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Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges.

ABSTRACT: At present, whole-brain radiation therapy/stereotactic radiosurgery is one of the main local treatments for brain metastasis of non-small-cell lung cancer (NSCLC). Currently, it has been proved that radiotherapy (RT) can regulate the immune response, and small-sample studies have shown that patients with NSCLC brain metastases (BMs) can benefit from RT combined with immunotherapy (IO). However, the efficacy and safety of the combination treatment have not been deeply elaborated. Notably, as a challenge that is still being explored, the timing of RT combined with IO is likely to be an important factor affecting efficacy and prognosis. This article reviews the current application and challenges of RT combined with IO from the perspectives of molecular mechanism, combination timing, safety, and efficacy. The purpose is to provide information on clinical evidence-based medicine of combination between RT with IO. For further investigation, we also discuss the major challenges and prospects of RT combined with IO in NSCLC BMs.

SUBMITTER: Chen ZY

PROVIDER: S-EPMC9883424 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges.

Chen Zi-Ying ZY Duan Xiao-Tong XT Qiao Si-Miao SM Zhu Xiao-Xia XX

Cancer medicine 20220819 2

At present, whole-brain radiation therapy/stereotactic radiosurgery is one of the main local treatments for brain metastasis of non-small-cell lung cancer (NSCLC). Currently, it has been proved that radiotherapy (RT) can regulate the immune response, and small-sample studies have shown that patients with NSCLC brain metastases (BMs) can benefit from RT combined with immunotherapy (IO). However, the efficacy and safety of the combination treatment have not been deeply elaborated. Notably, as a ch ...[more]

PMID: 35986515

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Project description:Cancer immunotherapy (CIT) with antibodies targeting the programmed cell death 1 protein (PD-1)/programmed cell death 1 ligand 1 (PD-L1) axis have changed the standard of care in multiple cancers. However, durable antitumor responses have been observed in only a minority of patients, indicating the presence of other inhibitory mechanisms that act to restrain anticancer immunity. Therefore, new therapeutic strategies targeted against other immune suppressive mechanisms are needed to enhance anticancer immunity and maximize the clinical benefit of CIT in patients who are resistant to immune checkpoint inhibition. Preclinical and clinical studies have identified abnormalities in the tumor microenvironment (TME) that can negatively impact the efficacy of PD-1/PD-L1 blockade. Angiogenic factors such as vascular endothelial growth factor (VEGF) drive immunosuppression in the TME by inducing vascular abnormalities, suppressing antigen presentation and immune effector cells, or augmenting the immune suppressive activity of regulatory T cells, myeloid-derived suppressor cells, and tumor-associated macrophages. In turn, immunosuppressive cells can drive angiogenesis, thereby creating a vicious cycle of suppressed antitumor immunity. VEGF-mediated immune suppression in the TME and its negative impact on the efficacy of CIT provide a therapeutic rationale to combine PD-1/PD-L1 antibodies with anti-VEGF drugs in order to normalize the TME. A multitude of clinical trials have been initiated to evaluate combinations of a PD-1/PD-L1 antibody with an anti-VEGF in a variety of cancers. Recently, the positive results from five Phase III studies in non-small cell lung cancer (adenocarcinoma), renal cell carcinoma, and hepatocellular carcinoma have shown that combinations of PD-1/PD-L1 antibodies and anti-VEGF agents significantly improved clinical outcomes compared with respective standards of care. Such combinations have been approved by health authorities and are now standard treatment options for renal cell carcinoma, non-small cell lung cancer, and hepatocellular carcinoma. A plethora of other randomized studies of similar combinations are currently ongoing. Here, we discuss the principle mechanisms of VEGF-mediated immunosuppression studied in preclinical models or as part of translational clinical studies. We also discuss data from recently reported randomized clinical trials. Finally, we discuss how these concepts and approaches can be further incorporated into clinical practice to improve immunotherapy outcomes for patients with cancer.

Project description:BackgroundDiabetic kidney disease (DKD) is the most common cause of the end-stage renal disease (ESRD). Regardless of intensive treatments with hyperglycemic control, blood pressure control, and the use of renin-angiotensin system blockades, the prevalence of DKD remains high. Recent studies suggest that the spectrum of DKD has been changed and many progresses have been made to develop new treatments for DKD. Therefore, it is time to perform a systemic review on the new developments in the field of DKD.SummaryAlthough the classic clinical presentation of DKD is characterized by a slow progression from microalbuminuria to macroalbuminuria and by a hyperfiltration at the early stage and progressive decline of renal function at the late stage, recent epidemiological studies suggest that DKD patients have a variety of clinical presentations and progression rates to ESRD. Some DKD patients have a decline in renal function without albuminuria but display prominent vascular and interstitial fibrosis on renal histology. DKD patients are more susceptible to acute kidney injury, which might contribute to the interstitial fibrosis. A large portion of type 2 diabetic patients with albuminuria could have overlapping nondiabetic glomerular disease, and therefore, kidney biopsy is required for differential diagnosis for these patients. Only a small portion of DKD patients eventually progress to end-stage renal failure. However, we do not have sensitive and specific biomarkers to identify these high-risk patients. Genetic factors that have a strong association with DKD progression have not been identified yet. A combination of circulating tumor necrosis factor receptor (TNFR)1, TNFR2, and kidney injury molecular 1 provides predictive value for DKD progression. Artificial intelligence could enhance the predictive values for DKD progression by combining the clinical parameters and biological markers. Sodium-glucose co-transporter-2 inhibitors should be added to the new standard care of DKD patients. Several promising new drugs are in clinical trials.Key messagesOver last years, our understanding of DKD has been much improved and new treatments to halt the progression of DKD are coming. However, better diagnostic tools, predictive markers, and treatment options are still urgently needed to help us to better manage these patients with this detrimental disease.

Dataset Information

Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges.

Publications

Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges.

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