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Amsterdam-Zuidoost, Netherlands

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.4-4 | Award Amount: 7.73M | Year: 2012

Age-related Macular Degeneration (AMD), a neurodegenerative disease of the retina, is a major cause of blindness in elderly people. Due to the aging population, AMD has been referred to as a time bomb in society. In the exudative form of AMD, high levels of vascular endothelial cell growth factor (VEGF) and low levels of pigment-epithelial derived factor (PEDF), an inhibitor of vascularization and a neuroprotective factor produced by retinal pigment epithelial (RPE) cells result in subretinal neovascularization and retinal pigment cell degeneration. The current treatment by monthly injections of anti-VEGF antibodies is only effective for ~30% of patients. To avoid the severe side effects, high costs and the overall continuing burden on health care associated with monthly antibody injections, inducing a higher level of PEDF expression to inhibit neovascularization would be a viable therapeutic alternative. TargetAMD will subretinally transplant genetically modified, patient-derived, iris- or RPE cells that overexpress PEDF to provide a long-lasting cure of AMD. Stable PEDF gene delivery will be based on the non-viral Sleeping Beauty transposon system, which combines the efficacy of viral delivery with the safety of naked DNA plasmids. Academic scientists and SME partners will produce innovative gene delivery technologies, reagents and devices to be translated into a simple and safe gene therapeutic treatment for exudative AMD. Experienced clinicians will perform two clinical trials, comprising isolation and PEDF-transfection of a patients pigment epithelial cells and implantation of transfected cells into the patient during a single, 60-minute surgical session. This project will bring a significant enhancement on quality of life to AMD patients, highlight the synergistic power of academic, clinical and industrial cooperation to the scientific arena, and open new markets for novel products for clinical applications of transposon-based gene therapy to industry.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.4-4 | Award Amount: 8.26M | Year: 2012

The aim of this research is to exploit technology for nucleic acid delivery through the clinical testing of adoptive engineered T cells to treat cancer. Recent innovative developments in cancer gene-immunotherapy have led to very encouraging early clinical results. However, the use of engineered T cells is a challenging and complex field with further development and more proof-of-principle trials needed. This proposal builds upon previous EU funded pre-clinical projects and comprises a multidisciplinary and translational research group with wide-ranging relevant expertise. Building on encouraging clinical results targeting NY-ESO-1 in melanoma and the availability of clinical grade vector, the consortium proposes to rapidly initiate two landmark studies in this field: the first to examine the activity of engineered T cells in oesophago-gastric cancer as an example of a hard to treat common epithelial cancer; the second to undertake a randomised phase II study to determine whether an optimised cell production system developed by the partners improves the current clinical response rates in patients with metastatic melanoma treated with NY-ESO-1 targeted T-cells. Success in these trials will enable the consortia and others to carryout larger trials and potentially approval of this type of therapy as a treatment for multiple cancer types. The inclusion of a major industrial partner focused on cell therapy technology and two SMEs focus on the delivery of cell therapy will facilitate future development of this area following these trials; indeed the project also includes plans to further automate and streamline cell processing to facilitate this development. This project would enhance European expertise and competitiveness in an important emerging market. The research will also support the European biotechnology industry which will be important for the exploitation of these therapies and the successful outcome of this project.

Van Den Berg J.H.,Netherlands Cancer Institute | Van Den Berg J.H.,Amsterdam BioTherapeutics Unit | Gomez-Eerland R.,Netherlands Cancer Institute | Van De Wiel B.,Netherlands Cancer Institute | And 11 more authors.
Molecular Therapy | Year: 2015

