Measuring food preference and reward: application and cross-cultural adaptation of the leeds food preference questionnaire in human experimental research

Decisions about what we eat play a central role in human appetite and energy balance. Measuring food reward and its underlying components of implicit motivation (wanting) and explicit sensory pleasure (liking) is therefore important in understanding which foods are preferred in a given context and at a given moment in time. Among the different methods used to measure food reward, the Leeds Food Preference Questionnaire (LFPQ) is a well-established tool that has been widely used in the scientific field for over 10 years. The original LFPQ measures explicit liking and implicit wanting for the same visual food stimuli varying along two nutritional dimensions: fat (high or low) and taste (sweet or savoury/non-sweet). With increasing use of the LFPQ (in original or adapted forms) across different cultural and scientific contexts, there is a need for a set of recommendations for effective execution as well as cultural and nutritional adaptations of the tool. This paper aims to describe the current status of the LFPQ for researchers new to the methodology, and to provide standards of good practice that can be adopted for its cultural adaptation and use in the laboratory or clinic. This paper details procedures for the creation and validation of appropriate food stimuli; implementation of the tool for sensitive measures of food reward; and interpretation of the main end-points of the LFPQ. Following these steps will facilitate comparisons of findings between studies and lead to a better understanding of the role of food reward in human eating behaviour

New insights into the kinetics and variability of egg excretion in controlled human hookworm infections

Four healthy volunteers were infected with 50 Necator americanus infective larvae (L3) in a controlled human hookworm infection trial and followed for 52 weeks. The kinetics of fecal egg counts in volunteers was assessed with Bayesian multilevel analysis, which revealed an increase between weeks 7 and 13, followed by an egg density plateau of about 1000 eggs/g of feces. Variation in egg counts was minimal between same-day measurements but varied considerably between days, particularly during the plateau phase. These analyses pave the way for the controlled human hookworm model to accelerate drug and vaccine efficacy studies

Decision-making for marketing approval of cell and gene based therapy products in the European union, United States and Canada

Innovative characteristics of gene and cell-based therapy products (GCTs) often hinder standardized regulatory assessment based on existing guidance documents. As a result, decision-making for marketing approval in this area is still largely done on a case-by-case basis. We aimed to compare assessment procedures for approved GCTs in the European Union (EU), United States (US) and Canada. A comparative analysis was designed to provide insight in the assessment procedures until December 2016. Data was collected in relation to 1) product profiles, 2) scientific evidence and 3) regulatory assessment criteria. We subsequently analysed how these three components relate to each other in decisions for approval between jurisdictions. We included 8 assessment procedures in the EU, 5 in the US and 1 in Canada. Two products were approved in both the EU and US. Product profiles consisted of cell based therapy products (n = 10) and gene based therapy products (n = 4) that mainly target cancers and musculoskeletal diseases. Additional EU and Canadian GCTs target congenital and immunologic disorders, whereas US products include a cosmetic and periodontal GCT. Three GCTs were based on allogeneic starting material. Concerning evidence, significant results on the primary efficacy endpoints were provided for a large proportion of approvals (10/14). Less than half of approvals involved orphan drugs (EU = 4, US = 1). Orphan drugs in the EU were often approved under alternative (e.g. conditional approval) pathways (3/4), enabling single arm trial design and non-significant results on clinical endpoints. On the contrary, approvals under US (4/5) and Canadian (1/1) alternative (e.g. US accelerated approval) pathways are predominantly based on randomized, controlled, phase III trial design (US, Canada) and significant results on clinical endpoints (US). Unmet medical need is often considered together with safety and efficacy uncertainties in decision-making for approval in the EU (5/8; US 2/5; CA 1/1). In conclusion, product profiles differ between jurisdictions, which influences scientific evidence and regulatory assessment criteria to gain GCT approval. More orphan drug designation in the EU results in approval under alternative pathways based on less robust clinical trial design and efficacy evidence compared to the US

Decision-making for marketing approval of cell and gene based therapy products in the European union, United States and Canada

