Circulating tumor cells: advancing personalized therapy in small cell lung cancer patients.

Small cell lung cancer (SCLC) is a highly aggressive cancer with a dismal 5-year survival of < 7%, despite the addition of immunotherapy to first-line chemotherapy. Specific tumor biomarkers, such as delta-like ligand 3 (DLL3) and schlafen11 (SLFN11), may enable the selection of more efficacious, novel immunomodulating targeted treatments like bispecific T-cell engaging monoclonal antibodies (tarlatamab) and chemotherapy with PARP inhibitors. However, obtaining a tissue biopsy sample can be challenging in SCLC. Circulating tumor cells (CTCs) have the potential to provide molecular insights into a patient's cancer through a "simple" blood test. CTCs have been studied for their prognostic ability in SCLC; however, their value in guiding treatment decisions is yet to be elucidated. This review explores novel and promising targeted therapies in SCLC, summarizes current knowledge of CTCs in SCLC, and discusses how CTCs can be utilized for precision medicine.

Asbestos history and use.

All six fiber types called asbestos can cause all the diseases related to exposure, including lung cancer. Known to the ancients, the modern history of asbestos hazards started in the 1890s with more and more data accumulating over time. Use increased exponentially in the middle of the 20th century with major use coming in construction and ship building. The recognition of asbestos as causing lung cancer dates to the early 1940s.

Circulating tumor cell detection may offer earlier diagnosis in patients suspected of asbestos-related lung cancer.

Asbestos-Related Lung Cancer (ARLC) presents ongoing diagnostic challenges despite improved imaging technologies. The long latency period, coupled with limited access to occupational and environmental data along with the confounding effects of smoking and other carcinogens adds complexity to the diagnostic process. Compounding these challenges is the absence of a specific histopathologic or mutational signature of ARLC. A correlation between PD-L1 expression and response to immune checkpoint inhibition has not yet been proven. Thus, new biomarkers are needed to allow accurate diagnoses of ARLC, to enable prognostication and to offer personalized treatments. Liquid biopsies, encompassing circulating DNA and circulating tumor cells (CTCs), have gained attention as novel diagnostic methods in lung cancer to screen high-risk populations including those exposed to asbestos. CTCs can be enumerated and molecularly profiled to provide predictive and prognostic information. CTC studies have not been undertaken in populations at risk of ARLC to date. The potential of CTCs to provide real-time molecular insight into ARLC biology may significantly improve the diagnosis and management of ARLC patients.

Locoregional delivery of CAR-T cells in the clinic.

Cellular therapies utilizing T cells expressing chimeric antigen receptors (CARs) have garnered significant interest due to their clinical success in hematological malignancies. Unfortunately, this success has not been replicated in solid tumors, with only a small fraction of patients achieving complete responses. A number of obstacles to effective CAR-T cell therapy in solid tumors have been identified including tumor antigen heterogeneity, poor T cell fitness and persistence, inefficient trafficking and inability to penetrate into the tumor, immune-related adverse events due to on-target/off-tumor toxicity, and the immunosuppressive tumor microenvironment. Many preclinical studies have focused on improvements to CAR design to try to overcome some of these hurdles. However, a growing body of work has also focused on the use of local and/or regional delivery of CAR-T cells as a means to overcome poor T cell trafficking and inefficient T cell penetration into tumors. Most trials that incorporate locoregional delivery of CAR-T cells have targeted tumors of the central nervous system - repurposing an Ommaya/Rickham reservoir for repeated delivery of cells directly to the tumor cavity or ventricles. Hepatic artery infusion is another technique used for locoregional delivery to hepatic tumors. Locoregional delivery theoretically permits increased numbers of CAR-T cells within the tumor while reducing the risk of immune-related systemic toxicity. Studies to date have been almost exclusively phase I. The growing body of evidence indicates that locoregional delivery of CAR-T cells is both safe and feasible. This review focuses specifically on the use of locoregional delivery of CAR-T cells in clinical trials.

Asbestos-related lung cancer: Clinical characteristics and survival outcomes in an Australian cohort seeking workers compensation.

