BioInsights - Spotlights

CELL & GENE THERAPY INSIGHTS

Spotlights 2023

Preclinical & translational R&D

February

Preclinical & translational R&D

Sven Kili

Sven Kili, CEO at Antion Biosciences

Challenges and innovation in model development and application
- How is innovation in animal models enabling better prediction of efficacy in the cellular cancer immunotherapy field?
- What progress in developing models looking at dosing and at combinations? (Eg. how to incorporate the standard of care in dosing models?)
- Are in vitro models (patient-derived models, organoids, etc) ready to fill the preclinical knowledge gap caused by insufficiently predictive animal models?
- How to drive further improvement in nonclinical models by leveraging iPSCs? Emerging genome editing platforms?
What is the latest progress with, and outstanding innovation needs surrounding, the application of single cell sequencing technology in advanced therapies discovery and nonclinical R&D?
How and where is AI and machine learning being applied productively in nonclinical/translational R&D (eg. in mining clinical and genomics data; in target analysis)?
How is biomarker development and validation in cell and gene therapy evolving in step with regulatory pathways?
Exploring challenges in developing functional assays for off-target and on-target, off-tumor effect detection

Cell Therapy Materials & Upstream Processing/Analytics

March

Cell Therapy Materials & Upstream Processing/Analytics

Cell therapy raw and starting materials
- Optimizing cell collection, CQA identification and testing, and control of autologous cell therapy starting materials
- How can we grow our currently limited understanding of the impact of donor materials on allogeneic cell therapies, and how to account for donor variability?
- Challenges and opportunities in starting materials supply for induced pluripotent stem cell (iPSC)-derived cell therapies
- Meeting the need for robust analytics to meet the ever-increasing expectations of regulators around cellular starting materials quality
- Assessing upstream supply chain/logistics tools and technologies
Cellular immuno-oncology manufacturing business models
- Is it best to pursue an in-house or an outsourced commercial manufacturing strategy?
- Cost of goods and manufacturing timeline/complexity reduction
- Centralized versus decentralized manufacturing – what’s shaping future strategy?
Comparing and contrasting upstream cell processing tools and devices
Which tools are delivering required gains in productivity and quality?
- What is the latest in closed, automated upstream processing system innovation?
  - How effectively are long-standing issues of technology integration and interoperability being addressed?
  - How adaptable are current ‘all in one’ manufacturing devices in practical application?
- Assessing the state of the art – and future innovation needs - in cell sorting/separation and enrichment
- Optimizing upstream process analytics
Analyzing trends in the cell therapy CDMO sector – what do they mean for industry, and for the field in general?

Vector bioprocessing & raw materials

April

Vector bioprocessing & raw materials

Andrew D. Tustian

Andrew D. Tustian, Senior Director, Preclinical Manufacturing and Process Development at Regeneron Pharmaceuticals

Vector processing
- Analyzing shifting in-house vs outsourced manufacturing strategies in the viral vector field – what will be the repercussions for the gene therapy sector as a whole?
- Viral vector process development and intensification – assessing recent breakthroughs and toolkit evolution/innovation requirements to cost-effectively increase titer, yield, recovery, and purity
- Understanding and addressing challenges in the manufacture of novel engineered AAV capsids
- How to standardize manufacturing processes/equipment and adopt a platform-based approach to reduce vector manufacturing costs, improve quality, and accelerate timelines?
- Preparing for the challenges of commercial vector manufacture – what are the key considerations and pitfalls (eg. in process characterization, validation of commercial lots, QbD, supply chain)?
Raw & Starting Materials
- Overcoming issues in plasmid cost, quality and supply
- Addressing the current scarcity of/long lead times for critical reagents and equipment/consumables needed for viral vector manufacturing and testing
- What are the ‘must-have’s for industry in terms of vector raw materials specifications at each stage of product development?