Innovative characteristics of gene and cell-based therapy products (GCTs) often hinder standardized regulatory assessment based on existing guidance documents. As a result, decision-making for marketing approval in this area is still largely done on a case-by-case basis. We aimed to compare assessment procedures for approved GCTs in the European Union (EU), United States (US) and Canada. A comparative analysis was designed to provide insight in the assessment procedures until December 2016. Data was collected in relation to 1) product profiles, 2) scientific evidence and 3) regulatory assessment criteria. We subsequently analysed how these three components relate to each other in decisions for approval between jurisdictions. We included 8 assessment procedures in the EU, 5 in the US and 1 in Canada. Two products were approved in both the EU and US. Product profiles consisted of cell based therapy products (n = 10) and gene based therapy products (n = 4) that mainly target cancers and musculoskeletal diseases. Additional EU and Canadian GCTs target congenital and immunologic disorders, whereas US products include a cosmetic and periodontal GCT. Three GCTs were based on allogeneic starting material. Concerning evidence, significant results on the primary efficacy endpoints were provided for a large proportion of approvals (10/14). Less than half of approvals involved orphan drugs (EU = 4, US = 1). Orphan drugs in the EU were often approved under alternative (e.g. conditional approval) pathways (3/4), enabling single arm trial design and non-significant results on clinical endpoints. On the contrary, approvals under US (4/5) and Canadian (1/1) alternative (e.g. US accelerated approval) pathways are predominantly based on randomized, controlled, phase III trial design (US, Canada) and significant results on clinical endpoints (US). Unmet medical need is often considered together with safety and efficacy uncertainties in decision-making for approval in the EU (5/8; US 2/5; CA 1/1). In conclusion, product profiles differ between jurisdictions, which influences scientific evidence and regulatory assessment criteria to gain GCT approval. More orphan drug designation in the EU results in approval under alternative pathways based on less robust clinical trial design and efficacy evidence compared to the US

Decision-making on marketing authorization of advanced therapy medicinal products in the European union

Introduction: Advanced Therapy Medicinal Products (ATMPs) are innovative products receiving increasing interest. While many clinical trials with GCTs have been performed in Europe, currently only fifteen marketing authorization (MA) applications have been submitted (December 2016), which resulted in eight MAs. This study aims to investigate how decision-making and the underlying evidence for (non-)MA is built up in the EU. Methodology: A comparative analysis was used to investigate the justification of MA-decision procedures of ATMPs. This was subcategorized and scored into product profiles, scientific evidence and regulatory assessment criteria. How these factors relate to each other is compared between MAs and non-MAs. Preliminary Results: Eight applications were granted approval, including standard MA (n = 5) and alternative MA (n = 3). Six applications were not granted approval (non-MA). Clinical trial design differed between standard and alternative MA, whereas the clinical trial designs of the non-approved products showed high variability. Alternative MA (n = 3) trials included less patients (mean alternative MA = 57 vs. mean standard MA = 244) and randomized controlled phase III trials were not conducted. Furthermore, these alternative MAs were all designated as orphan drugs, for which alternative treatment was lacking, and the products showed added clinical benefit. Moreover, considerations of unmet medical need were part of decisionmaking for these alternative MA products. For standard MA, decision was always based on statistical significant results on the primary efficacy endpoints, whereas such results were not always obtained for alternative MAs. Moreover, for the non-MA products statistical significant efficacy on primary and secondary endpoints were lacking. Conclusion: This study suggests that key assessment criteria in approval of ATMPs in the EU are trial design, significant outcomes, orphan designation and unmet medical need. In particular, ATMPs developed for orphan indications generally enter alternative regulatory pathways, which influences clinical trial design, clinical outcomes and the weight of unmet medical need in decisionmaking for ATMP approval

Decision-making on marketing authorization of advanced therapy medicinal products in the European union

