Bringing you the latest cutting-edge research and commentary in bioscience.

Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

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Journal

Welcome to the latest issue of Cell and Gene Therapy Insights – the open access, peer-reviewed publication that brings you the latest insight and commentary from leading experts from academia and industry.

Commercial Insights
Regulatory Insight

Clinical trials of advanced therapy investigational medicinal products in Spain: preparing for the European clinical trials regulation

Spotlight Article

Regulatory Insight

Juan Estévez Álamo, Marcos Timón, Cristina González Gómez-Platero, Carmen Doadrio Abad, Marta Velasco González, María Yolanda de Mingo Ballesteros, María Ángeles Martín de la Sierra San Agustín & María Antonia Serrano Castro

Clinical Trial Designs For Advanced Therapies

Clinical trials (CT) of Advanced Therapy Medicinal Products are a reality worldwide. Although ATMPs are still very innovative therapies, it is interesting to investigate what relevant information can be obtained from the analyses of authorized CT and the investigated products. The aim of this study was to follow the evolution of CT with Advanced Therapy investigational Medicinal Products (ATiMP) authorized in Spain from May 2004 to June 2019 on the basis of information available at the Spanish Agency for Medicinal Products and Medical Devices and their real status (also taking into consideration their status in three different official Registries). We will also discuss how sponsors and Authorities can prepare for the coming new clinical trial regulation and take advantage of the opportunities it may present.

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Interview

Assessing the future prospects of upstream bioprocessing systems for commercial AAV production

Interview

Scott A Jeffers

Clinical Trial Designs For Advanced Therapies


VECTOR CHANNEL: ADHERENT CULTURE METHODS


Scott A Jeffers is a Director of Process Development at uniQure LLC. He has been in and out of gene therapy since 1997 when as a graduate student at Purdue University in Dr David A Sanders’ lab where he worked on pseudotyping lentiviral and retroviral gene therapy vectors with Ebola virus glycoproteins. He moved out of gene therapy and became a virologist studying SARS virus with Dr Kathryn V Holmes and then made the jump to France were he worked at the Institute Pasteur with Dr Felix Ray elucidating the x-ray crystal structures of the glycoproteins of Rift Valley fever virus and other deadly viruses. He finally broke into industry and back into gene therapy when he worked at Brammer Bio in Florida.

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Keys to success for foundation: industry clinical development collaborations

Spotlight Article

Interview

Brian Fiske

Clinical Trial Designs For Advanced Therapies

Brian Fiske joined The Michael J. Fox Foundation for Parkinson’s Research (MJFF) in 2004. As Senior Vice President, Research Programs, Brian co-manages a team of professionals who stay closely linked to the Parkinson’s community in order to develop an aggressive and innovative agenda for accelerating research and drug development for Parkinson’s disease. This ensures that MJFF priorities reflect and best serve the ultimate needs of patients. Brian regularly meets with academic and industry scientists around the world to identify promising ideas to support, providing troubleshooting and ongoing management of projects as they go forward. He currently oversees the teams focused on MJFF’s strategies for developing disease-modifying and symptomatic therapies for Parkinson’s patients. Brian earned an undergraduate degree in biology from Texas A&M University and a PhD in Neuroscience from the University of Virginia. After completing postdoctoral research at Columbia University, Brian spent several years as an editor for the prestigious scientific journal, Nature Neuroscience. He brings this broad experience and knowledge to the Foundation to help bring new treatments to people with Parkinson’s.

