030, HR 2.69). Also, a high Treg count after 2 weeks of ICI treatment was associated with significantly prolonged PFS (p = 0.016, HR 2.33). CONCLUSION: In summary, our findings suggest that CD4 + TEM and TCM baselines and an early increase in the Treg count induced by PD-1 inhibitors and the proportion of CD28 + ICOS- T cells may be useful in predicting the response in NSCLC and MM patients.
- MeSH
- antigeny CD278 metabolismus MeSH
- antigeny CD279 antagonisté a inhibitory MeSH
- antigeny CD28 MeSH
- CD8-pozitivní T-lymfocyty imunologie účinky léků metabolismus MeSH
- dospělí MeSH
- inhibitory kontrolních bodů * terapeutické užití farmakologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- melanom * farmakoterapie imunologie krev patologie MeSH
- nádory plic * farmakoterapie imunologie krev patologie MeSH
- nemalobuněčný karcinom plic * farmakoterapie imunologie krev patologie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
BACKGROUND: High-grade serous ovarian carcinoma (HGSOC) is the most common and aggressive subtype of epithelial ovarian carcinoma. It is primarily diagnosed at stage III or IV when the 5-year survival rate ranges between 20% and 40%. Here, we aimed to validate the hypothesis, based on HGSOC cell lines, that proposed the existence of two distinct groups of HGSOC cells with high and low oxidative phosphorylation (OXPHOS) metabolism, respectively, which are associated with their responses to glucose and glutamine withdrawal. METHODS: We isolated and cultivated primary cancer cell cultures from HGSOC and nontransformed ovarian fibroblasts from the surrounding ovarium of 45 HGSOC patients. We tested the metabolic flexibility of the primary cells, particularly in response to glucose and glutamine depletion, analyzed and modulated endoplasmic reticulum stress, and searched for indices of the existence of previously reported groups of HGSOC cells with high and low OXPHOS metabolism. RESULTS: The primary HGSOC cells did not form two groups with high and low OXPHOS that responded differently to glucose and glutamine availabilities in the cell culture medium. Instead, they exhibited a continuum of OXPHOS phenotypes. In most tumor cell isolates, the responses to glucose or glutamine withdrawal were mild and surprisingly correlated with those of nontransformed ovarian fibroblasts from the same patients. The growth of tumor-derived cells in the absence of glucose was positively correlated with the lipid trafficking regulator FABP4 and was negatively correlated with the expression levels of HK2 and HK1. The correlations between the expression of electron transport chain (ETC) proteins and the oxygen consumption rates or extracellular acidification rates were weak. ER stress markers were strongly expressed in all the analyzed tumors. ER stress was further potentiated by tunicamycin but not by the recently proposed ER stress inducers based on copper(II)-phenanthroline complexes. ER stress modulation increased autophagy in tumor cell isolates but not in nontransformed ovarian fibroblasts. CONCLUSIONS: Analysis of the metabolism of primary HGSOC cells rejects the previously proposed hypothesis that there are distinct groups of HGSOC cells with high and low OXPHOS metabolism that respond differently to glutamine or glucose withdrawal and are characterized by ETC protein levels.
- Publikační typ
- časopisecké články MeSH
Several regimens combining immunotherapy and tyrosine kinase inhibitors (TKIs) have recently been validated for the first-line treatment of patients with metastatic renal cell carcinoma (mRCC). While immunotherapy is typically discontinued after 2 years in patients who neither progress nor experience limiting toxicity, according to the protocols of most recent phase III clinical trials, TKIs are to be continued until disease progression or the emergence of limiting toxicity. However, the prolonged use of TKIs is associated with significant toxicity and financial costs. This has sparked considerable debate about whether TKIs can be safely discontinued, particularly in mRCC patients who have achieved a verified complete response. This concise review examines the available evidence on TKI discontinuation in the context of mRCC management.
- MeSH
- imunoterapie MeSH
- inhibitory proteinkinas farmakologie terapeutické užití MeSH
- inhibitory tyrosinkinasy MeSH
- karcinom z renálních buněk * patologie MeSH
- lidé MeSH
- nádory ledvin * farmakoterapie patologie MeSH
- retrospektivní studie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
BACKGROUND: Treatment options for metastatic renal cell carcinoma (mRCC) are rapidly expanding, and immunotherapy using checkpoint inhibitors is a first- or second-line option for most patients. OBJECTIVE: The objective of the present retrospective analysis was to explore the real-world impact of checkpoint inhibitor-based immunotherapy compared with therapy using other types of targeted therapies using a large real-world database. METHODS: RenIS, a registry of patients with mRCC was used as a data source. Outcomes were compared for cohorts treated with TKIs or mTOR inhibitors only [targeted therapy (TT) cohort] versus patients who received immunotherapy (IO) using a checkpoint inhibitor in any line of treatment (IO cohort). Data from a total of 1981 patients were extracted from the registry, including 1767 patients in the TT cohort and 214 patients in the IO cohort. RESULTS: The median overall survival from the initiation of first-line treatment was 24.5 months versus not reached (p < 0.001) in the TT cohort versus the IO cohort, respectively [HR 0.23, 95% CI (0.17-0.31), p < 0.001]. The probability of 5-year survival was 24.2 versus 67.9% in the TT cohort versus the IO cohort, respectively. Immunotherapy in any line of treatment was associated with a lower risk of death. Overall survival was superior for patients receiving immunotherapy as the first or second treatment line compared with patients treated with non-immunological targeted therapy. CONCLUSION: In real-world patients with mRCC, immunotherapy is associated with significant survival benefit. The present retrospective analysis shows the real-world benefit of second-line immunotherapy in patients previously treated with tyrosine-kinase inhibitors.
