ExCeL centre, London, 14-15 March, 2023
On the 14th and 15th of March 2023, PMM team members Atiyeh Razavi, Isabela Garcia Pleijlar, and Clotilde Vazquez attended the Advanced Therapies Congress held at the London ExCeL. The Advanced Therapies Congress explored, defined, and attempted to tackle the main challenges currently being faced when it comes to the development of patient access to advanced therapy medicinal products (ATMP). The Congress included presentations, panels, a startup zone, and much more on topics ranging from the latest COVID-19 vaccine development to gene editing. Presentations on these topics were given by world-leading experts and companies. Here, we describe some of the most crucial and innovative therapies in ATMPs that were discussed at the Advanced Therapies Congress.
13:30-13:50 Unlocking the full potential of in vivo gene therapy – Federico Mingozi
Track 5: Cell Therapy & Manufacturing
Written by Atiyeh Razavi
The host, Dr Eric David from BridgeBio, welcomed the attendees, highlighting the changes that have occurred since the last gathering, which was held in May 2019. “The reality and truth of biotech is that it has always been, and always will be a cyclical business”, he said. Many have been fooled by the unusually long period from 2011 to 2022, when in reality the frequency of cyclicality is much greater than that. Despite the ups and downs of the industry, Dr David emphasized that significant advances have been made in gene therapy, making it the most innovative advanced therapy available today. The focus of the conference was on novel platforms for tissues that have not received sufficient attention from a therapeutic perspective.
Dr Federico Mingozzi, Chief Scientist Officer at Spark Therapeutics, the first speaker of the track at the conference, was introduced by Dr David, who highlighted Federico´s unique perspective derived from extensive experience within both academia and industry. Dr Mingozzi has been involved in several first-in-human clinical studies of gene therapy using the adeno-associated virus (AAV) vector platform. AAV has wide applications in gene therapy as it is non-pathogenic and non-toxic. During his talk, Dr Mingozzi discussed the challenges and current issues being faced in the field of gene therapy and focused his presentation on the AAV vector.
According to Dr Mingozzi, it is important to first picture the end result of the therapy in order to determine the right approach to be taken for developing the therapy. In terms of AAV vectors, in his view, it is crucial to focus on the effective delivery of the gene therapy to specific tissues and not just on its engineering. Dr Mingozzi also highlighted the areas of innovation that are important for the field, including improving the vector itself, improvement of the devices that are used for targeting tissues, and the administration of the therapy. However, some challenges still remain. These include selecting the most appropriate delivery methods and determining the amount of the vector to be used.
Dr Mingozzi talked about his successful project to develop a therapy to control the regulation of genes in haemophilia B in a mouse model. This project was initiated at Spark Therapeutics and was then passed on to Pfizer. While AAV vectors have immense potential, it is important to note their limitations, such as their ability to provoke the innate and adaptive immune responses and to induce the production of antibodies against the virus following prolonged exposure.
Spark Therapeutics has devised several solutions to overcome these issues. These include using plasmapheresis, decreasing the half-life of antibodies, and using enzymes to digest these antibodies. In conclusion, AAV vectors have immense potential for use in in vivo gene therapy, but it is important to address their limitations and to “unlock” their full potential by finding ways to better regulate their immunogenicity.
13:30-13:50 Developing cell and gene therapies for commercialization: A large pharma perspective, from idea to manufactured cell therapy product – Elsa Abranches
Track 5: Cell Therapy & Manufacturing
Written by Clotilde Vázquez
Elsa Abranches, Head of Cell Therapy Bioprocess Development and Manufacturing of AstraZeneca, gave a brilliant talk about developing cell and gene therapies for commercialization from a pharmaceutical perspective. Cell and gene therapies are very novel therapies.
Cell therapy involves transferring new, healthy cells into the body to replace diseased cells and thereby modulate other cells present in patient´s body. Cell therapy can be used to reverse disease and restore damaged organs. Understanding disease mechanisms and developing gene and protein technologies as well as advances in cell cultures and manufacturing have allowed the field of cell therapy to see significant growth in the last 30 years.