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Breaking new ground: bringing an iPS cell therapy to the clinic

Spotlight Article

Interview

Kapil Bharti

Clinical Trial Designs For Advanced Therapies

Kapil Bharti holds a bachelor’s degree in biophysics from the Panjab University in Chandigarh, India, where he graduated with highest honors. This was followed by a Masters degree in biotechnology at the Maharaja Sayaji Rao University in Baroda, India and a diploma in molecular cell biology at the Johann Wolfgang Goethe University at Frankfurt in Germany. Supported by an international PhD student fellowship, he obtained his PhD from the same institution, graduating summa cum laude. His PhD work involved basic biology in the areas of heat stress, cellular chaperones, and epigenetics. From Germany, Dr Bharti came to the National Institute of Neurological Disorders and Stroke to work with Dr Heinz Arnheiter as a postdoctoral fellow. While there, he published numerous papers in the areas of transcription factor regulation, pigment cell biology, and the developmental biology of the eye. It is perhaps this combination of diverse backgrounds that led him to develop an interest in the emerging field of stem cell biology, particularly of the retinal pigment epithelium, as he moved into the role of staff scientist. Dr Bharti has authored numerous publications and has won several awards, including, most recently, being a finalist in the prestigious trans-NIH Earl Stadtman Symposium.

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Expert Insight

Post-marketing safety and efficacy surveillance of cell and gene therapies in the EU: A critical review

Spotlight Article

Expert Insight

Enrico Fritsche, Magdi Elsallab, Michaela Schaden, Spencer Phillips Hey, Mohamed Abou-El-Enein

Clinical Trial Designs For Advanced Therapies

The implementation of new regulatory tools, such as the PRIority MEdicine (PRIME) scheme, by regulatory authorities in Europe enabled faster patient access to innovative therapies. This early access tool goes along with a clear need for a thorough assessment of safety and efficacy upon marketing authorization. Due to the higher degree of uncertainty when evaluating novel therapies such as advanced therapy medicinal products (ATMPs), post-marketing surveillance studies for these products should be designed to make up the evidential shortfall and provide additional evidence to inform clinical practice. Here, we describe the status and regulatory requirements of post-marketing surveillance for ATMPs, which we found often resembling traditional, pre-market trials, focusing on biological mechanisms and efficacy in narrowly defined patient populations. We close by proposing the pragmatic trial concept as a potential solution to improve data quality and evidence generation in settings closer to real-world.

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CRISPR surgery for inherited retinal diseases: landmarks in the 21st century

Spotlight Article

Expert Insight

Alexander H Chai & Stephen H Tsang

Clinical Trial Designs For Advanced Therapies

Gene therapy was first conceptualized in 1972 as clarification on viral DNA-altering mechanisms was done. Since then, the field of gene therapy has transformed from a biological fantasy into a valid clinical treatment in humans, in part due to significant innovations in the field of molecular genetics. The development of gene therapy technology and the ensuing research has laid a strong foundation for the advancement of gene therapy, which has the potential to correct dominantly inherited disorders that were previously incurable. In November 2018, a drug named Luxturna became the first in vivo CRISPR/Cas9 genome surgery treatment to be FDA-approved for use in clinical trials, which are set to take place in patients with Leber congenital amaurosis 10 in the fall of 2019 [1]. However, there remain a number of scientific and practical barriers to resolve before genomic medicine can become a widespread treatment.

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Bayesian Phase 1/2 trial designs and cellular immunotherapies: a practical primer

Spotlight Article

Expert Insight

Jordan Gauthier, Ying Yuan & Peter Thall

Clinical Trial Designs For Advanced Therapies

Bayesian Phase 1/2 trial designs remain underused in biomedical research and are virtually absent from the field of cellular therapy. In this review, we highlight the severe limitations of the maximum tolerated dose (MTD) concept and the traditional Phase 1/Phase 2 paradigm. Next, we introduce statistical concepts underlying most adaptive Bayesian trial designs. We use the EffTox design [1,2], one of many adaptive Bayesian designs, as an example to illustrate ‘state-of-the-art’ Phase 1/2 designs. We highlight how these designs can be helpful to the cellular therapy field specifically. Furthermore, we provide the reader with practical examples, links to freely available web applications, and R packages. We hope this will incentivize investigators to implement these designs for chimeric antigen-receptor-engineered T cell therapy trials, as well as other T cell-based therapies.

