Heterogeneity of CT products persists as the industry lacks the required analytics to define and control product quality and function
This year’s ISCT2022 conference saw industry heavy weights, small biotech, academic leaders, clinicians and regulators converge in San Francisco’s SoMa district to consider emerging innovations and persistent challenges in the Cell and Gene Therapy (C>) Industry.
Spanning the C> translational pathway, the programme offered a mix of sessions focused on scientific innovation and first-in-human through to clinical acceleration, commercialisation and patient access. The conference kicked-off with over 20 roundtables, facilitating focused discussion between expert panels and audience members on industry pain-points like potency assay development and Mode of Action (MOA), starting materials, cold chain management, supply chain and work force development. ValitaCell attended to take in the latest scientific and technological advanced, bringing along a poster on our CELLIMAGE work with partners Waters to spark discussion on advanced cell therapy characterisation tools.
Across this expansive scope, a recurring theme emerged – heterogeneity is challenging the industry at every stage of product development and commercialisation, from product quality to manufacturing processes and regulatory guidance.
Tackling Heterogeneity in C> – MSCs and EVs
Mesenchymal Stem/Stromal Cell’s (MSCs) were well represented this year with sessions that focused on Mechanisms of Action (MoA) across indications, in-vivo activity and the impact of patient biology on MSC responsiveness. The MoA debate kicked off on day one with a roundtable to consider the role of efferocytosis versus Extracellular Vesicles (EVs) in MSC paracrine effects. Later in the programme, Professor Tracey Heng of Monash University presented her most recent data on the role of apoptosis in MSC therapeutic function, demonstrating attenuated immunosuppressive activity of apoptosis-resistant MSCs in an in-vivo lung inflammation model. Sara Enes of Lund University closed the session with data to demonstrate disease specific MSC activation in lung disease models.
Historically, a lack of clarity around MoA has hampered efforts to develop the functionally relevant potency assays that are needed to improve manufacturing. Potency assay development, novel MSC biomarkers and the persistence of heterogeneity in trialled MSC products dominated discussions around translation to the clinic, with calls for enhanced rigour in MSC product characterisation to improve phase I/II and phase III comparability. A good potency assay should allow for transfer of manufacturing facility with demonstrated consistency of product function – and this should be developed as early as possible!
Saturday’s Signature Series ‘Therapeutic advances with native and engineered Human EVs’, was a collaborative effort between ISCT and the International Society of Extracellular Vesicles (ISEV), that highlighted the scope of exciting work ongoing in the EV field. UK ESSEN’s Dr Bernd Giebel kicked off the series with a view on the functional heterogeneity observed across different MSC-EV preparations, outlining recent efforts to resolve this issue with immortalised MSCs. Randolph Corteling followed with a description of ReNeuron’s stem cell-derived EV production platform, leveraging multiple proprietary immortalised lines or iPSCs to provide a consistent EV product. An exciting development from ASTAR’s Sai Kiang Lim came in the form of an ELISA-based potency assay for quantification of functionally relevant MSC-EVs in a Psoriasis model.
It is no surprise that heterogeneity observed at the cellular level translates to variation in the therapeutic impact of MSC derived EVs, and while various immortalisation strategies can and are being exploited to provide a more robust EV production system, work continues to elucidate what cell features are driving this variation.
Tackling Heterogeneity in cell processing – The power of Automation
The 4 day conference offered scientific talks that focused on numerous cell, gene and extracellular vesicle therapy types targeting many different indications, and hammering home the message that this industry is not simply following in the footsteps of therapeutic protein production, where efforts largely focused on development and optimisation of a relatively uniform process suitable for multiple drugs, like monoclonal antibodies (mAbs). Rather, the C> effort is split across diverse therapy types, many of which have specific development and manufacturing requirements.
Vendor showcases and the buzz of the exhibition hall highlighted the diversity of manufacturing platforms and technologies available to therapy developers, as well as one of the biggest questions they face when developing their process – which technologies are best for my product and how to I integrate them?
Cellares and Staubli Robotics sponsored one of the first roundtable sessions of the event, setting out their vision for the future of cell therapy manufacturing as modular automated process platforms capable of flexible end-to-end processing. This concept boasts many advantages over manual processes. The design and cost of a manufacturing facility, as well as the requirement for highly trained personnel can be reduced significantly when systems are closed and require less clean room space for manual processing. The modular system approach allows for scale, flexibility and optimisation of process scheduling leading to less downtime. A significant advantage in the proposed solution, is automation of data capture and full digitization of the process – saving hundreds of pages of documentation per single therapy batch. The Cellares mission, outlined by CEO Fabian Gerlinghaus, is to identify the most effective integration paradigms and enable the use of these process platforms as early as possible in the development and clinical trial process, reducing the requirement for scaling related process changes and expensive clinical bridging studies. Looking to the future, Fabian hopes to leverage integrated PAT technologies and see more automation of QC assays. While current technologies enable sampling through flow for cell count and viability assessment – the challenge and ambition has been set to bring more powerful QC assay methods in line and enable real time analysis of quality attributes relevant to function.
Tackling Heterogeneity in C> Regulatory Guidance
Chemistry, Manufacturing, and Control (CMC)-focused sessions provided attendees with the opportunity to learn from the industries experience so far, and take in advice from regulators on common pitfalls and potential solutions. The ‘Let’s talk particulates: Risk Assessment and Mitigation Practices for CGT Product Development’ roundtable saw a lively discussion unfold around current guidelines on particulates in biological drug preparations, and whether these are suitable for the diverse therapy types being developed under the C> umbrella. The challenge lies in understanding the real risks associated with particulates, how and when to measure them, and how best to demonstrate safety. Therapy sponsors and manufacturers are looking for a unified and defined approach to understanding and controlling particulates in C> manufacturing, highlighting divergence is advice within agencies – let alone between them. Calls for consistency and clarity in regulatory reviewers approach and decisions making processes were echoed at last week’s American Society of Gene and Cell Therapy (ASGCT) meeting.
Overall, ISCT2022 successfully fostered discussion across the length of the C> translational pipeline – which we believe is a key ingredient to progress in this sector. ValitaCell is looking forward to contributing to the next wave of innovation to drive this sector forward.
A big thank you to the ISCT team who organised a great event!