How can we improve delivery of DNA to T cells?
How can we increase the packaging capacity of AAV?

Generation of CAR-T cells to treat cancer is a major growth area. CAR-T treatments for non-oncogenic diseases will also increase in the coming years. Genetic manipulation is required to craft more potent and safe therapies. However, T-cells and other immune cells of interest suffer from high toxicity to exogenous DNA. This limits both the size of cargo sequences we can introduce into a T-cell and limites the number of genes we can introduce, thereby hampering development of truly novel highly edited CAR-T therapies. Overcoming this DNA toxicity burden and improving our ability to manipulate T-cell genomes will allow accelerated development of these therapies.

One platform to overcome DNA toxicity is the use of AAV to introduce new sequences. However, packaging size within AAV genome is limited. If we can increase this capacity this will again allow improved manipulation of primary T cells for therapies

How can we develop “fail-safe” kill (suicide) switches for cell therapy products that kill 100% of cells?

Current kill swiches and sufficiency switches (eg iCasp9) do not provide complete control over cell therapies. Minimising such escape is an important part of the journey to completely safe cell therapies.

How can we manipulate allogeneic cell therapies to prevent rejection induced by the host alloimmune response?

Allogenic therapies predominatly rely on removal of B2M gene to ablate surface expression of HLAs. This has unwanted side effects in some settings. What alternatives are there?

How can we develop cells as therapeutic delivery vehicles?

Cell Therapies to attach cancers or replace damaged tissues are set to revolutionise medicine. Could they also replace admistration of biologic therapies by localised in-person drug production? The development of theranoistic sense-and-respond systems could trigger new ways to treat chronic disease.

How can we improve pre-clinical models to better predict the safety of Cell therapies prior to entry into the clinic

Current in-vivo models all have compromises for understanding biodistribution, responses and toxicities in humans. How can we develop better models for improved translatability for living drugs?

When developing cell therapies, how can we ensure selection of the optimal product? How do we test for and define key attributes critical for clinical success?

What mechanisms can we exploit to eliminate AAV from host cells if necessary (i.e. generate an antidote towards AAV gene therapy toxicity)?

AAV provides an excellent platform for introducing new genetic sequences into a variety of cell types. However, the genome is episomally maintained and can remain for years. Under certain settings, removal of the AAV genome is desired or required. How can we do this? (e.g. impact of manufacturing process; capsid; cassette design; dose; patient co-morbidities; route of administration; role of direct toxicity versus immune response)?

How can we improve therapeutic cell persistence and homing for solid tumours? What would make the ideal solid tumour preclinical model (in vitro, in vivo, or ex vivo) to build confidence for regulators that a new therapy would be safe and/or effective?

CAR-T cell therapies to treat cancers work well in a liquid tumour setting, but less so in the solid tumour setting. One reason for this is the ability of the CAR-T cells to find the tumour in the body, to remain at the tumour site, and to proliferate to efficacious levels to elimate the tumour. How can this homing and persistance be improved? How could throughput be increased at preclinical stages to assess more therapies at an earlier stage?

Cell and gene therapies (CGT) are likely to become a viable option in the step care of patient-centred treatments in the near future. Patients will receive multiple initial interventions and this intersection of therapies will be difficult to track and coordinate for the many stakeholders involved in their care. Add to this that GMO requirements will mean patients will need to be followed up for decades. How can we bridge the technology gap and integrate the data we need? How can AI/ML help us? What needs to be considered to make CGT the vanguard of patient care (and not the last resort!) when developing the digital / data ecosystem alongside the potentially curative bespoke biology?

ATMPS Ltd have developed the award winning Hataali software platform to track CoI, CoC and CoE for CGT. We have shown this digital enabler can treat many more patients within the existing physical CGT infrastructure as compared to legacy paper based methodologies. We believe that even more can be done by co-creating the digital and data architecture alongside the cell line and biological innovation.
We are also working on ensuring our platform is interoperable with novel Decentralised Identity technologies, ensuring every individual / patient has access, control and say over their data – a genuine mechanism for human data rights and real patientcentricity!

