Dendritic cell (DC) based cancer immunotherapy aims at the activation of the immune system, and in particular tumor-specific cytotoxic T lymphocytes (CTLs) to eradicate the tumor. DCs represent a ...heterogeneous cell population, including conventional DCs (cDCs), consisting of cDC1s, cDC2s, plasmacytoid DCs (pDCs), and monocyte-derived DCs (moDCs). These DC subsets differ both in ontogeny and functional properties, such as the capacity to induce CD4
and CD8
T-cell activation. MoDCs are most frequently used for vaccination purposes, based on technical aspects such as availability and
expansion. However, whether moDCs are superior over other DC subsets in inducing anti-tumor immune responses, is unknown, and likely depends on tumor type and composition of the tumor microenvironment. In this review, we discuss cellular aspects essential for DC vaccination efficacy, and the most recent findings on different DC subsets that could be used for DC-based cancer immunotherapy. This can prove valuable for the future design of more effective DC vaccines by choosing different DC subsets, and sheds light on the working mechanism of DC immunotherapy.
Context:
In vitro and in vivo experiments have assigned both oncosuppressive and oncogenic properties to thyroid hormones. Population-based studies have found inconclusive results.
Objective:
We ...aimed to prospectively assess the relation between thyroid function and incident cancer in a population-based setting.
Design, Setting, and Participants:
The current study is a prospective population-based cohort study including 10 318 participants for whom baseline measurements of free T4 (FT4) and/or TSH were available.
Main Outcome Measures:
Cox proportional hazards models were used to assess hazard ratios (HRs) of any solid non-skin cancer, as well as lung, breast, prostate, and gastrointestinal cancer specifically.
Results:
Higher FT4 levels were associated with a higher risk of any solid cancer (HR, 1.42; 95% confidence interval CI, 1.12–1.79), lung cancer (HR, 2.33; 95% CI, 1.39–3.92) and breast (HR, 1.77; 95% CI, 1.10–2.84) cancer. The risk estimates were similar after exclusion of thyroid-altering medication, but the association lost significance for breast cancer. Compared with the lowest FT4 tertile, the highest tertile was associated with a 1.13-fold increased risk of any solid, 1.79-fold increased risk of lung, and 1.14-fold increased risk of breast cancer (P for trend <.05 for all). For TSH levels we found no associations with cancer risk. There was no differential effect of sex or age on the association between thyroid function and cancer risk.
Conclusions:
Higher FT4 levels are significantly associated with an increased risk of any solid, lung, and breast cancer. Further research should elucidate the underlying pathophysiological mechanisms.
In this prospective population-based cohort study, higher serum FT4 levels were associated with an increased risk of any solid cancer, lung cancer and breast cancer.
Maintenance therapy is associated with improved survival in patients with non-small-cell lung cancer (NSCLC), but few studies have compared active agents in this setting. AVAPERL evaluated the safety ...and efficacy of bevacizumab with or without pemetrexed as continuation maintenance treatment.
Patients with advanced nonsquamous NSCLC received first-line bevacizumab 7.5 mg/kg, cisplatin 75 mg/m(2), and pemetrexed 500 mg/m(2) once every 3 weeks for four cycles. Those achieving response or stable disease were randomly assigned at a ratio of 1:1 to maintenance bevacizumab 7.5 mg/kg or bevacizumab 7.5 mg/kg plus pemetrexed 500 mg/m(2) once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was progression-free survival (PFS) after random assignment.
In total, 376 patients received induction treatment, 71.9% achieved disease control, and 67.3% were randomly assigned to maintenance therapy, with 125 and 128 receiving single-agent bevacizumab and bevacizumab plus pemetrexed treatment, respectively. At a median follow-up of 8.1 months, PFS from random assignment was significantly improved in the bevacizumab plus pemetrexed arm (median, 3.7 v 7.4 months; hazard ratio, 0.48; 95% CI, 0.35 to 0.66; P < .001) per a stratified model. The PFS benefit extended across age, performance status, smoking history, and induction response (stable disease v partial response) subgroups. Any grade, grade ≥ 3, and serious adverse events occurred more often with bevacizumab plus pemetrexed maintenance. No new safety signals were observed.
