Despite the marked success of applications of PD-1/PD-L1 checkpoint blockades in clinical, the efficacy and responsiveness of these agents varies greatly among different tumor types and across ...individual patients. Therefore, establishment of predictive biomarkers for checkpoint blockades is of the most importance to maximize the therapeutic benefits. In this review, we discuss the current progress and challenges of developing predictive biomarkers of immunotherapy responsiveness, aiming to provide some directions for future studies. PD-L1 expression is a logical biomarker for the prediction of response to anti-PD-(L)1 immunotherapies. However, the predictive values of PD-L1 expressions for immunotherapy are currently debating and challenging. Multiplex detecting methods and combined biomarkers may provide new strategies. For example, tumor mutation and neoantigens burden, some oncogene mutations, like EGFR, ALK, KRAS and STK11. In addition, with development of new probes and tracers, immuno-PET provide a new, non-invasive and quantitative strategy to monitor treatment response. As current evidence of those potential predictors, a consensus and standardization is needed to establish to widely applied in future studies. Multiplex detecting methods and combined biomarkers may provide new strategies.
•The predictive values of PD-L1 expressions for immunotherapy are currently debating and challenging.•Multiplex detecting methods and combined biomarkers, like tumor mutation burden, oncogene mutations, and immuno-PET, may provide new strategies.•This review discuss the current progress and challenges of predictive biomarkers, aiming to provide some directions for future studies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract
Radiotherapy (RT) is delivered for purposes of local control, but can also exert systemic effect on remote and non-irradiated tumor deposits, which is called abscopal effect. The view of RT ...as a simple local treatment has dramatically changed in recent years, and it is now widely accepted that RT can provoke a systemic immune response which gives a strong rationale for the combination of RT and immunotherapy (iRT). Nevertheless, several points remain to be addressed such as the interaction of RT and immune system, the identification of the best schedules for combination with immunotherapy (IO), the expansion of abscopal effect and the mechanism to amplify iRT. To answer these crucial questions, we roundly summarize underlying rationale showing the whole immune landscape in RT and clinical trials to attempt to identify the best schedules of iRT. In consideration of the rarity of abscopal effect, we propose that the occurrence of abscopal effect induced by radiation can be promoted to 100% in view of molecular and genetic level. Furthermore, the “radscopal effect” which refers to using low-dose radiation to reprogram the tumor microenvironment may amplify the occurrence of abscopal effect and overcome the resistance of iRT. Taken together, RT could be regarded as a trigger of systemic antitumor immune response, and with the help of IO can be used as a radical and systemic treatment and be added into current standard regimen of patients with metastatic cancer.
Highlights • PD-1/PD-L1 blockades present a new paradigm shift in immunotherapy for cancer. • It is crucial to identify a biomarker predicting the response to checkpoint blockades. • PD-L1 is an ...important and widely-explored predictive biomarker. • There are many challenges to overcome when examining PD-L1 as a predictive biomarker. • Gene analysis might be new approach for judging the potential clinical benefit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
PD-1/PD-L1 checkpoint blockades have achieved significant progress in several kinds of tumours. Pembrolizumab, which targets PD-1, has been approved as a first-line treatment for advanced non-small ...cell lung cancer (NSCLC) patients with positive PD-L1 expression. However, PD-1/PD-L1 checkpoint blockades have not achieved breakthroughs in treating glioblastoma because glioblastoma has a low immunogenic response and an immunosuppressive microenvironment caused by the precise crosstalk between cytokines and immune cells. A phase III clinical trial, Checkmate 143, reported that nivolumab, which targets PD-1, did not demonstrate survival benefits compared with bavacizumab in recurrent glioblastoma patients. Thus, the combination of a PD-1/PD-L1 checkpoint blockade with RT, TMZ, antibodies targeting other inhibitory or stimulatory molecules, targeted therapy, and vaccines may be an appealing solution aimed at achieving optimal clinical benefit. There are many ongoing clinical trials exploring the efficacy of various approaches based on PD-1/PD-L1 checkpoint blockades in primary or recurrent glioblastoma patients. Many challenges need to be overcome, including the identification of discrepancies between different genomic subtypes in their response to PD-1/PD-L1 checkpoint blockades, the selection of PD-1/PD-L1 checkpoint blockades for primary versus recurrent glioblastoma, and the identification of the optimal combination and sequence of combination therapy. In this review, we describe the immunosuppressive molecular characteristics of the tumour microenvironment (TME), candidate biomarkers of PD-1/PD-L1 checkpoint blockades, ongoing clinical trials and challenges of PD-1/PD-L1 checkpoint blockades in glioblastoma.