Analysis of Off-target Effects and Risk Assessment Leading from Preclinical to Clinical Trials of Gene-edited Therapeutic Products.

Objective: Concerns about off-target effects (OTEs) of genomic DNA cleavages by gene-editing enzymes have been raised, especially for OTEs that go undetected due to technical limitations. Since no explicit guidelines have been in place for risk assessment of OTEs, the regulatory authorities' concept of an acceptable evaluation scheme for OTEs in the investigational drug application (IND) has not been clear. Here, we clarify the regulatory expectations by examining reports on OTE evaluations of leading gene-editing products that have achieved IND clearance.

In Vivo Antitumor Effects of MK615 Led by PD-L1 Downregulation.

Background/aim: MK615 extracted from Prunus mume was reported to have anti-inflammatory effects. In this article, we examined the in vivo antitumor effect of MK615 (an extract from Japanese apricot) using mouse tumor xenografts and focusing on the downregulation of PD-L1 (programmed death-ligand 1), a ligand of programmed cell death-1, a surface protein of activated T cells.

Materials And Methods: B16/BL6 melanoma cells were injected into C57BL/6 or BALB/c-nu/nu mice to establish lung metastasis.

[Adoptive Cell Therapy with Immune Checkpoint Blockade].

Cancer immunotherapy are taking a leading role of cancer therapy due to the development of the immune checkpoint blockade. To date, however, only about 20% of patients have clinical responses and the cancer-specific T cells in cancer site are required to obtain beneficial effects. There has been an innovative development in the field of adoptive cell therapy, especially receptor gene-modified T cells in recent years.

RT-qPCR analysis of the tumor antigens TOMM34 and RNF43 in samples extracted from paraffin-embedded specimens of colorectal cancer.

Comprehensive genetic analysis of colorectal malignant tumors by microarrays has identified translocase of the outer mitochondrial membrane 34 (TOMM34) and ring finger protein 43 (RNF43) as highly expressed oncogenes in malignant colorectal tumors. Vaccine therapy using cancer peptides synthesized using the amino acid sequences of tumor antigens is currently undergoing clinical trials. Since it is important to perform vaccine therapy based on the oncogene expression levels in individual tumors, analysis of tumor antigen expression is necessary for this therapy.

Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.

Background: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments.

Methods: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group.

A Comparative Safety Profile Assessment of Oncolytic Virus Therapy Based on Clinical Trials.

Oncolytic virus therapy (OVT) represents a new class of therapeutic agents in cancer treatment. The molecular and cellular mechanisms of action of OVTs have been evaluated in nonclinical/clinical phase trials. Various genetically modified viruses have been developed as oncolytic agents, and the first approval of an OVT for clinical use was issued by the US Food and Drug Administration in 2015.

Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study.

We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine.

Applicability of Selective Data Collection to Cancer Clinical Studies for Supplemental Marketing Approvals: Frequency of Adverse Reactions Observed During Supplemental Approval Compared With First Approval.

Background: In 2012, the US Food and Drug Administration (FDA) issued the draft guidance "Determining the Extent of Safety Data Collection Needed in Late Stage Premarket and Postapproval Clinical Investigations." The selective data collection approach proposed in this guidance leads to reductions in costs and work time and may improve the quality of the database for clinical trials. The current study evaluated the applicability of selective data collection for oncology drugs.

Compassionate use of drugs and medical devices in the United States, the European Union and Japan.

Compassionate use, also called expanded access, provides an important pathway for patients with life-threatening conditions to gain access to unapproved investigational drugs, biologics and medical devices. Although the United States (US) and the countries of the Europe Union (EU) have mechanisms that are associated with the use of unapproved products, as of May 2015 there was no such mechanism in Japan. Instead, unapproved products are used under a physician's discretion in conjunction with the Japan Medical Practitioners' Act or Advanced Medical Care B.

Approaches to improve development methods for therapeutic cancer vaccines.

Therapeutic cancer vaccines are an immunotherapy that amplify or induce an active immune response against tumors. Notably, limitations in the methodology for existing anti-cancer drugs may subsist while applying them to cancer vaccine therapy. A retrospective analysis was performed using information obtained from ClinicalTrials.

New concepts of biomarkers and clinical outcomes for therapeutic cancer vaccines in clinical trials.

Aim: This study aimed to derive meaningful parameters for immune monitoring during cancer vaccine development by analysis of the literature.

Methods: This retrospective study was based on analysis of clinical trials registered at ClinicalTrials.gov and published data available on PubMed.

Fever-range whole-body heat treatment stimulates antigen-specific T-cell responses in humans.

Increase in body temperature has been thought to play an important role in the regulation of immune responses, although its precise mechanisms are still under investigation. Here, we examined the effects of physiologically relevant thermal stress on the cytokine production from human peripheral T cells. Volunteers were heated using a whole-body hyperthermia device, the rectal temperature was maintained above 38.