In an unselected population of patients with nonsquamous NSCLC who had achieved disease control with platinum-based chemotherapy plus bevacizumab, bevacizumab plus pemetrexed maintenance was associated with a significant PFS benefit compared with bevacizumab alone. The combination was well tolerated.
Malignant mesothelioma is a universally lethal cancer that is increasing in incidence worldwide. There is a dearth of effective therapies, with only one treatment (pemetrexed and cisplatin ...combination chemotherapy) approved in the past 13 years. However, the past 5 years have witnessed an exponential growth in our understanding of mesothelioma pathobiology, which is set to revolutionize therapeutic strategies. From a genomic standpoint, mesothelioma is characterized by a preponderance of tumour suppressor alterations, for which novel therapies are currently in development. Other promising antitumour agents include inhibitors against angiogenesis, mesothelin and immune checkpoints, which are at various phases of clinical trial testing.
In preclinical models, statins showed vaccine adjuvant activities and synergized with PD-1 inhibitors. We analyzed the impact of statin treatment on clinical outcome in thoracic cancer patients ...treated with PD-1 inhibitors.
A total of 82 malignant pleural mesothelioma (MPM) and 179 advanced non-small cell lung cancer (aNSCLC) patients treated with PD-1 inhibitors as second or further line treatment were examined. Seventy-seven MPM patients treated with standard chemotherapy were analyzed as control cohort. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were calculated.
Among 253 patients with available data, statin use was associated with increased ORR (32% versus 18%, P = .02), PFS (median 6.7 versus 2.9 months, hazard ratio HR 0.57, 95% CI 0.39–0.83, P < .01), and OS (median 13.1 versus 8.7 months, HR 0.67, 95% CI 0.45–1.00, P = .05). In the control MPM cohort treated with chemotherapy (n = 77), no association was found. MPM patients who used statins showed improved ORR (22% versus 6%, P = .05), PFS (median 6.7 versus 2.4 months, P < .01), and OS (median not reached versus 6.0 months, P = .01). In aNSCLC patients, statin use was associated with improved ORR (40% versus 22%, P = .04) and PFS (median 7.8 versus 3.6 months, P = .03), but no significant difference in OS was found (median 13.1 versus 10.1 months, P = .30). Multivariable analysis confirmed the correlation between statin use and better PFS and OS in MPM and better PFS in aNSCLC. In the whole cohort, high but not low/moderate-intensity statins were associated with better OS compared to no user (P = .02 and P = .59, respectively).
Our study showed that statins are associated with better clinical outcome in MPM and aNSCLC patients treated with PD-1 inhibitors in an intensity-dependent manner.
•In pre-clinical models, statins synergized with PD-1 inhibitors.•Statins associated with outcome in MPM and NSCLC patients treated with PD-1 inhibitors.•This association was stronger in patients who used high-intensity statins.•No association found between statins & outcome in the control MPM chemotherapy cohort.
Malignant pleural mesothelioma (MPM) is an uncommon but aggressive and treatment resistant neoplasm with low survival rates. In the last years we assisted to an exponential growth in the appreciation ...of mesothelioma pathobiology, leading several new treatments to be investigated both in the early stage of the disease and in the advanced setting. In particular, expectations are now high that immunotherapy will have a leading role in the next years. However, caution is required as results from phase II studies in MPM were often not replicated in larger, randomized, phase III trials. In this review, we describe the most promising emerging therapies for the treatment of MPM, discussing the biological rationale underlying their development as well as the issues surrounding clinical trial design and proper selection of patients for every treatment.