Here, we describe a fatal serious adverse event observed in a patient infused with autologous T-cell receptor (TCR) transduced T cells. This TCR, originally obtained from a melanoma patient, recognizes the well-described HLA-A∗0201 restricted 26-35 epitope of MART-1, and was not affinity enhanced. Patient 1 with metastatic melanoma experienced a cerebral hemorrhage, epileptic seizures, and a witnessed cardiac arrest 6 days after cell infusion. Three days later, the patient died from multiple organ failure and irreversible neurologic damage. After T-cell infusion, levels of IL-6, IFN-γ, C-reactive protein (CRP), and procalcitonin increased to extreme levels, indicative of a cytokine release syndrome or T-cell-mediated inflammatory response. Infused T cells could be recovered from blood, broncho-alveolar lavage, ascites, and after autopsy from tumor sites and heart tissue. High levels of NT-proBNP indicate semi-acute heart failure. No cross reactivity of the modified T cells toward a beating cardiomyocyte culture was observed. Together, these observations suggest that high levels of inflammatory cytokines alone or in combination with semi-acute heart failure and epileptic seizure may have contributed substantially to the occurrence of the acute and lethal event. Protocol modifications to limit the risk of T-cell activation-induced toxicity are discussed. © The American Society of Gene & Cell Therapy.

Agency: Cordis | Branch: FP7 | Program: CP-FP | Phase: HEALTH.2012.1.2-1 | Award Amount: 7.69M | Year: 2012

Cervical cancer (CC) is the second most common cause of cancer deaths in women worldwide. The main objective of the RAIDs project is to use this model system which is accessible to repeat biopsies to learn how to stratify patients into targeted therapies. The patients tumors will be classified into molecular subtypes based on their molecular profile by use of high-throughput technologies (sequencing, RPPA) combined with integrative bioinformatics analysis. Stratification is a learning process which will need constant readaptation. It will rely on prognostic and predictive biomolecular information gained from patients who will receive either standard therapy (the cognitive cohort) or patients who receive (first generation) targeted therapy. Bioinformatics will be an essential tool to allow integrative genome/proteome analysis and provide functional interpretation of the results at each step. Machine learning techniques will be used to select the most reliable biomarkers. These tools will be used to predict response to cc treatment or progression. Moreover, systems biology approaches will be used to unravel the gene regulatory networks and signaling pathways involved in the tumor progression and should be helpful to select predictive biomarkers and putative drug targets. Tumor material will be sampled before and following standard therapy or therapeutic HPV vaccination and/or novel targeted drug treatments. Clinical annotation by imaging methods as well as through biomarkers will have quality control procedures and relevant statistical models will be applied. RAIDS is a multidisciplinary approach integrating genomic studies, protein arrays, viral genotyping and immunohistochemical investigations on CC cells and tissues between academic clinical centers and SMEs . The project is expected to provide new tools for early diagnosis and targeted treatments exploited by SMEs and to accelerate innovation of CC therapy and improve quality of life.

Gomez-Eerland R.,Netherlands Cancer Institute | Nuijen B.,Netherlands Cancer Institute | Nuijen B.,Amsterdam BioTherapeutics Unit | Heemskerk B.,Netherlands Cancer Institute | And 11 more authors.
Human Gene Therapy Methods | Year: 2014

Advances in genetic engineering have made it possible to generate human T-cell products that carry desired functionalities, such as the ability to recognize cancer cells. The currently used strategies for the generation of gene-modified T-cell products lead to highly differentiated cells within the infusion product, and on the basis of data obtained in preclinical models, this is likely to impact the efficacy of these products. We set out to develop a good manufacturing practice (GMP) protocol that yields T-cell receptor (TCR) gene-modified T-cells with more favorable properties for clinical application. Here, we show the robust clinical-scale production of human peripheral blood T-cells with an early memory phenotype that express a MART-1-specific TCR. By combining selection and stimulation using anti-CD3/CD28 beads for retroviral transduction, followed by expansion in the presence of IL-7 and IL-15, production of a well-defined clinical-scale TCR gene-modified T-cell product could be achieved. A major fraction of the T-cells generated in this fashion were shown to coexpress CD62L and CD45RA, and express CD27 and CD28, indicating a central memory or memory stemlike phenotype. Furthermore, these cells produced IFNγ, TNFα, and IL-2 and displayed cytolytic activity against target cells expressing the relevant antigen. The T-cell products manufactured by this robust and validated GMP production process are now undergoing testing in a phase I/IIa clinical trial in HLA-A∗02:01 MART-1-positive advanced stage melanoma patients. To our knowledge, this is the first clinical trial protocol in which the combination of IL-7 and IL-15 has been applied for the generation of gene-modified T-cell products. © Copyright 2014, Mary Ann Liebert, Inc. 2014.

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