Some of the fields of medicine that could benefit from the use of cell and gene therapy are cardiovascular, renal, and metabolic diseases, where pluripotent stem cells could be used as therapeutics. Immune cell therapies could help to restore the balance of endogenous cells in certain respiratory and immunology conditions. It may also be possible to use these types of therapies to treat other types of conditions. Elsa stressed that collaboration between scientists, medical professionals, and the commercial sector is essential when trying to accelerate of the development of cell therapies.
The session focused on the use of cell therapy for heart failure. Heart failure occurs when the heart is unable to pump sufficient blood. Human Ventricular Progenitor cells (HPVs) have been proposed as a regenerative cell therapy for the treatment of heart failure. AstraZeneca has tested the use of HPVs injected into the heart to determine whether these can differentiate and integrate, leading to the regeneration of new functional cardiac tissue. A preclinical study has demonstrated that HPVs can promote the regeneration of healthy cardiac tissue and reduce scarring following a heart attack.
HPVs can be differentiated from pluripotent stem cells. (Poch et al., 2022 Nature Cell Biology). They have been found to migrate to the injury site area in heart slices ex vivo. Furthermore, in an in vivo model, they were also found to migrate to the cardiac injury site. They muscularized and reduced the injury site, alleviating the cardiac function decline.
Challenges remain in the development of cell therapies, particularly in the area of cardiac regeneration. Some challenges arise at different stages of the manufacturing process. When talking about cell therapy manufacturing, it is important to be aware of which specific types of cells to use, risks in manufacturing pluripotent stem cells, and ensuring that there are GMP (good manufacturing process) protocols in place.
There are many factors to take account of when developing cell therapies. These include the viability and vascularization of the cell, retention and integration, immunogenicity, rejection, tumorigenicity, cell potency, and the type of animal model used. These are all important factors that have a significant impact on the quality and viability of developing these therapies. Health and economic implications must also be considered in addition to regulatory requirements.
The process of developing a cell therapy involves selecting the right cell for differentiation, providing enough cells to enable engrafting, and ensuring that the cell population is pure in order to avoid the risk of a teratoma (a common tumor where stem cells differentiate into different types of tissues). It is also essential to develop robust quality control processes for reproducibility of the product. A key factor to bear in mind when developing novel therapies and products in general, is the importance of keeping the endpoint in mind and developing the process end-to-end, in order to be able to bridge between research and clinical applications more effectively.
A final point that was made in the talk, and that I very much agree with, is the need to work in a collaborative way. Collaboration platforms that create an environment that enables innovation and advances in the area of healthcare are essential, to provide and facilitate that a much-needed bridge between academic research and the clinic.
Particulate strategy for cell gene therapy products – Irina Kadiyala
Track 1: Cell & Gene Therapy Development & Commercialisation
Written by Atiyeh Razavi
This talk was given by Dr Kadiyala, a biophysics specialist with over 22 years of industrial experience. She is currently leading the Heme Process Development group at Vertex Cell Gene Therapies. In her presentation, Dr Kadiyala discussed the challenges of producing cell-based products at pharmaceutical companies. Vertex is responsible for manufacturing six marketed products related to cystic fibrosis, a condition that causes sticky mucus to build up in the lungs and digestive system. Manufacturing these drugs requires meticulous control and regulation.
Dr Kadiyala highlighted that one of the main challenges when working with cell-based products is that sterilizing cells is not an easy task, as filters and radiation cannot be used. Therefore, particulate matter, which consists of solid or liquid particles present in the air, could potentially end up in the products. Removing these particulates is crucial, as they can negatively affect the quality of the product as well as its efficacy and can disturb the establishment of acceptable quality limits. However, there is currently not enough regulatory guidance on how to deal with particulates in cell gene therapy products.
To address this challenge, Vertex has developed comprehensive strategies for detecting and eliminating particulates from their batches. The process begins with thorough particulate characterization and identification using advanced techniques and instruments. This allows Vertex to identify the specific type of particulate present in the production environment. Once the particulates are identified, Vertex conducts a detailed risk assessment to evaluate the potential impact on product quality. This assessment considers factors such as the size, composition, and origin of the particulates. Based on the risk assessment, they then implement appropriate measures to reduce or eliminate the presence of particulates.