Introduction: Advanced Therapy Medicinal Products (ATMPs) are innovative products receiving increasing interest. While many clinical trials with GCTs have been performed in Europe, currently only fifteen marketing authorization (MA) applications have been submitted (December 2016), which resulted in eight MAs. This study aims to investigate how decision-making and the underlying evidence for (non-)MA is built up in the EU. Methodology: A comparative analysis was used to investigate the justification of MA-decision procedures of ATMPs. This was subcategorized and scored into product profiles, scientific evidence and regulatory assessment criteria. How these factors relate to each other is compared between MAs and non-MAs. Preliminary Results: Eight applications were granted approval, including standard MA (n = 5) and alternative MA (n = 3). Six applications were not granted approval (non-MA). Clinical trial design differed between standard and alternative MA, whereas the clinical trial designs of the non-approved products showed high variability. Alternative MA (n = 3) trials included less patients (mean alternative MA = 57 vs. mean standard MA = 244) and randomized controlled phase III trials were not conducted. Furthermore, these alternative MAs were all designated as orphan drugs, for which alternative treatment was lacking, and the products showed added clinical benefit. Moreover, considerations of unmet medical need were part of decisionmaking for these alternative MA products. For standard MA, decision was always based on statistical significant results on the primary efficacy endpoints, whereas such results were not always obtained for alternative MAs. Moreover, for the non-MA products statistical significant efficacy on primary and secondary endpoints were lacking. Conclusion: This study suggests that key assessment criteria in approval of ATMPs in the EU are trial design, significant outcomes, orphan designation and unmet medical need. In particular, ATMPs developed for orphan indications generally enter alternative regulatory pathways, which influences clinical trial design, clinical outcomes and the weight of unmet medical need in decisionmaking for ATMP approval

Identification and prevalence of CD8(+) T-cell responses directed against Epstein-Barr virus-encoded latent membrane protein 1 and latent membrane protein 2

Epstein-Barr virus (EBV) is associated with several human malignancies that each show different viral gene expression profiles. In malignancies such as Hodgkin's disease and nasopharyngeal carcinoma only Epstein-Barr nuclear antigen 1 (EBNA1) and varying levels of latent membrane proteins 1 and 2 (LMP1 and -2) are expressed. Since endogenously expressed EBNA1 is protected from CTL recognition, LMP1 and LMP2 are the most likely target antigens for anti-tumor immunotherapy. Therefore, we sought to identify in a systematic way CD8(+) T-cell responses directed against eptitopes derived from LMP1 and LMP2. Using IFNgamma-ELISPOT assays of interferon-gamma release, peripheral blood mononuclear cells (PBMC) of healthy donors were screened with peptide panels (15 mer overlapping by 10) spanning the LMP1 and LMP2 sequences of the prototype EBV strain B95.8. When positive responses were found, CD4(+) or CD8(+) T cells were depleted from donor PBMC to determine the origin of the responder population. We detected CD8(+) T-cell responses to LMP1 in 9/50(18%) donors and to LMP2 in 15/28 (54%) donors. In addition to the already described epitopes, 3 new LMP1- and 5 new LMP2-derived CD8(+) epitopes were identified. In most donors LMP1- and LMP2-specific CD8(+) precursor frequencies were low compared with precursors against immunodominant EBV epitopes from latent (EBNA3A, -3B and -3C) and lytic cycle antigens. These results demonstrate that CD8(+) memory T cell responses to LMP1 and especially to LMP2 do exist in Caucasians, albeit at low levels and could potentially be exploited for therapeutic use

Preclinical Development of Autologous Hematopoietic Stem Cell-Based Gene Therapy for Immune Deficiencies: A Journey from Mouse Cage to Bed Side

Recent clinical trials using patient’s own corrected hematopoietic stem cells (HSCs), such as for primary immunodeficiencies (Adenosine deaminase (ADA) deficiency, X-linked Severe Combined Immunodeficiency (SCID), X-linked chronic granulomatous disease (CGD), Wiskott–Aldrich Syndrome (WAS)), have yielded promising results in the clinic; endorsing gene therapy to become standard therapy for a number of diseases. However, the journey to achieve such a successful therapy is not easy, and several challenges have to be overcome. In this review, we will address several different challenges in the development of gene therapy for immune deficiencies using our own experience with Recombinase-activating gene 1 (RAG1) SCID as an example. We will discuss product development (targeting of the therapeutic cells and choice of a suitable vector and delivery method), the proof-of-concept (in vitro and in vivo efficacy, toxicology, and safety), and the final release steps to the clinic (scaling up, good manufacturing practice (GMP) procedures/protocols and regulatory hurdles)