What will it take to bring cell therapy to the masses? What needs to change for these life changing therapies to become available to the many?

Hub and spoke model or localised distribution? Autologous or allogeneic? Reimbursement models? Challenges of manufacturing at scale?

What do academics see as the key challenges to translating ATMP-based therapeutics or related technology? What are the current bottlenecks and what are the future needs that could enable progress in Cell & Gene Therapy?

Technologies could include ATMP manufacture process or analytics.

Can we use the precision of gene therapy approaches to develop a multi-target treatment for complex diseases? What are the pre-clinical, clinical, and regulatory considerations we need to make for a multi-target therapy?

With our proprietary technology we are exploring the possibilities of developing multi-target gene therapy for complex neurodegenerative diseases. We have identified potential candidates and are developing pre-clinical evidence of efficacy.

What research is being conducted in the use of single domain ab such as VHH in C&G therapy?

Isogenica is a Cambridge based biotechnology company with a focus on developing therapeutics based on single domain antibodies (VHHs).

How can we improve therapeutic cell persistence and homing for solid tumours? What would make the ideal solid tumour preclinical model (in vitro, in vivo, or ex vivo) to build confidence for regulators that a new therapy would be safe and/or effective?

CAR-T cell therapies to treat cancers work well in a liquid tumour setting, but less so in the solid tumour setting. One reason for this is the ability of the CAR-T cells to find the tumour in the body, to remain at the tumour site, and to proliferate to efficacious levels to elimate the tumour. How can this homing and persistance be improved? How could throughput be increased at preclinical stages to assess more therapies at an earlier stage?

With prospects for modification of either protein-coding DNA regions, or non-protein coding transcribed regions of the genome using genome engineering in patients, what are the main technical hurdles to overcome for efficient targeted delivery to the ‘right cells, at the right time’ and what non-clinical safety data will be critical and compelling in order to gain approval for clinical entry?

A growing number of clinical trials are underway to evaluate the efficacy and safety of modifying patients’ cells in vivo using single course gene editing, such as CRISPR/cas9 (ATTR amyloidosis; NCT04601051), base editors (heterozygous familial hypercholesterolemia; NCT05398029), with many more genome engineering technologies poised to be assessed (TALENS, Zinc fingers, prime and RNA editors).

Is there a role for high throughput screening in Cell & Gene Therapy?

How does scaling of experiments enable advancements.

What are the advantages / disadvantages of single cells vs cell microenvironment cultures?

Scale versus complexity; regulatory and technical performance considerations; etc…

What do academics see as the key challenges to translating ATMP-based therapeutics or related technology? What are the current bottlenecks and what are the future needs that could enable progress in Cell & Gene Therapy?

Technologies could include ATMP manufacture process or analytics.

Novel delivery technologies to enhance biodistribution of in vivo gene therapies

Limited biodistribution has been observed in the clinic with in vivo gene therapies. How should we target novel tissues, or existing tissues better, or access novel cell types?

What are the advantages / disadvantages of single cells vs cell microenvironment cultures?

Scale versus complexity; regulatory and technical performance considerations; etc…

What will it take to bring cell therapy to the masses? What needs to change for these life changing therapies to become available to the many?

Hub and spoke model or localised distribution? Autologous or allogeneic? Reimbursement models? Challenges of manufacturing at scale?

What mechanisms can we exploit to eliminate AAV from host cells if necessary (i.e. generate an antidote towards AAV gene therapy toxicity)?

AAV provides an excellent platform for introducing new genetic sequences into a variety of cell types. However, the genome is episomally maintained and can remain for years. Under certain settings, removal of the AAV genome is desired or required. How can we do this? (e.g. impact of manufacturing process; capsid; cassette design; dose; patient co-morbidities; route of administration; role of direct toxicity versus immune response)?