Vertex employs a combination of preventive and corrective actions to minimize particulate contamination. Preventive measures include modifications to the production process, such as optimizing equipment design, implementing strict cleaning protocols, and ensuring a controlled manufacturing environment. These modifications aim to reduce the generation and introduction of particulates during the production process.
In addition, Vertex utilizes advanced particulate removal technologies. These technologies can include various filtration methods, such as depth filters, membrane filters, or combination systems, which are designed to capture and remove particulate matter. The selection of the appropriate filtration method depends on the characteristics of the particulates and the specific requirements of the product. They also regularly monitor and evaluate the effectiveness of their particulate removal strategies through rigorous testing and quality control measures. This ensures that the products meet the required specifications for purity and effectiveness.
Dr Kadiyala emphasized that particulate removal is a challenging yet essential aspect of drug product manufacturing. Even products that are listed as particulate-free may still contain particulates, albeit within acceptable limits. Therefore, Vertex and other pharmaceutical companies continuously strive to improve their processes and technologies to ensure the highest level of product quality and patient safety. For more specific information about Vertex’s particulate removal strategies and their commitment to maintaining product quality, you can visit their official website. The website provides detailed insights into their manufacturing practices and technologies employed for particulate control in cell-based products.
17:00-18:00 Cell Therapy Panel
The pros and cons of alternative allogeneic approaches – Ross Macdonald, Raphael G. Ogmar, Jonathan Fisher, and Miguel Forte
Written by Isabela Garcia Pleijlar
The first day of the Congress concluded with a panel of speakers discussing the pros and cons of alternative allogeneic approaches. The open discussion was held between the four speakers, Ross Macdonald, Managing Director and CEO at Cynata Therapeutics Ltd., Raphael G. Ogmar, CEO and Co-Founder of NKILT Therapeutics, Jonathan Fisher, paedriatic oncologist at UCLH NHS Foundation Trust, and Miguel Forte, the president Elect, ISCT, entrepreneur in Residence at AdBio Partners.
Miguel Forte opened the discussion with a brief summary of the pros and cons of autologous transplants and the concept of allogeneicity. He stated that one benefit of autologous approaches compared to allogeneic approaches is that there is no rejection from either the host or the cell. However, he mentioned that autologous cells can be very limited depending on the ability to generate the cells, and the time required to provide this off the shelf. He explained that the main aim of allogeneicity is to have cells that can be easily sourced and which are available off the shelf for use in any patient.
Miguel Forte then passed the microphone to Ross Macdonald, who said he had been spoiled because for many years he has worked with mesenchymal stem cells (MSCs) where the problem of immunorejection is not a particular impediment in the MSC context. However, he emphasized that it comes down to the product itself, stating that, “the best donor is a healthy donor”. In an autologous setting, the donor is compromised. In his view, it does not make sense to use cells from a patient who already has a profound disease to treat them. He supported the idea that autologous therapy will always be an option for practitioners, but believes that in the MSC context, the allogeneic ‘off the shelf’ approach is the future.
The next speaker was Raphael Ogmar, who began by acknowledging that autologous technologies are an incredible source of knowledge. He believes that it is an approach that scientists should continue to investigate. The biggest challenges to the use of this approach are access and cost. Raphael Ogmar pointed out that at the moment, using an allogeneic approach means that a patient’s outcome is somewhat sacrificed, but that the current challenges with it will likely be overcome in the future. He emphasized that autologous approaches, as much as efficient, won’t make much of a difference if it can only be delivered to a handful of patients. He concluded that despite allogeneic off the shelf approaches being the future, we should not position ourselves against autologous technology. The main issue and main priority should be to improve access to therapy rather than the type of therapy being used.
