Cancer immunotherapy:From the lab to clinical applications - Potential impact on cancer centres' organisation

This report covers the Immunotherapy sessions of the 2016 Organisation of European Cancer Institutes (OECI) Oncology Days meeting, which was held on 15th–17th June 2016 in Brussels, Belgium. Immunotherapy is a potential cancer treatment that uses an individual’s immune system to fight the tumour. In recent years significant advances have been made in this field in the treatment of several advanced cancers. Cancer immunotherapies include monoclonal antibodies that are designed to attack a very specific part of the cancer cell and immune checkpoint inhibitors which are molecules that stimulate or block the inhibition of the immune system. Other cancer immunotherapies include vaccines and T cell infusions. This report will summarise some of the research that is going on in this field and will give us an update on where we are at present

Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment

Background: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. Patients and methods: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. Results: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. Conclusions: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making.publishedVersio

Ipilimumab in a real-world population: A prospective Phase IV trial with long-term follow-up

Ipilimumab was the first treatment that improved survival in advanced melanoma. Efficacy and toxicity in a real-world setting may differ from clinical trials, due to more liberal eligibility criteria and less intensive monitoring. Moreover, high costs and lack of biomarkers have raised cost-benefit concerns about ipilimumab in national healthcare systems and limited its use. Here, we report the prospective, interventional study, Ipi4 (NCT02068196), which aimed to investigate the toxicity and efficacy of ipilimumab in a real-world population with advanced melanoma. This national, multicentre, phase IV trial included 151 patients. Patients received ipilimumab 3 mg/kg intravenously and were followed for at least 5 years or until death. Treatment interruption or cessation occurred in 38%, most frequently due to disease progression (19%). Treatment-associated grade 3 to 4 toxicity was observed in 28% of patients, and immune-related toxicity in 56%. The overall response rate was 9%. Median overall survival was 12.1 months (95% CI: 8.3-15.9); and progression-free survival 2.7 months (95% CI: 2.6-2.8). After 5 years, 20% of patients were alive. In a landmark analysis from 6 months, improved survival was associated with objective response (HR 0.16, P = .001) and stable disease (HR 0.49, P = .005) compared to progressive disease. Poor performance status, elevated lactate dehydrogenase and C-reactive protein were identified as biomarkers. This prospective trial represents the longest reported follow-up of a real-world melanoma population treated with ipilimumab. Results indicate safety and efficacy comparable to phase III trials and suggest that the use of ipilimumab can be based on current cost-benefit estimates.publishedVersio

Serum cytokine profiles and metabolic tumor burden in patients with non-small cell lung cancer undergoing palliative thoracic radiation therapy

Purpose: Radiation therapy effectively kills cancer cells and elicits local effects in the irradiated tissue. The aim of this study was to investigate the kinetics of cytokines in the serum of patients with lung cancer undergoing radiation therapy and to identify associations with metabolic tumor burden as determined by 2-deoxy-2-fluoro-D-glucose (18F-FDG) positron emission tomography (PET). Methods and materials: Forty-five patients with advanced non-small cell lung cancer were included in a phase 2 clinical trial and randomized between fractionated thoracic radiation therapy alone or concurrent with an epidermal growth factor receptor inhibitor. Blood was sampled at 4 different time points: prior to treatment, midtherapy, at the end of therapy, and 6 to 8 weeks after the start of treatment. The serum concentrations of 48 cytokines and 9 matrix metalloproteinases were measured with multiplex immunoassays. A subset of patients was examined by 18F-FDG PET/computed tomography before, during, and after radiation therapy. The maximum standardized uptake values (SUVmax) of the primary lung tumor, whole-body metabolic tumor volume, and total lesion glycolysis were calculated, and correlations between the PET parameters and cytokines were investigated. Results: The SUVmax decreased from baseline through midtherapy to posttherapy 18F-FDG PET/computed tomography (P = .018). The serum levels of C-C motif chemokine ligand (CCL) 23, CCL24, C-X3-C motif chemokine ligand 1, and interleukin-8 (C-X-C motif ligand [CXCL]8) were significantly correlated to SUVmax, metabolic tumor volume, and total lesion glycolysis before, during, and after radiation therapy. CXCL2 (P = .030) and CXCL6 (P = .010) decreased after the start of therapy and changed significantly across the sample time points. Serum concentrations of CCL15 (P = .031), CXCL2 (P = .028), and interleukin-6 (P = .007) were positively correlated to the irradiated volume during the second week of treatment. Conclusions: Cytokine serum levels vary and correlate with metabolic tumor burden in patients with advanced non-small cell lung cancer undergoing palliative thoracic radiation therapy