Gene delivery platform evolution part 1: viral

May

Gene delivery platform evolution part 1: viral

Aravind Asokan

Aravind Asokan, Professor in Surgery, Director of Gene Therapy, Professor of Biomedical Engineering, Professor of Molecular Genetics and Microbiology, at Duke University School of Medicine

Development progress and target indication trends in the AAV-driven gene therapy field
- What are the major bottlenecks holding back gene therapy’s migration to disease indications with larger patient populations?
Addressing growing concerns over viral vector safety – to what extent are we able to mitigate them?
- What is our current level of understanding of AAV safety concerns underpinning the recent rash of SAEs and clinical holds
- Lentiviral vectors: what do we know about toxicity the of LV vectors, and both the ex vivo and in vivo gene therapies that utilize them?
- Impurity profile of the viral vector product and toxicity
Efficacy and durability of expression
- Improvements delivered by next generation engineered AAV and LV vectors in the clinic
- Is redosing of AAV possible or not?
How to expand the reach of in vivo viral delivery beyond the liver?
- Evaluating recent progress in opening up novel delivery pathways/ routes of administration and tissues (eg. to muscle)
- Examining the application to date of AAV vectors in delivering in vivo gene editing therapeutics
How do we ensure viral vector-driven approaches can play a role in driving expanded global patient access to cell and gene therapies?

Gene delivery platform evolution Part 2: Non-viral

June

Gene delivery platform evolution Part 2: Non-viral

Lynn Zechiedrich

Lynn Zechiedrich, Kyle & Josephine Morrow Chair & Professor in Molecular Virology & Microbiology at Baylor College of Medicine

How and where will mRNA continue to impact/disrupt the advanced therapies field?
Analyzing the evidence to date that non-viral delivery platforms can match or improve upon the safety, specificity, efficiency, durability, and cost of viral delivery platforms
- Lipid nanoparticles (LNPs)
  - Is the specific cell targeting/systemic delivery potential and broad applicability of LNPs and other nanoparticle platforms going to play out in in vivo gene therapy clinical application?
  - Evaluating mRNA approaches for CAR T cell transfection
- Electroporation and mechanoporation
  - How far advanced is GMP electroporation today? Can it stand up to viral vectors from an efficiency/cost perspective?
  - How do the various established and emerging electroporators and mechanoporators on the market compare?
- Extracellular vesicles (including exosomes)
- Plasmid/dbDNA
- Transposons (e.g. Sleeping Beauty)
Non-viral versus viral gene delivery in the context of gene editing therapeutics – weighing up the options and their pros and cons

Gene therapy CMC & analytics

July

Gene therapy CMC & analytics

Lauren Drouin

Lauren Drouin, Director, Analytical Development at Alexion, AstraZeneca Rare Disease

Tools for characterizing and measuring empty-full-partially full capsid ratio in the final vector product
Understanding packaged DNA (in capsid) impurities
How to adapt analytics to novel AAV serotypes?
What benefits is the new wave of key analytical tools and techniques delivering to gene therapy developers in practice?
- Non-cell-based assay technology
- Next-generation sequencing (NGS)
Optimizing approaches to gene therapy potency assay development
Leveraging viral vector critical quality attributes and critical process parameters to inform manufacturing
- PAT in the gene therapy space
Regulatory considerations for analytical technology changes
Dealing with batch-to-batch variability in gene therapy products
Template-based CMC packages for AAV-based gene therapy
Tools to meet regulatory expectations in gene editing product characterization

New horizons in immunotherapy

August

New horizons in immunotherapy

David Morrow

David Morrow, Scientific Programme Manager, Translational Medicine & Drug Development at EATRIS

Immunotherapy in solid tumors
- Allogeneic cell therapy: how to match autologous cell therapy safety, efficacy, and persistence?
- Extending the durability of response for autologous and allogeneic cellular immunotherapies
- Reviewing immune cell types and next-generation engineered approaches in development
Tools/technology convergence and innovation
- High-content screening, spatial genomics/transcriptomics, and proteomics
- Which emerging tools are driving the translation of new insights into the clinic?
- Harnessing AI and machine learning
- Gene editing and non-viral transfection platforms
State of the art in applications beyond cancer
Latest progress with in vivo CAR-T and other modalities
Lessons from the relative successes and issues encountered by approved CAR T cell therapies
- Enabling earlier line cancer treatment with autologous cell therapies