Jonathan Fisher spoke next, moving the discussion into the context of oncology. He stated that using an allogeneic approach could help to treat hard to manage patients and difficult cases. With solid tumors, it is possible to perform surgery or radiotherapy, which are not possible in the case of leukemia. Therefore, in his view, the main aim is to tailor the characteristics of the therapies to the target. He emphasized the need for employing a well thought-out and careful design, and not a one-size-fit-all approach. Similarly, to Raphael, Jonathan positioned patients in the center, stating that he believes that the drive will be in picking the right approach in the right setting, rather than just choosing one approach over the other. As evidence to his argument, he mentioned that autologous approaches have been working very well in the context of hematology, as well as for solid tumors (depending on the stage of the cancer). However, he does believe that we will begin to see the development of more allogeneic approaches and believes that this approach gives scientists more tools to work with. He agrees that we should appreciate the value of autologous and understand the evolution of the business model and therefore strive for the allogeneic approach. In conclusion, all four speakers provided their opinion with very different and interesting views. All agreed that the allogeneic approach seems to be the future.
1:30pm-1:50pm Xenotransplantation from bench to patient – Eliezer Katz
Track 8: Innovation Showcase
Written by Isabela Garcia Pleijlar
On the second day of the congress, the innovation showcase track began with the history of xenotransplantation. Xenotransplantation is the transplantation of any cells, tissue, or organs that are derived from a non-human donor. A very clear explanation was provided by Elizier Katz, the chief Medical Officer at eGenesis, who began his presentation by describing the current problems with traditional organ transplantation. He gave us an insight into the discrepancy between the high number of end term organ disease failure patients that are currently on waiting lists for organ transplants, and the low number of patients that actually live long enough to receive an organ transplant. Currently, only around 40% of patients that are on waiting lists receive a transplant organ before it is too late. This underscores the urgent need for further research into alternatives such as xenotransplantation.
eGenesis’s approach to xenotransplantation is to utilize porcine cells (cells derived from pigs), to efficiently clone and produce animal donors. There are still several challenges that need to be overcome to achieve successful xenotransplantation. One of these challenges is hyper-acute rejection. It is reasonable to question the possibility of receiving an organ from an animal such as a pig as there is significant genetic variability between humans and animals. However, in 1990 scientists identified the main xenoantigens in pigs to which the human immune system reacts against. Antigens are molecules that are recognized as foreign by the immune system, triggering it to produce antibodies against them. If a person´s immune system attacks the transplanted organ due to the detection of such antigens, then the immune system and the body will reject the organ. The term xenoantigens refers to antigens that may be shared between species. Therefore, the discovery of the main xenoantigens was critical to addressing hyper-acute rejection. This discovery, together with the development of novel gene-editing technologies such as CRISPR-Cas9, has allowed for the knockout of the three main genes that encode these xenoantigens. Think of CRISPR-Cas9 as biological scissors that genetic material to be altered either by inserting, inactivating, or deleting particular genes. Therefore, modifying or removing the genes that encode xenoantigens can eliminate the problem of hyper-acute rejection.
A further challenge encountered when attempting to transplant animal organs into humans is that of zoonosis, or the transfer of animal pathogens into humans. This is a real and dangerous problem, as we have all been made aware of through the COVID-19 pandemic. To address this potential risk, eGenesis has found a way to inactivate the endogenous retrovirals, consequently mitigating the risk of retroviral infection. In other words, there is no risk of getting infected. Similarly to the way in which the xenoantigen genes are knocked out, CRISPR-Cas9 could be used to inactivate retroviruses, to generate a clone that is free of this risk, which could potentially serve as a viable donor for humans.
In order to achieve successful xenotransplantion, scientists first engineer the genome of a single porcine cell through CRISPR-Cas9. The engineered cell is then expanded, and next generation sequencing (NGS) is used to ensure that the cell carries the desired gene and protein expression so that hyper-acute rejection and zoonosis is prevented. The nucleus of the engineered cells is then introduced into an enucleated oocyte that is artificially activated and subsequently transferred into a surrogate. In theory, if these steps are successful, the cloning should result in the production of efficient animal donors that do not contain animal pathogens and which will not cause immune rejection when their organs are transplanted into humans. It is important to note that long term survival post-transplantation has not yet been achieved, and further research is still needed to make this approach a successful form of personalized medicine.