Low-dose interferon-alpha preconditioning and adoptive cell therapy in patients with metastatic melanoma refractory to standard (immune) therapies: a phase I/II study

BackgroundAdoptive cell therapy (ACT) with tumor-reactive T cells has shown consistent clinical efficacy. We evaluated the response to ACT in combination with interferon alpha (IFNa) preconditioning in patients with stage IV metastatic melanoma, most of which were progressive on cytotoxic T-lymphocyte-associated protein 4 and/or programmed cell death protein 1 checkpoint blockade therapy.MethodsThirty-four patients were treated with ex vivo expanded tumor reactive T cells, derived from mixed lymphocyte autologous tumor cultures, or with autologous tumor-infiltrating lymphocytes and evaluated for clinical response. Clinical and immunological parameters associated with response were also evaluated.ResultsBest overall response defined as clinical benefit, comprising either complete response, partial response or stable disease >6 months, was observed in 29% of the patients. Forty-three per cent of the 14 immunotherapy-naïve patients and 20% of the 20 patients progressive on prior immunotherapy benefited from ACT. The overall survival (OS) was 90% versus 28.6% at 1 year and 46.7% versus 0% at 3 years follow-up, of responder and non-responder patients, respectively. Median OS was 36 versus 7 months, respectively. IFNa pretreatment resulted in leukopenia, neutropenia and lymphopenia, which was sustained during the treatment in clinical responders and associated with response. Differences in antigen specificity, but not in phenotype, cytokine profile or CD8+ T cell number of the ACT products correlated with clinical response. Cross-reactivity of the ACT products to one or more allogeneic human leukocyte antigen-matched melanoma cell lines was associated with short OS after treatment while the ACT products of very long-term survivors showed no cross-reactivity but recognized patient-specific neoantigens.ConclusionThis study demonstrates that ACT in combination with a mild IFNa preconditioning regimen can induce clinical benefit even in immunotherapy pretreated patients, although with lower success than in immunotherapy-naïve patients. ACT products comprising neoantigen reactivity may be more effective

A decade of marketing approval of gene and cell-based therapies in the United States, European Union and Japan : An evaluation of regulatory decision-making

There is a widely held expectation of clinical advance with the development of gene and cell-based therapies (GCTs). Yet, establishing benefits and risks is highly uncertain. We examine differences in decision-making for GCT approval between jurisdictions by comparing regulatory assessment procedures in the United States (US), European Union (EU) and Japan. A cohort of 18 assessment procedures was analyzed by comparing product characteristics, evidentiary and non-evidentiary factors considered for approval and post-marketing risk management. Product characteristics are very heterogeneous and only three products are marketed in multiple jurisdictions. Almost half of all approved GCTs received an orphan designation. Overall, confirmatory evidence or indications of clinical benefit were evident in US and EU applications, whereas in Japan approval was solely granted based on non-confirmatory evidence. Due to scientific uncertainties and safety risks, substantial post-marketing risk management activities were requested in the EU and Japan. EU and Japanese authorities often took unmet medical needs into consideration in decision-making for approval. These observations underline the effects of implemented legislation in these two jurisdictions that facilitate an adaptive approach to licensing. In the US, the recent assessments of two chimeric antigen receptor-T cell (CAR-T) products are suggestive of a trend toward a more permissive approach for GCT approval under recent reforms, in contrast to a more binary decision-making approach for previous approvals. It indicates that all three regulatory agencies are currently willing to take risks by approving GCTs with scientific uncertainties and safety risks, urging them to pay accurate attention to post-marketing risk management