Organoid co-culture models of the tumor microenvironment promote precision medicine

In recent years,the three-dimensional(3D)culture system has emerged as a promising preclinical model for tumor research owing to its ability to replicate the tissue structure and molecular characteristics of solid tumors in vivo.This system offers several advantages,including high throughput,efficiency,and retention of tumor heterogeneity.Traditional Matrigel-submerged organoid cultures primarily support the long-term proliferation of epithelial cells.One solution for the exploration of the tumor microenvironment is a reconstitution approach involving the introduction of exogenous cell types,either in dual,triple or even multiple combinations.Another solution is a holistic approach including patient-derived tumor fragments,air-liquid interface,suspension 3D culture,and microfluidic tumor-on-chip models.Organoid co-culture models have also gained popularity for studying the tumor microenvironment,evaluating tumor immunotherapy,identifying predictive biomarkers,screening for effective drugs,and modeling infections.By leveraging these 3D culture systems,it is hoped to advance the clinical application of therapeutic approaches and improve patient outcomes.

Deaths and adverse events from adjuvant therapy with immune checkpoint inhibitors in solid malignant tumors:A systematic review and network meta-analysis

Background:By prolonging overall survival and reducing disease recurrence rates,immune checkpoint inhibitors(ICIs)are an emerging adjuvant therapy option for patients with resectable malignant tumors.However,the safety profile(deaths and adverse events[AEs])of adjuvant ICIs has not been fully described.Methods:We searched the literature for phase III randomized clinical trials that compared PD-1,PD-L1,and CTLA-4 inhibitors in solid malignant tumors.Incidences of death,discontinuation,AEs of any cause,treatment-related adverse events(TRAEs),and immune-related adverse events(IRAEs)were extracted for the network meta-analysis.Network meta-analyses with low incidence and poor convergence are reported as incidences with 95%confidence intervals(95%CIs).Results:Ten randomized clinical trials that included 9243 patients who received ICI adjuvant therapy were eligible.In total,21 deaths due to TRAEs were recorded,with an overall incidence of 0.40%(95%CI:0.26–0.61).The treatment-related mortality rates for ipilimumab(0.76%,95%CI:0.31–1.55)and atezolizumab(0.56%,95%CI:0.18–1.31)were higher than for pembrolizumab(0.24%,95%CI:0.10–0.56)and nivolumab(0.30%,95%CI:0.08–0.77).The most frequent causes of death were associated with the gastrointestinal(0.10%,95%CI:0.04–0.24)and pulmonary(0.08%,95%CI:0.03–0.21)systems.Compared with the control arm,we found that nivolumab(odds ratio[OR]:2.73,95%CI:0.49–15.85)and atezolizumab(OR:12.43,95%CI:2.42–78.48)caused the fewest grade≥3 TRAEs and IRAEs.Commonly reported IRAEs of special interest were analyzed,and two agents were found to have IRAEs with incidences>10%,i.e.,hepatitis for atezolizumab(14.80%,95%CI:12.53–17.32)and hypophysitis for ipilimumab(13.53%,95%CI:11.38–15.90).Conclusions:Ipilimumab and atezolizumab were correlated with higher treatment-related death rates than pembrolizumab and nivolumab,in which the gastrointestinal and pulmonary systems were mostly involved.Regarding severe TRAEs and IRAEs,nivolumab and atezolizumab are likely to be the safest agent,respectively.This study will guide clinical practice for ICI adjuvant therapies.