BACKGROUND AND OBJECTIVES: Due to difficulties in identifying sufficient-sized cohorts there remains uncertainty about prognostic and clinical differences that may be unique to asbestos-related lung cancer (ARLC). In this study, we use the Helsinki Criteria to define a group of ex-workers with lung cancer attributable to asbestos exposure and investigate differences that may exist. METHODS: A total of 529 patients seeking workers' compensation for their lung cancer were assigned to either ARLC or the non-ARLC based on parameters defined in the Helsinki Criteria. Clinical and survival details were collected and analyzed. RESULTS: In our study population, ARLC patients were on average older (72.1 ± 7.8) than non-ARLC patients (66.5 ± 10.2, P < 0.001) and were more likely to be diagnosed as a result of incidental findings or screening program (P < 0.001). The groups were similar in terms of clinical characteristics with the only difference being that plaques were more prevalent among ARLC patients (P < 0.001). Differences were observed for median overall survival (OS), ARLC (9 months) and non-ARLC (13 months, P = 0.005), as well for treatment (P = 0.01). After adjusting for age, however, these differences disappeared. CONCLUSIONS: Age at diagnosis, pleural plaques, and asymptomatic presentation were the attributes that we identified as significantly different between asbestos-related cancer and other lung cancers. In this cohort, ARLC patients were older diagnosis and with worse overall survival.

Hitting the Bull's-Eye: Mesothelin's Role as a Biomarker and Therapeutic Target for Malignant Pleural Mesothelioma.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options and poor prognosis. MPM originates from the mesothelial lining of the pleura. Mesothelin (MSLN) is a glycoprotein expressed at low levels in normal tissues and at high levels in MPM. Many other solid cancers overexpress MSLN, and this is associated with worse survival rates. However, this association has not been found in MPM, and the exact biological role of MSLN in MPM requires further exploration. Here, we discuss the current research on the diagnostic and prognostic value of MSLN in MPM patients. Furthermore, MSLN has become an attractive immunotherapy target in MPM, where better treatment strategies are urgently needed. Several MSLN-targeted monoclonal antibodies, antibody-drug conjugates, immunotoxins, cancer vaccines, and cellular therapies have been tested in the clinical setting. The biological rationale underpinning MSLN-targeted immunotherapies and their potential to improve MPM patient outcomes are reviewed.

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC.

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

Asbestos and Zeolites: from A to Z via a Common Ion.

Asbestos and zeolites are silicate-based minerals, linked inextricably via paradoxical similarities and differences which have emanated from different geological epochs. Both have been employed in the service of humanity through millennia: asbestos, for its "inextinguishable" quality of being an insulator against heat and fire; zeolite, a "boiling stone" with its volcanic and marine sedimentary rock origins, for its propensity to adsorb water and remove metals and toxins. Serious adverse health effects observed in asbestos miners as long ago as the 1st Century AD did not halt the rising popularity of asbestos. As the miracle material of the 1900s, asbestos production and consumption exploded, culminating in its ubiquity in ships, vehicles, homes, commercial buildings, and over 3000 different industrial and household products. Through the 1940s and 1950s, epidemiological studies concluded that asbestos was a likely cause of asbestosis, lung cancer, and malignant mesothelioma, and it is now banned in many but far from all countries. The long latency between exposure to asbestos and the occurrence of cancer has obscured the deadly consequences of asbestos exposure for centuries. Even today, a considerable part of the world population is insufficiently aware of the dangers of asbestos, and millions of tons of this carcinogen continue to be mined and used worldwide. Zeolites, both natural and synthetic, are microporous aluminosilicate minerals commonly used in a myriad of processes, in the petrochemical industry, in domestic appliances and cleaning agents, as commercial adsorbents and exchangers for toxins and pollutants, and as catalysts. Zeolites are found in agriculture, veterinary science, and human health. More recently, new materials such as carbon nanotubes are being employed in materials requiring durability and thermal and electrical conductivity, yet nanotubes are now joining the ranks of more established particulates such as asbestos and silica, in causing human disease. In this review, we compare and contrast the similarities and differences of these two groups of silicate minerals and their waxing and waning use in the employ of humanity.

Anti-Mesothelin CAR T cell therapy for malignant mesothelioma.

Malignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

Asbestos-related cancers: the 'Hidden Killer' remains a global threat.