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Radiotherapy (RT) is used routinely as a standard treatment for more than 50% of patients with malignant tumors. The abscopal effect induced by local RT, which is considered as a systemic anti-tumor ...immune response, reflects the regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation. Since the application of immunotherapy, especially with immune checkpoint inhibitors, can enhance the systemic anti-tumor response of RT, the combination of RT and immunotherapy has drawn extensive attention by oncologists and cancer researchers. Nevertheless, the exact underlying mechanism of the abscopal effect remains unclear. In general, we speculate that the immune mechanism of RT is responsible for, or at least associated with, this effect. In this review, we discuss the anti-tumor effect of RT and immune checkpoint blockade and discuss some published studies on the abscopal effect for this type of combination therapy. In addition, we also evaluate the most appropriate time window for the combination of RT and immune checkpoint blockade, as well as the optimal dose and fractionation of RT in the context of the combined treatment. Finally, the most significant purpose of this review is to identify the potential predictors of the abscopal effect to help identify the most appropriate patients who would most likely benefit from the combination treatment modality.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Cancer remains a leading cause of death worldwide with more than 10 million new cases every year. Tumor-targeted nanomedicines have shown substantial improvements of the therapeutic index of ...anticancer agents, addressing the deficiencies of conventional chemotherapy, and have had a tremendous growth over past several decades. Due to the pathophysiological characteristics that almost all tumor tissues have lower pH in comparison to normal healthy tissues, among various tumor-targeted nanomaterials, pH-responsive polymeric materials have been one of the most prevalent approaches for cancer diagnosis and treatment. In this review, we summarized the types of pH-responsive polymers, describing their chemical structures and pH-response mechanisms; we illustrated the structure-property relationships of pH-responsive polymers and introduced the approaches to regulating their pH-responsive behaviors; we also highlighted the most representative applications of pH-responsive polymers in cancer imaging and therapy. This review article aims to provide general guidelines for the rational design of more effective pH-responsive nanomaterials for cancer diagnosis and treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immune checkpoint inhibitors targeting programmed cell death 1 (PD-1), programmed cell death ligand-1 (PD-L1), and others have shown potent clinical efficacy and have revolutionized the treatment ...protocols of a broad spectrum of tumor types, especially non-small-cell lung cancer (NSCLC). Despite the substantial optimism of treatment with PD-1/PD-L1 inhibitors, there is still a large proportion of patients with advanced NSCLC who are resistant to the inhibitors. Preclinical and clinical trials have demonstrated that radiotherapy can induce a systemic antitumor immune response and have a great potential to sensitize refractory "cold" tumors to immunotherapy. Stereotactic body radiation therapy (SBRT), as a novel radiotherapy modality that delivers higher doses to smaller target lesions, has shown favorable antitumor effects with significantly improved local and distant control as well as better survival benefits in various solid tumors. Notably, research has revealed that SBRT is superior to conventional radiotherapy, possibly because of its more powerful immune activation effects. Thus, PD-1/PD-L1 inhibitors combined with SBRT instead of conventional radiotherapy might be more promising to fight against NSCLC, further achieving more favorable survival outcomes. In this review, we focus on the underlying mechanisms and recent advances of SBRT combined with PD-1/PD-L1 inhibitors with an emphasis on some future challenges and directions that warrant further investigation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The synergistic effect of radiotherapy (RT) in combination with immunotherapy has been shown in several clinical trials and case reports. The overlapping pulmonary toxicity induced by thoracic RT and ...programmed death 1/programmed death ligand-1 (PD-1/PD-L1) blockades is an important issue of clinical investigation in combination treatment. Thus far, the underlying mechanism of this toxicity remains largely unknown.