Scale-up/-out of cell & gene therapy manufacturing

September

Scale-up/-out of cell & gene therapy manufacturing

John Moscariello

John Moscariello, Vice President, Cell Therapy Drug Product Process Development at Bristol Myers Squibb

What does evolution in the biotech and CDMO sectors mean for scale-up/scale-out strategy?
- Is it better to start with small in-house capacity and then scale-up to outsourced manufacture, or vice versa?
Staff sourcing, development, and retention
Technological breakthroughs - and barriers – in the scalability of:
- AAV vectors
- Lentiviral vectors
- Cellular immunotherapies
- Stem cell therapies
- iPSCs
Scalability and automation
- What is the availability of genuinely scalable machinery such as bioreactors in the cell and gene therapy space?
Considerations for validating a scale-out strategy for commercial.
Demonstrating comparability along the scale-up/scale-out process. What steps to take at each stage of development?
How to enable viral vector process intensification at smaller scales?

Fulfilling the potential of gene editing: at the tipping point

October

Fulfilling the potential of gene editing: at the tipping point

Claudio Mussolino

Claudio Mussolino, Group Leader, Genome and Epigenome Engineering at University of Freiberg

Reviewing today’s menu of gene editing tools and platforms. What are the relative pros and cons and considerations for the application of the various options available? (Eg. CRISPR, TALEN, ZFNs, ARCUS, base editing, prime editing, transposons)
Examining the platforms/approaches utilized, and the latest safety and efficacy data:
- In vivo gene editing advanced therapies
  - Clinical safety and efficacy data generated to date
  - What are the most promising approaches to solving the in vivo delivery challenge?
  - Where do we stand with regards to durability?
- Ex vivo cell therapy engineering
- iPSC engineering
How could/should recent regulatory guidance pertaining to the utilization of gene editing be interpreted and leveraged by cell and gene therapy developers?
Where next for innovation in gene editing – how will tomorrow’s platforms and components improve upon todays?
How to make gene editing more ‘commercializable’?
- How/where to reduce costs?
- How/where to increase quality/robustness?
- Addressing IP-related issues and allowing freedom to operate RNA

RNA vaccines and therapeutics shared with Vaccine Insights

October

RNA vaccines and therapeutics shared with Vaccine Insights

Tackling stability, immunogenicity, and cost of materials
Overcoming challenges in mRNA process development andnmanufacturing
Improving delivery with modified LNPs or polymer-based delivery systems
Regulatory considerations

Cell therapy downstream processing & CMC

November

Cell therapy downstream processing & CMC

Key considerations stemming from recent regulatory guidance relating to the stability and release testing of T-cell therapy products
Cell therapy product characterization/analytical development – getting it right early to avoid CMC-related issues later in development
- Is the picture any clearer in terms of the specific measurements required in order to characterize a cell therapy sufficiently for commercialization?
- Potency
- Comparability
- QC and release testing
- How to maximize the value of the CMC-related help available from regulators (eg. in the pre-IND meeting)?
- Unpacking the ICH Q14 (draft) guidance on analytical development – what does it mean for cell therapy developers and manufacturers (eg. in terms of the application of QbD principles)?
Profiling the latest process and analytical innovations – and remaining technology gaps - in specific downstream processing steps:
- Cell harvest and washing
- Filter and concentrate
- Formulation and fill-finish

Clinical trends / 2023 Tools of tomorrow

December

Clinical trends / 2023 Tools of tomorrow

Reviewing the major clinical development stories from the past 12 months and their likely repercussions for the cell and gene therapy field
Profiling key enabling technology innovation trends and advances for the years to come