Species D human adenovirus type 9 exhibits better virus-spread ability for antitumor efficacy among alternative serotypes

Species C human adenovirus serotype 5 (HAdV-C5) is widely used as a vector for cancer gene therapy, because it efficiently transduces target cells. A variety of HAdV-C5 vectors have been developed and tested in vitro and in vivo for cancer gene therapy. While clinical trials with HAdV-C5 vectors resulted in effective responses in many cancer patients, administration of HAdV-C5 vectors to solid tumors showed responses in a limited area. A biological barrier in tumor mass is considered to hinder viral spread of HAdV-C5 vectors from infected cells. Therefore, efficient virus-spread from an infected tumor cell to surrounding tumor cells is required for successful cancer gene therapy. In this study, we compared HAdV-C5 to sixteen other HAdV serotypes selected from species A to G for virus-spread ability in vitro. HAdV-D9 showed better virus-spread ability than other serotypes, and its viral progeny were efficiently released from infected cells during viral replication. Although the HAdV-D9 fiber protein contains a binding site for coxsackie B virus and adenovirus receptor (CAR), HAdV-D9 showed expanded tropism for infection due to human CAR (hCAR)-independent attachment to target cells. HAdV-D9 infection effectively killed hCAR-negative cancer cells as well as hCAR-positive cancer cells. These results suggest that HADV-D9, with its better virus-spread ability, could have improved therapeutic efficacy in solid tumors compared to HAdV-C5

Analysis of DOC and Ram for NSCLC

Background: Current clinical trials demonstrated that combination regimens comprising chemotherapy and immunotherapy lead to better patient outcomes compared to chemotherapy alone as the first line of treatment for non-small cell lung cancer (NSCLC). In addition, the combination therapy of docetaxel (Doc) and ramucirumab (Ram) was considered one of the standard treatments for advanced or relapsed NSCLC patients. However, little is known about the therapeutic responders of this combination therapy among previously treated NSCLC patients. In the present study, we aimed to identify predictive factors for therapeutic response, including programmed death-ligand 1 (PD-L1) expression in tumors, for Doc treatment in combination with Ram. Methods: We retrospectively analyzed a total of 135 advanced or relapsed NSCLC patients who were refractory to platinum-based chemotherapy at eleven institutions in Japan between July 2016 and November 2018. Results: Our observations showed that PD-L1 expression in tumors is not associated with the efficacy of combined therapy of Doc and Ram in previously treated NSCLC patients. Analysis of the patient clinical profiles indicated that prior treatment with immune checkpoint inhibitors (ICIs) is a reliable predictor for the good progression-free survival (PFS) to this combination therapy (P=0.041). Conclusions: Our retrospective study indicated that combination regimens comprising chemotherapy and ICIs followed by Doc and Ram could be an optimal therapeutic option for NSCLC patients regardless of the PD-L1 status of tumors. Further investigations are required to strengthen clinical evidence demonstrating the effectiveness of the combination therapy of Doc plus Ram in previously treated NSCLC patients

AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells

Education Program for Male Patients with Chronic Obstructive Pulmonary Disease to Change Dietary Behavior

Patients with chronic obstructive pulmonary disease (COPD) need to maintain proper eating behavior in order to maintain muscle mass and prevent weight loss. In this study, we measured the effects of a support program on patient attitude, social influences, and self-efficacy and aimed to positively change their dietary behavior. We recruited male patients from two Japanese outpatient clinics and assigned each to an intervention or a control group. The intervention group participated in a support program and was assisted in acquiring knowledge and skills related to adopting and maintaining suitable eating behavior. Data were gathered through medical records, patient interviews, self-assessment questionnaires, and anthropometric measurements. The follow-up period was approximately 15 weeks. The final sample comprised 22 participants, with 11 each in the intervention and control groups. In the intervention group, the body weight was maintained. However, there were statistically significant improvements in energy intake and dietary measures such as eating fresh foods, compared with the control group. The intervention was observed to increase both meal suitability and energy intake among participants. Future support programs should also incorporate participants’ physical activity levels, and the effects should be studied over a longer period

Cellular uptake of HAdV-D9 independently of human CAR.

