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BackgroundNivolumab improves the survival of advanced non-small cell lung cancer (NSCLC), but a significant number of patients still fail to benefit from this treatment. In this study, we evaluated the efficacy of the time-series behavior of neutrophil-to-lymphocyte ratio (NLR) in a complete blood count from advanced NSCLC patients as a predictive marker of the anticancer effect of nivolumab.MethodsWe performed a retrospective review of medical records and collected data on patients with advanced NSCLC treated with nivolumab as second- and further-line treatments from December 2015 to March 2017. The NLRs were calculated before each treatment cycle for four cycles. These parameters were tested for its association with the overall survival (OS), progression-free survival (PFS) and time to treatment failure (TTF).ResultsNineteen patients were treated with nivolumab. Stratified by the response to nivolumab, the median OS was 2.8 months in progressive disease (PD) and 14.0 months in non-PD (p = 0.002). Before discontinuation of PD or toxicity, an NLR is rising from baseline in 5 out of 7 patients with PD and all of 4 patients with discontinuation due to toxicity. Patients with an >30% increase in NLR were associated with a significantly shorter TTF compared with those with stable or decrease in NLR both after first cycle (p = 0.014) and second cycle (p < 0.001).ConclusionsThe NLR is suggested to be useful not only as a prognostic marker but also as a predictive marker for treatment with nivolumab. Further prospective study is warranted to develop a predictive algorithm to detect PD cases as early as possible by focusing the time-series behavior of NLR.

Background/Aim: Immune checkpoint inhibitors (ICI) are a novel medication for non-small cell lung cancer (NSCLC). Recent reports indicated that baseline tumor size (BTS) relates to the efficacy of ICI therapy for melanoma, but no study exists for NSCLC. This study aimed to evaluate the utility of BTS for ICI therapy. Patients and Methods: Data from 58 patients diagnosed with NSCLC who underwent ICI monotherapy, were retrospectively analyzed. Patients were divided into two groups according to BTS (below 101 mm, above 101 mm). The primary endpoint was progression-free survival (PFS) and the secondary endpoint was overall survival (OS). Results: PFS of patients with a large BTS was significantly shorter than that of those with a small BTS (median; 2.07 [95% confidence interval [CI]=0.99-6.77] months versus 6.39 [95%CI=4.17-11.50] months) (p=0.044). OS of patients with large BTS was also significantly shorter (p<0.01). Conclusion: BTS is a predictive and prognostic negative factor of ICI therapy for NSCLC. Lung cancer is one of the leading causes of cancer-related death worldwide (1). Advanced non-small cell lung cancer (NSCLC) is treated using systemic therapies, including chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitor (TKI), anaplastic lymphoma kinase-TKI, c-ros oncogene 1 inhibitor, a combination of BRAF/MET inhibitor, and an immune checkpoint inhibitor (ICI) (2). The immune system protects the host against cancer cells via seven steps termed the cancer-immunity cycle (3). The seven steps include 'priming and activation' and 'recognition of cancer by T cells' (3). These processes are regulated and activated by various molecules and cytokines, including programmed death-ligand 1 (PD-L1) and programmed death-1 (PD-1), which suppress the cancer-immune cycle (3, 4). Cancer cells can express PD-L1 on their surfaces, facilitating recognition by PD-1, which is expressed on the surface of T-cells and acts as a PD-L1 receptor. Binding of PD-L1 to T cells has a profound inhibitory effect on immune functions such as cytokine secretion, growth, and cytotoxicity. Hence, PD-1 and PD-L1 are thought to be important target molecules for the control of cancer. ICI is a novel and promising medication for NSCLC. Nivolumab, a fully human IgG4 anti-PD-1 receptor-blocking monoclonal antibody (5), was the first ICI available for treatment of NSCLC in Japan. The Checkmate 017 and Checkmate 057 studies indicated the superiority of nivolumab over docetaxel for patient progression-free survival (PFS) and overall survival (OS) (6, 7). In addition to nivolumab, various other ICIs are now available, including pembrolizumab (an anti-PD-1 blocking antibody), atezolizumab and durvalumab (anti-PD-L1 blocking antibodies). Use of these ICIs has also been shown to lead to superior PFS and OS (8-10). Previous studies (Checkmate 017, 057, and Keynote-010) showed that the effects of ICI differed according to PD-L1 expression. As ICI is more effective against NSCLC expressing a higher tumor proportion score (TPS) of PD-L1 (6, 7),...