Nivolumab is administered in a weight-based or fixed-flat dosing regimen. For patients with non-small cell lung cancer (NSCLC), a potential exposure-response relationship has recently been reported ...and may argue against the current dosing strategies. The primary objectives were to determine nivolumab pharmacokinetics (PK) and to assess the relationship between drug clearance and clinical outcome in NSCLC, melanoma, and renal cell cancer (RCC).
In this prospective observational cohort study, individual estimates of nivolumab clearance and the impact of baseline covariates were determined using a population-PK model. Clearance was related to best overall response (RECISTv1.1), and stratified by tumor type.
Two-hundred-twenty-one patients with metastatic cancer receiving nivolumab-monotherapy were included of whom 1,715 plasma samples were analyzed. Three baseline parameters had a significant effect on drug clearance and were internally validated in the population-PK model: gender, BSA, and serum albumin. Women had 22% lower clearance compared to men, while the threshold of BSA and albumin that led to > 20% increase of clearance was > 2.2m
and < 37.5 g/L, respectively. For NSCLC, drug clearance was 42% higher in patients with progressive disease (mean: 0.24; 95% CI: 0.22-0.27 L/day) compared to patients with partial/complete response (mean: 0.17; 95% CI: 0.15-0.19 L/day). A similar trend was observed in RCC, however, no clearance-response relationship was observed in melanoma.
Based on the first real-world population-PK model of nivolumab, covariate analysis revealed a significant effect of gender, BSA, and albumin on nivolumab clearance. A clearance-response relationship was observed in NSCLC, with a non-significant trend in RCC, but not in melanoma. Individual pharmacology of nivolumab in NSCLC appears important and should be prospectively studied.
Dendritic cells (DCs) are antigen-presenting cells (APCs) that are essential for the activation of immune responses. In various malignancies, these immunostimulatory properties are exploited by ...DC-therapy, aiming at the induction of effective anti-tumor immunity by vaccination with
antigen-loaded DCs. Depending on the type of DC-therapy used, long-term clinical efficacy upon DC-therapy remains restricted to a proportion of patients, likely due to lack of immunogenicity of tumor cells, presence of a stromal compartment, and the suppressive tumor microenvironment (TME), thereby leading to the development of resistance. In order to circumvent tumor-induced suppressive mechanisms and unleash the full potential of DC-therapy, considerable efforts have been made to combine DC-therapy with chemotherapy, radiotherapy or with checkpoint inhibitors. These combination strategies could enhance tumor immunogenicity, stimulate endogenous DCs following immunogenic cell death, improve infiltration of cytotoxic T lymphocytes (CTLs) or specifically deplete immunosuppressive cells in the TME, such as regulatory T-cells and myeloid-derived suppressor cells. In this review, different strategies of combining DC-therapy with immunomodulatory treatments will be discussed. These strategies and insights will improve and guide DC-based combination immunotherapies with the aim of further improving patient prognosis and care.
To determine the psychometric properties and minimal clinically important differences (MCIDs) of the World Health Organization Quality of Life-BREF (WHOQOL-BREF) in advanced stage lung cancer ...patients.
Patients (n = 153) completed the WHOQOL-BREF and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Confirmatory factor analysis (CFA) was performed and reliability and construct validity determined. MCIDs were estimated with two distribution-based methods (0.5 standard deviation (SD) and 1 standard error of measurement (1 SEM)).
CFA confirmed WHOQOL-BREF domain structure. All domains demonstrated good internal consistency (α > 0.70), except Social Relationships (α = 0.57). Nineteen of the 24 WHOQOL-BREF items had correlations of ≥ 0.40 with their intended domain. Four items had higher correlations with a domain other than their intended domain. Moderate to strong correlations were observed for corresponding domains of the two questionnaires, except for the social domains (r = 0.07). For 0.5 SD, MCIDs ranged from 0.88 to 1.55, and for 1 SEM MCIDs ranged from 1.76 to 2.72.
The WHOQOL-BREF has satisfactory psychometric properties in patients with advanced stage lung cancer, whereas the observed MCIDs provide a method for interpretation of scores.
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