Development of a novel in vivo cancer model using cell sheet engineering.

Aim: Standard in vivo cancer models entail injecting single cancer cells, but this technique is not always successful. We developed a novel cancer cell sheet by using temperature-responsive polymer poly(N-isopropyl acryl amide)-coated plates, which allow controlled attachment and detachment of living cancer cells via simple temperature changes.

Materials And Methods: Four human cancer cell lines were used to make cell sheets.

Approval Status and Regulatory Actions for Radiopharmaceuticals in the United States and Japan.

The aim of this study was to identify the differences between Japan and the United States in the approval status and regulatory actions for radiopharmaceuticals. The package inserts of radiopharmaceuticals that have been approved in the United States and Japan were used to investigate the status of approval in each country, examining the similarities and differences thereof and taking the regulatory systems of the 2 countries into account. Results revealed that since 1995, fewer products have been approved in Japan than in the United States: 16 radiopharmaceuticals have been approved in the United States, compared to only 7 in Japan.

[Establishment of induced pluripotent stem cells from adipose tissue-derived stem cells for dendritic cell-based cancer vaccines].

Recently, studies on regenerative stem cell therapy are being encouraged, and efforts to generate dendritic cells, which play important roles in cancer immunotherapy, from stem cells are being made in the field of tumor immunology. Therapeutic acquisition of stem cells has important clinical applications. Studies on induced pluripotent stem(iPS)cells generated from somatic cells with pluripotent genes have advanced in recent years.

Phase I clinical trial of multiple-peptide vaccination for patients with advanced biliary tract cancer.

Background: The prognosis of patients with advanced biliary tract cancer (BTC) is extremely poor and only a few standard treatments are available for this condition. We performed a phase I trial to investigate the safety, immune response and anti-tumor effect of vaccination with three peptides derived from cancer-testis antigens.

Methods: This study was conducted as a phase I trial.

Final storage of radioactive cesium by pollucite hydrothermal synthesis.

The Fukushima nuclear accident has highlighted the importance of finding a better final storage method for radioactive cesium species. Cs is highly soluble in water, and can easily exchange with other alkali ions in zeolites or clays to form stable complexes. However, Cs(+) is released from Cs(+) complexes into water when surrounded by an excess of water.

Immunological responses to a multi-peptide vaccine targeting cancer-testis antigens and VEGFRs in advanced pancreatic cancer patients.

The prognosis of patients with advanced pancreatic cancer is extremely poor and there are only a few standard treatments. Here, we report the results of a Phase I clinical trial to investigate the safety, immunostimulatory effects, and antineoplastic activity of a multi-target vaccine composed of four distinct peptides derived from cancer-testis (CT) antigens and vascular endothelial growth factor receptors (VEGFRs). Nine patients with unresectable, advanced pancreatic cancer who were refractory to standard chemotherapy were enrolled.

Postoperative dendritic cell vaccine plus activated T-cell transfer improves the survival of patients with invasive hepatocellular carcinoma.

The recurrence rate after surgery in patients with hepatocellular carcinoma (HCC) is very high, while prognosis is quite poor. However, there is no standard treatment to prevent recurrence of HCC after a curative operation. In this study, we investigated the clinical utilization of an autologous tumor lysate-pulsed dendritic cell vaccine plus ex vivo activated T cell transfer (ATVAC) in an adjuvant setting for postoperative HCC as a non-randomized controlled trial.

Global development strategy for companion diagnostics based on the usage and approval history for biomarkers in Japan, the USA and the EU.

Aim: The aim of this study was to identify gaps between Japan and the West in biomarker usage and the development of companion diagnostics. We also elaborated potential scenarios for companion diagnostic development.

Methods: Information on drug labels in Japan, the USA and the EU was obtained from each regulatory authority's web site, as well as label information on in vitro diagnostic testing in Japan and the USA.

Immunological monitoring of anticancer vaccines in clinical trials.

Therapeutic anticancer vaccines operate by eliciting or enhancing an immune response that specifically targets tumor-associated antigens. Although intense efforts have been made for developing clinically useful anticancer vaccines, only a few Phase III clinical trials testing this immunotherapeutic strategy have achieved their primary endpoint. Here, we report the results of a retrospective research aimed at clarifying the design of previously completed Phase II/III clinical trials testing therapeutic anticancer vaccines and at assessing the value of immunological monitoring in this setting.

Vaccination of biliary tract cancer patients with four peptides derived from cancer-testis antigens.

In the context of a Phase I clinical trial, the long-term vaccination of advanced biliary tract cancer patients with peptides derived from four distinct cancer-testis antigens resulted in remarkable disease stability and in the elicitation of antigen-specific T-cell responses.