In this review, we discuss the unique pattern of radiation recall pneumonitis (RRP) induced by PD-1 blockade. The clinical presentation is different from common radiation pneumonitis (RP) or RRP induced by cytotoxic drugs. The immune checkpoint inhibitors may evoke an inflammatory reaction in patients' previously irradiated fields, with infiltrating lymphocytes and potential involvement of related cytokines. All RRP patients have showed durable response to anti-PD-1/PD-L1. RRP is manageable; however, interruption of checkpoint blockades is necessary and immunosuppressive treatment should be started immediately. Further analyses of the predictive factors, including RT dosimetric parameters, tumor-infiltrating lymphocytes (TILs), and PD-L1 expression, are needed given the wide use of immune checkpoint inhibitors and high mortality from lung toxicity with the combination treatment.
Immune checkpoint inhibitors may evoke an RRP in the patients' previously irradiated fields. Interactions between immune checkpoint inhibitors and radiotherapy should be studied further.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A large number of studies have shown that programmed death-ligand 1 (PD-L1) is abnormally expressed in gliomas. However, the prognostic significance of PD-L1 expression in glioma patients remains ...unresolved. Accordingly, we conducted a meta-analysis to determine the prognostic role of high PD-L1 in patients with glioma. Electronic databases were searched to identify studies evaluating PD-L1 expression and overall survival (OS) in these patients. A total of 6 studies (published in 4 articles) that involved 1052 patients were included. Pooled results showed that high PD-L1 expression was associated with worse OS in glioma patients (HR = 1.30, 95% CI: 1.02-1.65, P = 0.032). Further subgroup analysis indicated that high PD-L1 expression in glioblastoma (GBM) was also associated with worse OS (HR = 1.40, 95% CI: 1.03-1.90, P = 0.030). Conversely, in index subgroup analysis, neither PD-L1 protein (HR = 1.43, 95% CI: 0.97-2.10, P = 0.068) nor gene (HR = 1.20, 95% CI: 0.83-1.74, P = 0.322) expression was significantly associated with OS. PD-L1 may represent a promising biomarker that predicts disease progression in patients with glioma or GBM. However, because of our limited sample size, further prospective or retrospective multi-centre, well-designed studies should be performed to verify this result.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The identification of surgical non-small cell lung cancer (NSCLC) patients with poor prognosis is a priority in clinical oncology because of their high 5-year mortality. This meta-analysis explored ...the prognostic value of maximal standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) on disease-free survival (DFS) and overall survival (OS) in surgical NSCLC patients.
MEDLINE, EMBASE and Cochrane Libraries were systematically searched until August 1, 2015. Prospective or retrospective studies that evaluated the prognostic roles of preoperative 18F-FDG PET/CT with complete DFS and OS data in surgical NSCLC patients were included. The impact of SUVmax, MTV or TLG on survival was measured using hazard ratios (HR). Sub-group analyses were performed based on disease stage, pathological classification, surgery only and cut-off values.
Thirty-six studies comprised of 5807 patients were included. The combined HRs for DFS were 2.74 (95%CI 2.33-3.24, unadjusted) and 2.43 (95%CI: 1.76-3.36, adjusted) for SUVmax, 2.27 (95%CI 1.77-2.90, unadjusted) and 2.49 (95%CI 1.23-5.04, adjusted) for MTV, and 2.46 (95%CI 1.91-3.17, unadjusted) and 2.97 (95%CI 1.68-5.28, adjusted) for TLG. The pooled HRs for OS were 2.54 (95%CI 1.86-3.49, unadjusted) and 1.52 (95%CI 1.16-2.00, adjusted) for SUVmax, 2.07 (95%CI 1.16-3.69, unadjusted) and 1.91 (95%CI 1.13-3.22, adjusted) for MTV, and 2.47 (95%CI 1.38-4.43, unadjusted) and 1.94 (95%CI 1.12-3.33, adjusted) for TLG. Begg's test detected publication bias, the trim and fill procedure was performed, and similar HRs were obtained. The prognostic role of SUVmax, MTV and TLG remained similar in the sub-group analyses.
High values of SUVmax, MTV and TLG predicted a higher risk of recurrence or death in patients with surgical NSCLC. We suggest the use of FDG PET/CT to select patients who are at high risk of disease recurrence or death and may benefit from aggressive treatments.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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