TTFields relies on the generation of an alternating current that disrupts mitotic spindle assembly,3 and has been reported to trigger adaptive immunity.4 In The Lancet Oncology, Ticiana Leal and ...colleagues5 report positive results from the pivotal phase 3 LUNAR clinical trial comparing TTFields therapy with investigator's choice of standard systemic therapy (a PD-1/PD-L1 immune checkpoint inhibitor6–8 or docetaxel) with systemic therapy alone in patients with metastatic non-small-cell lung cancer who had progressed on or after platinum-based therapy. 276 patients (median age 64 years IQR 59–70, 178 65% male) were enrolled and randomly assigned to treatment. In a subgroup analysis, median overall survival was increased by 7·7 months with immune checkpoint inhibitor plus TTFields versus immune checkpoint inhibitor alone, consistent with preclinical findings that predicted an augmentation of immune checkpoint inhibitor-induced adaptive immunity, through TTFields-induced cGAS-STING and AIM2 inflammasome activation.4 Conversely, no significant improvement in median overall survival was seen for the docetaxel subgroup, in which the hazard ratio confidence limits crossed unity. Between 2015 and 2017, docetaxel was temporarily usurped as the standard of care in relapsed non-small-cell lung cancer, due to several positive phase 3 clinical trials comparing it with PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab and the PD-L1 immune checkpoint inhibitor atezolizumab.6–8 However, subsequent advances in the development of front-line therapy, notably the discovery that a PD-L1 tumour proportion greater than 50% confers a marked sensitivity to PD-1 or PD-L1 monotherapy, and that combination PD-1/PD-L1 immune checkpoint inhibitor with standard platinum-based chemotherapy was superior to chemotherapy alone,9 led to a shift away from the use of immune checkpoint inhibitors for patients with relapsed non-small-cell lung cancer.
Most mesotheliomas originate in the pleura and are due to asbestos exposure. The incidence is decreasing somewhat with asbestos remediation, but mortality remains high in part because of late ...diagnosis and treatment resistance. Pemetrexed–cisplatin and immune checkpoint inhibitors modestly extend survival.
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.
Over the past decade, immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. In mesothelioma, a rare cancer with a dismal prognosis generally caused by exposure to asbestos, ...treatment with single or dual ICIs results in robust improvements in overall survival over previous standard-of-care therapies, both in the first-line and relapsed disease settings. Predictive biological features that underpin response to ICIs remain poorly understood; however, insights into the immune microenvironment and genomic landscape of mesothelioma as well as into their association with response or acquired resistance to ICIs are emerging. Several studies of rational combinations involving ICIs with either another ICI or a different agent are ongoing, with emerging evidence of synergistic antitumour activity. Non-ICI-based immunotherapies, such as peptide-based vaccines and mesothelin-targeted chimeric antigen receptor T cells, have demonstrated promising efficacy. Moreover, results from pivotal trials of dendritic cell vaccines and viral cytokine delivery, among others, are eagerly awaited. In this Review, we comprehensively summarize the key steps in the development of immunotherapies for mesothelioma, focusing on strategies that have led to randomized clinical evaluation and emerging predictors of response. We then forecast the future treatment opportunities that could arise from ongoing research.
Small-cell lung cancer van Meerbeeck, Jan P, Prof; Fennell, Dean A, FRCP; De Ruysscher, Dirk KM, Prof
The Lancet (British edition),
11/2011, Letnik:
378, Številka:
9804
Journal Article
Recenzirano
Summary The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis relies on histology, with the use of immunohistochemical studies to ...confirm difficult cases. Typical patients are men older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities. Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to define disease as metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling pathways have been identified that might yield new drug targets.
The addition of novel agents to standard chemotherapy in phase 3 trials has not succeeded in changing practice. ...the front-line treatment setting remains a formidable hurdle for drug developers. ...Given that more than half of patients received post-study therapy in STELLAR, including vinorelbine and immunotherapy, we cannot rule out the substantial effect of this sub-population on the measured overall survival, particularly given the similarity in response and progression-free survival relative to historical controls. First-line systemic therapy for mesothelioma is rapidly evolving.
Inherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this ...process may result in the development of novel agents to enhance the sensitivity of cisplatin.
An isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed.
Characterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines.
Our results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer.
The decision tree analysis scoring systems is likely to be the most useful in routine clinical practice. First-line clinical trials are an appropriate option for patients with good PS and are ...recommended above any other option for second-line treatment, providing the patient is of adequate PS. Grade D. Research recommendations Prospective clinical trials of preoperative radiotherapy, postoperative radiotherapy after pleurectomy decortication and definitive radiotherapy after chemotherapy in MPM are required. ...prospective randomised clinical trials are required to determine the role of radiotherapy for symptom control in MPM and the optimal dose fractionation.
At picomolar concentrations, the endothelial barrier function of the neovasculature is impaired, enhancing chemotherapy penetration in murine models.6 In a previous phase 2 trial,7 NGR-hTNF ...monotherapy showed an arguably modest disease control with 44% of patients achieving disease control, with evidence of partial response (albeit 2%), and a median of 2·8 months progression-free survival. On the basis of evidence from preclinical studies and trials in lung cancer, a spindle poison (eg, vinorelbine) might well be the appropriate combination partner. Jonathan Ashton/Science Photo Library I report personal fees, advisory board participation, and research support from Roche and Bristol-Myers Squibb; grants and personal fees from Boehringer Ingelheim; and research support from Eli Lilly, Clovis Oncology, and Pierre Fabre, outside of the submitted work.
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