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Towards individualized, low toxic conditioning in autologous gene-transduced hematopoietic cell transplantation

Spotlight Article

Expert Insight

Rick Admiraal, Susan Prockop & Jaap Jan Boelens

Clinical Trial Designs For Advanced Therapies

Allogeneic hematopoietic cell transplantation (Allo-HCT) has become much safer over the last couple of years. This, together with the rapidly evolving autologous HCT-gene therapy options, is expected to result in an increase in the number of patients receiving HCT. Autologous HCT-gene therapy is a more advanced, safer and precise option for monogenetic life threatening disorders. The efficacy of gene therapy, however, does not only rely on the gene construct itself, but also on the conditioning applied before the gene therapy. In this review we describe how the conditioning can impact the outcomes of the allo-HCT and gene therapy and we will provide a future perspective on how to further improve the efficacy and reduce the short- and long-term toxicity of the conditioning.

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Evaluation of AAV vector production from the iCELLis fixed bed bioreactor vessel

Expert Insight

Shelley Nass, Bindu Nambiar, Maryellen Mattingly, Denise Woodcock & Catherine O’Riordan

Clinical Trial Designs For Advanced Therapies


VECTOR CHANNEL: ADHERENT CULTURE METHODS


AAV gene therapy vectors have demonstrated efficacy in numerous clinical trials, and gene therapy products are now a reality. In support of the commercialization of AAV gene therapy biologics, scalable, high capacity AAV production methods are necessary, and here we describe the use of the iCELLis® Fixed Bed Bioreactor Vessel (Pall Corporation), a versatile AAV production system that can be used for the production of both research grade and GMP AAV vectors. The iCELLis® system is ideally suited for use with the triple transfection AAV production method utilizing adherent HEK 293 cells. For routine AAV research vector production in the iCELLis® Nano high compaction 4 m2 vessel is used, with the option to combine up to four vessels in tandem, if vector yields greater than 1 × 1014 VGs are required. The use of the iCELLis® system provides a continuum in the vector production platform for pre-clinical AAV vector production to GMP AAV production for clinical trials and commercialization.

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Considerations for patient selection for cell and gene therapy trials using tumor associated antigens as target in early phase development

Spotlight Article

Expert Insight

Stephanie Traub & David Edwards

Clinical Trial Designs For Advanced Therapies

For cell and gene therapies, including those using tumor associated antigens (TAAs) as targets, effective patient selection is critical for success. In this paper, we discuss considerations for patient selection for cell and gene therapy products in early phase clinical development. Surprisingly, many obvious key factors like the TAA themselves, the major histocompatibility complex (MHC), as well as practical implication of patient selection on the trial design and conduct are not given the consideration that they should be given. The article focuses on ideal patient selection for cell and gene therapies using TAAs and implications for clinical trial design.

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The evolution of adeno-associated virus capsids for CNS gene therapy

Spotlight Article

Expert Insight

Steven J Gray

Clinical Trial Designs For Advanced Therapies

Adeno-associated virus (AAV) is emerging as a dominant gene therapy delivery vehicle, and the broad tool kit of naturally-occurring AAV capsid variants has allowed tailoring of approaches for specific applications. For example, Glybera® (AAV1) is targeted to muscle, Luxterna™ (AAV2) is targeted to the retina, and Zolgensma® (AAV9) is targeted to the central nervous system (CNS). In the context of CNS gene therapy, the discovery of AAV9 was largely responsible for a shift from direct intraparenchymal brain injections to approaches that more globally target the brain, such as intravenous injection and/or injection into the cerebrospinal fluid (CSF). In fact, one could divide CNS gene therapy into ‘pre-AAV9’ and ‘post-AAV9’ eras, due to the dramatic leap that this vector technology enabled. One can envision a similar future leap coming, as lab-derived improvements to capsids are being made that could further increase the efficiency and specificity of CNS-directed gene therapy. Recent advancements in AAV vectors are discussed.

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