Introduction: Asbestos, the most frequent cause of occupational cancer, continues to be consumed on a massive scale, with millions of people exposed on a daily basis. This review explains why we have failed in curtailing the silent epidemic of asbestos-related disease and why the numbers of asbestos victims are likely to remain high. Emerging and developed countries have to be reminded that asbestos exposure has yet to become a problem of the past. The worldwide spread of asbestos, followed by the surge of asbestos-related cancers, resembles the lung cancer epidemic caused by smoking and stimulated by manufacturers.Areas covered: Underreporting of malignant mesothelioma and asbestos-induced lung cancer, frequently-used arguments in the amphibole/chrysotile debate and the conclusion from bona-fide research organizations, that all forms of asbestos are carcinogenic, are reviewed. Special attention is paid to the consequences of ubiquitous environmental asbestos and the 'changing face' of malignant mesothelioma in countries with heavy asbestos use in the past.Expert opinion: Experts in oncology, respiratory medicine, occupational and public health, and basic researchers must take responsibility and acknowledge the ongoing silent epidemic of asbestos-related diseases. The call for a world-wide asbestos ban is more urgent than ever.

Manipulating microRNAs for the Treatment of Malignant Pleural Mesothelioma: Past, Present and Future.

microRNAs (miRNAs) are an important class of non-coding RNA that post-transcriptionally regulate the expression of most protein-coding genes. Their aberrant expression in tumors contributes to each of the hallmarks of cancer. In malignant pleural mesothelioma (MPM), in common with other tumor types, changes in miRNA expression are characterized by a global downregulation, although elevated levels of some miRNAs are also found. While an increasing number of miRNAs exhibit altered expression in MPM, relatively few have been functionally characterized. Of a growing number with tumor suppressor activity in vitro, miR-16, miR-193a, and miR-215 were also shown to have tumor suppressor activity in vivo. In the case of miR-16, the significant inhibitory effects on tumor growth following targeted delivery of miR-16-based mimics in a xenograft model was the basis for a successful phase I clinical trial. More recently overexpressed miRNAs with oncogenic activity have been described. Many of these changes in miRNA expression are related to the characteristic loss of tumor suppressor pathways in MPM tumors. In this review we will highlight the studies providing evidence for therapeutic effects of modulating microRNA levels in MPM, and discuss these results in the context of emerging approaches to miRNA-based therapy.

The Immune Microenvironment in Mesothelioma: Mechanisms of Resistance to Immunotherapy.

Although mesothelioma is the consequence of a protracted immune response to asbestos fibers and characterized by a clear immune infiltrate, novel immunotherapy approaches show less convincing results as compared to those seen in melanoma and non-small cell lung cancer. The immune suppressive microenvironment in mesothelioma is likely contributing to this therapy resistance. Therefore, it is important to explore the characteristics of the tumor microenvironment for explanations for this recalcitrant behavior. This review describes the stromal, cytokine, metabolic, and cellular milieu of mesothelioma, and attempts to make connection with the outcome of immunotherapy trials.

Transcriptional suppression of the miR-15/16 family by c-Myc in malignant pleural mesothelioma.

MicroRNA downregulation is frequent in malignant pleural mesothelioma (MPM), but the mechanisms responsible for loss of miR-15/16 and miR-193a are yet to be elucidated and were investigated in this study. Copy Number Variation (CNV) of microRNA-coding genes was analyzed in MPM cells by digital droplet PCR (ddPCR) and revealed heterozygous loss of miR-193a and miR-15a/16-1, but no change in miR-15b/16-2. Epigenetic control of microRNA expression was inferred following decitabine and Trichostatin A (TSA) treatment which did not substantially affect microRNA expression. Knockdown of c-Myc expression led to upregulation of SMC4, miR-15b and 16, and to a lesser extent DLEU2 and miR-15a, whereas c-Myc overexpression repressed microRNA expression. Chromatin immunoprecipitation (ChIP) assays confirmed the interaction of c-Myc with the DLEU2 and SMC4 promoters. Tumor microRNA expression was determined in samples from MPM patients, with samples of pleura from cardiac surgery patients used as controls. In tumor samples, a strong correlation was observed between the expression of miR-15b and 16 (R2=0.793), but not miR-15a and 16. Our data suggest that in MPM, the downregulation of miR-15/16 is due to transcriptional repression by c-Myc, primarily via control of the miR-15b/16-2 locus, while miR-193a-3p loss is due to genomic deletion.