Interaction of signal regulatory protein α (SIRPα) expressed on the surface of macrophages with its ligand CD47 expressed on target cells negatively regulates phagocytosis of the latter cells by the former. We recently showed that blocking Abs to mouse SIRPα enhanced both the Ab‐dependent cellular phagocytosis (ADCP) activity of mouse macrophages for Burkitt's lymphoma Raji cells opsonized with an Ab to CD20 (rituximab) in vitro as well as the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in nonobese diabetic (NOD)/SCID mice. However, the effects of blocking Abs to human SIRPα in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRPα expressed on macrophages of immunodeficient mice. With the use of Rag2−/−γc −/− mice harboring a transgene for human SIRPα under the control of human regulatory elements (hSIRPα‐DKO mice), we here show that a blocking Ab to human SIRPα significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti‐human SIRPα Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRPα‐DKO mice. Our results thus suggest that the combination of Abs to human SIRPα with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRPα‐DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials.

Extracellular vesicles (EVs) are circulating vesicles secreted by various cell types. EVs are classified into three groups according to size, structural components, and generation process of vesicles: exosomes, microvesicles, and apoptotic bodies. Recently, EVs have been considered to be crucial for cell-to-cell communications and homeostasis because they contain intracellular proteins and nucleic acids. Epithelial cells from mice suffering from bronchial asthma (BA) secrete more EVs and suppress inflammation-induced EV production. Moreover, microarray analyses of bronchoalveolar lavage fluid have revealed that several microRNAs are useful novel biomarkers of BA. Mesenchymal stromal cell-derived EVs are possible candidates of novel BA therapy. In this review, we highlight the biologic roles of EVs in BA and review novel EV-targeted therapy to help understanding by clinicians and biologists.

In the human intestinal tract, there are more than 100 trillion symbiotic bacteria, which form the gut microbiota. Approximately 70% of the human immune system is in the intestinal tract, which prevents infection by pathogenic bacteria. When the intestinal microbiota is disturbed, causing dysbiosis, it can lead to obesity, diabetes mellitus, inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, autism spectrum disorder and cancer. Recent metabolomics analyses have also made the association between the microbiota and carcinogenesis clear. Here, we review the current evidence on the association between the microbiota and gastric, bladder, hepatobiliary, pancreatic, lung and colorectal cancer. Moreover, several animal studies have revealed that probiotics seem to be effective for the prevention of carcinogenesis to some extent. In this review, we focused on this relationship between the microbiota and cancer, and considered how to prevent cancer using strategies involving the gut microbiota.

Highlights d Discovery of D4-2, a macrocyclic peptide with high affinity for mouse SIRPa d D4-2 inhibits the interaction of SIRPa with CD47 in an allosteric manner d D4-2 promotes macrophage-mediated phagocytosis of antibody-opsonized tumor cells d D4-2 enhances the antitumor effect of tumor-targeting antibodies in mice

Abstract:A 62-year-old male with lung adenocarcinoma harboring an exon 19 deletion in the Epidermal growth factor receptor (EGFR) was treated with EGFR-tyrosine kinase inhibitors (TKIs) and several cytotoxic agents. After administering a fifth-line chemotherapy regimen, a liver biopsy revealed a diagnosis of recurrence with a T790M mutation. After an 82-day course of osimertinib therapy, the patient developed osimertinib-induced interstitial lung disease (ILD). Osimertinib was discontinued, and oral prednisolone was started. The ILD quickly improved, but liver metastases progressed and osimertinib was restarted concurrently with prednisolone. The patient showed neither disease progression nor a recurrence of ILD at 5 months. In situations in which no alternative treatment is available, osimertinib rechallenge should thus be considered as an alternative treatment.