13:50-14:10 Cord blood banking in Europe – challenges and opportunities – Tomasz Baran
Track 7: Cord Blood
Written by Clotilde Vazquez
Tomasz Baran gave an interesting talk about the process of cord blood banking. Another presentation by Joanne Kurtzberg, entitled, Treating neurological conditions in children with cord blood and cord tissue derived therapies, at the Cord Blood track in the congress outlined the potential benefits cord blood and cord tissue derived therapies for treating non-genetic neurological diseases such as leukodystrophies, multiple sclerosis, autism, and cerebral palsy.
When the speaker “asked” ChatGPT what the challenges and opportunities of cord blood banking were, ChatGPT gave a few interesting answers including some that were inaccurate. One of the main difficulties currently faced by cord blood banks in Europe is regulation. Cord blood banking is highly regulated and complying with all of the regulations can be challenging. As Dr Baran mentioned, in some countries, family banks are only allowed to operate at private hospitals. Public awareness is also an issue, as many people do not know about the benefits of cord blood banking and this makes it difficult for cord blood banks to attract new customers. Furthermore, news headlines regarding cord blood banking can be confusing and the situation and regulations in place in each country differ, which can make it difficult for parents to decide whether or not to bank cord blood.
On the other hand, cord blood banking holds many opportunities. As more families become aware of the benefits of cord blood banking, the demand for these services is expected to increase. However, this still needs to overcome the challenges of getting the right information regarding cord blood banking across.
Research and development can benefit significantly from cord blood and this is an opportunity for cord blood banks as we move towards the era of personalized medicine and cell and gene therapies. Cord blood and tissue, which contain mainly hematopoietic stem cells, can be a starting material for the development of many new therapies, especially for the treatment of autoimmune diseases and hemato-oncology.
Challenges include the debate over private versus public banking. In the US, cord blood and stem cells are used more widely in the clinic than in Europe. While there is a great deal of high-quality research taking place in Europe, it tends to be in the US that most of the knowledge gained from this research is translated into actual treatments as there is far more investment and openness to these novel approaches and clinical trials in the US, as was mentioned in the panel “Biotech financing, where are we going in 2023”.
Further potential challenges faced by cord blood banks include a decreased number of births, which reduces the number of clients for banks, as well as the negative perception of consumers towards cord blood banking in relation to privacy and cost. However, most of the issues related to public awareness could be solved by providing better and more accurate information and via effective marketing campaigns. This could increase the demand for cord blood banking.
Much of the debate regarding cord blood banking comes from the “public vs family” dispute. Tomasz stressed that it is important to move away from a “versus” approach and towards an “and” approach, where both “public and family banking” work together collaboratively. At present, around 95% of cord blood is discarded. Proponents of cord blood banking believe that parents should be informed about all the cord blood opportunities available so that they can make an informed decision. They also advocate that while donation for public health is encouraged and should be encouraged, a family´s rights to choose should also be respected and that we should start to work towards hybrid models of cord blood banking where possible.
FamiCord is a cord blood bank that offers high quality cord blood banking. They work closely with local laboratories and authorities and offer and implement public, private and hybrid banking. FamiCord is currently developing new business lines to foster stem cells therapies. They have used WJ-MSC (Wharton Jelly’s Mesenchymal Stem Cells) to treat cerebral palsy and have treated 152 children with an allogeneic dose of WJ-MSC (1×106/kg of brain weight). The therapy was found to be both safe and well tolerated and improvement was observed, correlating with age. (Chroscinska-Krawczyck, Zdolinska-Malinowska; submitted; Int.J.Mol.Sci. 2023)
According to Tomasz Baran, cord blood banking represents “one more chance” to treat rare disorders, whether it applies to oneself, a family member or to an unknown recipient of the material, depending on the banking approach. Ultimately, cord blood banks are essential for the development of novel therapies and personalized medicine. However, different challenges and opportunities are faced by cord blood banks depending on the country that they are based in.