<p>Cells (CHO and CHO-hCAR) were infected with HAdV-C5 or HAdV-D9 at an MOI of 100 genomes/cell, and total cell DNA extracted from infected cells were used for qPCR analysis. (A) Cellular uptakes of HAdVs in CHO and CHO-hCAR were represented as a fold of genome transfer in HAdV-C5-infected CHO cells at 1 hour post-infection and normalized by cellular uptake of HAdV-C5 in CHO cells; HAdV-C5 (black bars) and HAdV-D9 (white bars). (B and C) Cellular uptakes of HAdVs in a time-dependent manner in CHO (B) and CHO-hCAR (C). Total cell DNA was extracted from infected cells at 0, 30, and 60 min post-infection and used for qPCR analysis; HAdV-C5 (black squares) and HAdV-D9 (white squares). Data points represent mean+standard error of the mean (n = 3). CHO; human CAR negative CHO cells and CHO-hCAR; CHO cells stably expressing human CAR. (D) CHO-hCAR cells were treated with the HAdV-C5 fiber knob protein at a final concentration of 0, 0.5, 5.0 or 50 µg/ml at 4°C for 1 hour and then infected with HAdV at an MOI of 100 genomes/cell at 37°C for 1 hour. HAdV-C5 (black bars) and HAdV-D9 (white bars). (E) Cellular uptakes of HAdV-D9 in cancer cells which express little or no hCAR. Cells were infected with HAdV-C5 or HAdV-D9 at an MOI of 100 genomes/cell for 1 hour post-infection, and total cell DNA extracted from infected cells was analyzed by qPCR. HAdV-C5 (black bars) and HAdV-D9 (white bars). Cellular uptakes of HAdVs in cell lines were represented as (A) a fold of genome transfer, (B, C and D) a percentage of genome transfer, and (E) Genome copy numbers per 50 ng of total DNA of each HAdV. Data points represent mean+standard error of the mean (n = 3).</p

Plaque morphology of HAdVs on A549 cells.

<p>HAdVs (HAdV-C5, D9, D51, E4, and F41) were serially diluted with medium containing 2% FBS and A549 cells were infected with HAdV at the range of dilution of 5.0×10⁻⁸ and 5.0×10⁻⁹ for 1 hour. We performed plaque assay as described in the Materials and Methods section. At 14 days post-infection, we stained cells with 2 ml of medium containing 0.75% agar and 0.033% neutral red in order to visualize individual single plaques on A549 cells. Photographs of plaque morphology of HAdVs were taken with a digital camera.</p

Release of HAdV-D9 from infected cells to culture medium.

<p>A549 cells were infected with HAdV-C5 or HAdV-D9 at an MOI of 10 PFU/cell and harvested at various time points. Samples to measure the infectious titer of HAdVs were prepared from infected cells harvested along with culture medium (A), a fraction extracted from infected cells without culture medium (B), and culture medium (C). Infectious titers of HAdVs contained in each fraction were measured by triplicate TCID50 assays. Data points represent mean+standard error of the mean (n = 3). Unpaired student <i>t</i>-test analysis was performed with respect to HAdV-C5 at each time point and significance is indicated by *<i>P</i><0.05.</p

Advanced Non-Small-Cell Lung Cancer in Elderly Patients: Patient Features and Therapeutic Management

Lung cancer has the highest mortality rate among all cancers in most developed countries. The number of elderly patients with lung cancer has been increasing, reflecting the global increase in aging population. Therefore, standard chemotherapeutic regimens for elderly patients with lung cancer need to be established. However, the effectiveness of chemotherapy in elderly patients with advanced non-small-cell lung cancer remains controversial because they are often excluded from clinical trials. Some clinical trials have shown that the therapeutic benefit of a third-generation anticancer drug alone was superior to best supportive care. In contrast, platinum-doublet was superior only in terms of overall survival and progression-free survival, and other trials reported an increased rate of treatment-related death in the elderly patients. In recent years, some novel treatment modalities for lung cancer have been developed and shown to significantly improve the therapeutic outcomes, including targeted therapy for lung cancer harboring driver mutation, combination therapy of angiogenesis inhibitor and cytotoxic agents, and immune checkpoint inhibitor. Although several clinical trials with these agents have shown favorable outcome regardless of age, their safety in the elderly patients has not been established. Herein, we discuss the current clinical status and future prospects in elderly patients with lung cancer

Tumor Neovascularization and Developments in Therapeutics

Tumors undergo fast neovascularization to support the rapid proliferation of cancer cells. Vasculature in tumors, unlike that in wound healing, is immature and affects the tumor microenvironment, resulting in hypoxia, acidosis, glucose starvation, immune cell infiltration, and decreased activity, all of which promote cancer progression, metastasis, and drug resistance. This innate defect of tumor vasculature can however represent a useful therapeutic target. Angiogenesis inhibitors targeting tumor vascular endothelial cells important for angiogenesis have attracted attention as cancer therapy agents that utilize features of the tumor microenvironment. While angiogenesis inhibitors have the advantage of targeting neovascularization factors common to all cancer types, some limitations to their deployment have emerged. Further understanding of the mechanism of tumor angiogenesis may contribute to the development of new antiangiogenic therapeutic approaches to control tumor invasion and metastasis. This review discusses the mechanism of tumor angiogenesis as well as angiogenesis inhibition therapy with antiangiogenic agents