The Synergistic Effect of Immune Checkpoint Blockade and Radiotherapy in Recurrent/Metastatic Sinonasal Cancer.
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ABSTRACT:
SUBMITTER: Yazici G
PROVIDER: S-EPMC6318133 | biostudies-literature | 2018 Oct
REPOSITORIES: biostudies-literature
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Project description:Immunotherapy has shown great promise in the field of oncology, and recent clinical trials have illustrated that immune checkpoint blockade (ICB) is safe and effective at treating a range of tumor types. Cervical cancer (CC) is the fourth most common malignancy in women. However, first-line treatments for locally advanced cervical cancer (LACC) and recurrent/metastatic (R/M) CC have limited efficacy. Thus, it is necessary to explore new treatment approaches. The National Comprehensive Cancer Network (NCCN) currently recommends pembrolizumab, a programmed cell death protein 1 (PD-1) monoclonal antibody, as a first line therapy for individuals with R/M CC. This study reviews the progress of ICB therapy for LACC and R/M CC and describes the current status of the combination of ICB therapy and other therapeutic modalities, including radiotherapy, chemotherapy, targeted therapy, and other immunotherapies. The focus is placed on studies published since 2018 with the aim of highlighting novel CC-specific immunotherapeutic approaches and treatment targets.
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Project description:Cervical cancer (CC) poses a serious threat to women's health. Although many early-stage patients have a good prognosis, there are still a lack of effective therapies for advanced and recurrent/metastatic CC. In this context, immunotherapy and immune checkpoint inhibitors (ICIs) are particularly likely to play a role in the treatment of cervical tumors in a variety of disease settings. Some promising immune checkpoints include programmed cell death 1 (PD-1), programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte antigen 4 (CTLA-4), which exert immunomodulatory effects as negative regulators of T-cell activation and suppress immune responses in cervical cancer through cancer cell immune evasion. Initial trials of ICIs for CC have shown encouraging results in terms of objective response rate (ORR), progression-free survival (PFS), and overall survival (OS), both monotherapy and combination strategies. Meanwhile, human papillomavirus, vaginal microecology and intestinal microenvironment play an important role in CC, which provides new treatment directions. This review analyzed a number of completed or ongoing clinical trials of ICIs in the treatment of advanced and recurrent/metastatic CC. And we also analyzed the important relationship between vaginal microecology and intestinal microecology with CC and their related immunotherapy prospects.
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Project description:PurposeThe effectiveness of immune checkpoint inhibitors (ICI) is limited in pancreatic ductal adenocarcinoma (PDAC). We conducted a phase I study to evaluate the safety of ICI with stereotactic body radiation therapy (SBRT) in patients with metastatic PDAC.Patients and methodsPatients enrolled must have received at least one line of prior systemic chemotherapy for metastatic disease. Cohorts A1 and A2 received durvalumab every 2 weeks plus either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. Cohorts B1 and B2 received durvalumab plus tremelimumab every 4 weeks and either 8 Gy in one fraction of SBRT on day 1 or 25 Gy in five fractions on day -3 to +1. ICIs were continued until unacceptable toxicity or disease progression. The primary objective was the safety and feasibility of treatment. Objective response was assessed in lesions not subjected to SBRT.ResultsFifty-nine patients were enrolled and 39 were evaluable for efficacy. No dose-limiting toxicities were seen. The most common adverse event was lymphopenia. Two patients achieved a partial response (one confirmed and the other unconfirmed). The overall response rate was 5.1%. Median PFS and OS was 1.7 months [95% confidence intervals (CI), 0.8-2.0 months] and 3.3 months (95% CI, 1.2-6.6 months) in cohort A1; 2.5 months (95% CI, 0.1-3.7 months) and 9.0 months (95% CI, 0.5-18.4 months) in A2; 0.9 months (95% CI, 0.7-2.1 months) and 2.1 months (95% CI, 1.1-4.3 months) in B1; and 2.3 months (95% CI, 1.9-3.4 months) and 4.2 months (95% CI, 2.9-9.3 months) in B2.ConclusionsThe combination of ICI and SBRT has an acceptable safety profile and demonstrates a modest treatment benefit in patients with metastatic PDAC.
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Project description:Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes; therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.
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Project description:ImportanceThere are a limited number of predictive biomarkers for hyperprogressive disease (HPD), which is induced by immune checkpoint blockade (ICB) therapy.ObjectiveTo evaluate the association of biomarkers in serum with the response to ICB therapy in patients with metastatic gastrointestinal tract cancer.Design, setting, and participantsCohort study in which patients with metastatic gastrointestinal tract cancer treated with ICB were enrolled at the Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Beijing, China, from August 1, 2015, to July 31, 2017, with the last follow-up date on January 1, 2018. Serum samples were collected at baseline and during the first visit to the clinic after starting treatment. Data analysis was conducted from January 16, 2018, to September 1, 2018.ExposuresA total of 59 factors, including cytokines/chemokines, growth factors, and soluble checkpoint-related proteins in serum, were examined by multiplexed bead immunoassays.Main outcomes and measuresTree-based estimators were used to evaluate the importance of serum protein levels to ICB treatment response. Progression-free survival and overall survival analyses were conducted with the Kaplan-Meier method and log-rank test.ResultsIn total, 56 patients were examined. All patients with HPD (5 [8.9%]) had significantly lower mean (SD) levels of serum monocyte chemoattractant protein 1 than patients without HPD at baseline (53.4 [17.3] pg/mL vs 106.4 [48.4] pg/mL; P = .02). All patients with HPD were also identified by lower leukemia inhibitory factor levels (<13.28 pg/mL) and higher cluster of differentiation 152 levels (≥31.81 pg/mL). Among the remaining 51 patients, responders with esophageal squamous cell carcinoma (ESCC) or colorectal cancer (CRC) showed larger decreases in interleukin 1 receptor antagonist levels than nonresponders (ESCC: -55.02% [95% CI, -86.52% to -23.51%] vs 43.44% [95% CI, 11.93% to 74.96%]; P < .001; CRC: -35.82% [95% CI, -67.38% to -4.26%] vs 59.14% [95% CI, -72.34% to 190.6%]; P = .04). Responders with gastric cancer (GC) had larger increases in brain-derived neurotrophic factor levels than nonresponders (44.77% [95% CI, 10.76% to 78.79%] vs -26.2% [95% CI, -58.53% to 6.12%]; P = .003). Furthermore, early decreases in serum interleukin 1 receptor antagonist in patients with metastatic ESCC and CRC were associated with longer progression-free survival (ESCC: not reached vs 2.1 months; hazard ratio, 0.19; 95% CI, 0.04 to 0.95; P = .04; CRC: not reached vs 2.1 months; hazard ratio, 0.06; 95% CI, 0.01 to 0.38; P < .001). Early increases in brain-derived neurotrophic factor levels in patients with metastatic GC were associated with longer progression-free survival (not reached vs 4.2 months; hazard ratio, 0.15; 95% CI, 0.03 to 0.84; P = .03).Conclusions and relevanceIn this study, baseline serum levels of monocyte chemoattractant protein 1, leukemia inhibitory factor, and cluster of differentiation 152 were associated with hyperprogressive metastatic gastrointestinal cancer among patients receiving ICB. An early decrease in serum interleukin 1 receptor antagonist levels in patients with metastatic ESCC or CRC and an early increase in serum brain-derived neurotrophic factor levels in patients with metastatic GC were better able to identify who would respond to ICB compared with microsatellite stability status or programmed cell death ligand 1 expression.
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