Prognostic value of PAM50 and risk of recurrence score in patients with early-stage breast cancer with long-term follow-up

Background The aim of this study was to investigate the prognostic value of the PAM50 intrinsic subtypes and risk of recurrence (ROR) score in patients with early breast cancer and long-term follow-up. A special focus was placed on hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) pN0 patients not treated with chemotherapy. Methods Patients with early breast cancer (n = 653) enrolled in the observational Oslo1 study (1995–1998) were followed for distant recurrence and breast cancer death. Clinicopathological parameters were collected from hospital records. The primary tumors were analyzed using the Prosigna® PAM50 assay to determine the prognostic value of the intrinsic subtypes and ROR score in comparison with pathological characteristics. The primary endpoints were distant disease-free survival (DDFS) and breast cancer-specific survival (BCSS). Results Of 653 tumors, 52.2% were classified as luminal A, 26.5% as luminal B, 10.6% as HER2-enriched, and 10.7% as basal-like. Among the HR+/HER2− patients (n = 476), 37.8% were categorized as low risk by ROR score, 22.7% as intermediate risk, and 39.5% as high risk. Median follow-up durations for BCSS and DDFS were 16.6 and 7.1 years, respectively. Multivariate analysis showed that intrinsic subtypes (all patients) and ROR risk classification (HR+/HER2− patients) yielded strong prognostic information. Among the HR+/HER2− pN0 patients with no adjuvant treatment (n = 231), 53.7% of patients had a low ROR, and their prognosis at 15 years was excellent (15-year BCSS 96.3%). Patients with intermediate risk had reduced survival compared with those with low risk (p = 0.005). In contrast, no difference in survival between the low- and intermediate-risk groups was seen for HR+/HER2− pN0 patients who received tamoxifen only. Ki-67 protein, grade, and ROR score were analyzed in the unselected, untreated pT1pN0 HR+/HER2− population (n = 171). In multivariate analysis, ROR score outperformed both Ki-67 and grade. Furthermore, 55% of patients who according to the PREDICT tool ( http://www.predict.nhs.uk/ ) would be considered chemotherapy candidates were ROR low risk (33%) or luminal A ROR intermediate risk (22%). Conclusions The PAM50 intrinsic subtype classification and ROR score improve classification of patients with breast cancer into prognostic groups, allowing for a more precise identification of future recurrence risk and providing an improved basis for adjuvant treatment decisions. Node-negative patients with low ROR scores had an excellent outcome at 15 years even in the absence of adjuvant therapy

Serum cytokine levels in breast cancer patients during neoadjuvant treatment with bevacizumab

A high concentration of circulating vascular endothelial growth factor (VEGF) in cancer patients is associated with an aggressive tumor phenotype. Here, serum levels of 27 cytokines and blood cell counts were assessed in breast cancer patients receiving neoadjuvant chemotherapy with or without bevacizumab (Bev) in a randomized cohort of 132 patients with non-metastatic HER2-negative tumors. Cytokine levels were determined prior to treatment and at various time-points. The cytotoxic chemotherapy regimen of fluorouracil, epirubicin, and cyclophosphamide (FEC) had a profound impact on both circulating white blood cells and circulating cytokine levels. At the end of FEC treatment, the global decrease in cytokine levels correlated with the drop in white blood cell counts and was significantly greater in the patients of the Bev arm for cytokines, such as VEGF-A, IL-12, IP-10 and IL-10. Among patients who received Bev, those with pathological complete response (pCR) exhibited significantly lower levels of VEGF-A, IFN-γ, TNF-α and IL-4 than patients without pCR. This effect was not observed in the chemotherapy-only arm. Certain circulating cytokine profiles were found to correlate with different immune cell types at the tumor site. For the Bev arm patients, the serum cytokine levels correlated with higher levels of cytotoxic T cells at the end of the therapy regimen, which was indicative of treatment response. The higher response rate for Bev-treated patients and stronger correlations between serum cytokine levels and infiltrating CD8T cells merits further investigation. KEYWORDS: Bevacizumab, VEGF-A, neoadjuvant, cytokines, immunit

Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics

Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines – the molecules coordinating and fine-tuning immune response – are still poorly characterized. Using two breast cancer cohorts (MicMa, n = 131, DCTB, n = 28) and the multiplex Luminex platform, we measured the levels of 27 cytokines in the serum of breast cancer patients prior to treatment. We investigated the cytokine levels in relation to clinicopathological characteristics and in perspective of the tumor infiltrating immune cells predicted from the bulk mRNA expression data. Unsupervised clustering analysis of the serum cytokine levels in the MicMa cohort identified a cluster of pro-inflammatory, pro-angiogenic, and Th2-related cytokines which was associated with poor prognosis. Notably high levels of platelet derived growth factor BB (PDGF) reflected a more aggressive tumor phenotype and larger tumor size. A significant positive correlation between serum levels of interferon gamma-induced protein 10 (IP10) and its mRNA expression at the tumor site suggested that tumor-IP10-production may outflow to the bloodstream. High IP10 serum levels were associated with a worse prognosis. Finally, we found serum levels of both PDGF and IP10 associated with enrichment scores of specific tumor infiltrating immune cells. Our study suggests that monitoring cytokine circulating levels in breast cancer could be used to characterize breast cancers and the immune composition of their microenvironment through readily available biological material. KEYWORDS: Breast cancer, cytokines, pathological markers, immune response, prognosi

Noninvasive profiling of serum cytokines in breast cancer patients and clinicopathological characteristics.

Cancers elicit an immune response by modifying the microenvironment. The immune system plays a pivotal role in cancer recognition and eradication. While the potential clinical value of infiltrating lymphocytes at the tumor site has been assessed in breast cancer, circulating cytokines – the molecules coordinating and fine-tuning immune response – are still poorly characterized. Using two breast cancer cohorts (MicMa, n = 131, DCTB, n = 28) and the multiplex Luminex platform, we measured the levels of 27 cytokines in the serum of breast cancer patients prior to treatment. We investigated the cytokine levels in relation to clinicopathological characteristics and in perspective of the tumor infiltrating immune cells predicted from the bulk mRNA expression data. Unsupervised clustering analysis of the serum cytokine levels in the MicMa cohort identified a cluster of pro-inflammatory, pro-angiogenic, and Th2-related cytokines which was associated with poor prognosis. Notably high levels of platelet derived growth factor BB (PDGF) reflected a more aggressive tumor phenotype and larger tumor size. A significant positive correlation between serum levels of interferon gamma-induced protein 10 (IP10) and its mRNA expression at the tumor site suggested that tumor-IP10-production may outflow to the bloodstream. High IP10 serum levels were associated with a worse prognosis. Finally, we found serum levels of both PDGF and IP10 associated with enrichment scores of specific tumor infiltrating immune cells. Our study suggests that monitoring cytokine circulating levels in breast cancer could be used to characterize breast cancers and the immune composition of their microenvironment through readily available biological material

Health-related quality of life in patients with advanced melanoma treated with ipilimumab: prognostic implications and changes during treatment

Background: We have previously reported that the safety and efficacy of ipilimumab in real-world patients with metastatic melanoma were comparable to clinical trials. Few studies have explored health-related quality of life (HRQL) in real-world populations receiving checkpoint inhibitors. This study reports HRQL in real-world patients receiving ipilimumab and assesses the prognostic value of patient-reported outcome measures. Patients and methods: Ipi4 (NCT02068196) was a prospective, multicentre, interventional phase IV trial. Real-world patients (N = 151) with metastatic melanoma were treated with ipilimumab 3 mg/kg intravenously as labelled. HRQL was assessed by the European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire at baseline and after 10-12 weeks. Results: The European Organisation of Research and Treatment of Cancer Quality of Life Questionnaire was completed by 93% (141/151 patients) at baseline, and by 82% at 10-12 weeks. Poor performance status and elevated C-reactive protein (CRP) were associated with worse baseline HRQL. Clinically relevant and statistically significant deteriorations in HRQL from baseline to weeks 10-12 were reported (P <0.05). Baseline physical functioning [hazard ratio (HR) 1.96, P = 0.016], role functioning (HR 2.15, P <0.001), fatigue (HR 1.60, P = 0.030), and appetite loss (HR 1.76, P = 0.012) were associated with poorer overall survival independent of performance status, lactate dehydrogenase (LDH), and CRP. We further developed a prognostic model, combining HRQL outcomes with performance status, LDH, and CRP. This model identified three groups with large and statistically significant differences in survival. Conclusions: Systemic inflammation is associated with impaired HRQL. During treatment with ipilimumab, HRQL deteriorated significantly. Combining HRQL outcomes with objective risk factors provided additional prognostic information that may aid clinical decision making