On the 5th of October, 2021, PMM team members Celeste Cohen, Shannon Hylton, and Aaron Logsdon 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, interactive roundtables, 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.
10:05-10:25 – Cell-based COVID-19 vaccine – Hans Keirstead
Written by Aaron Logsdon
The very first presentation of the congress kicked off on a very topical note: COVID-19. I know what you’re thinking; “I cannot bear to listen to another moment of depressing news”. Dr Hans Keirstead, the CEO of AIVITA Biomedical, Inc. Dr Keirstead and his team are developing a COVID vaccine enabling kit for producing personalized COVID vaccines onsite at hospitals.
Dr Keirstead says that the theory behind his vaccine enabling kit is simple. An individual such as a nurse can use a syringe to draw blood from the patient. The immune cells from a patient are mixed with the infamous COVID-19 spike protein by a nurse. Once ´educated´, the cells are infused back into the patient with the ability to recognize and kill the SARS-CoV-2 virus.
Training in the use of a syringe is all that is required to operate the kit. Dr Keirstead claims that his vaccine approach is more personalized and uses less foreign material than other COVID-19 vaccines. Therefore, AIVITA’s vaccine-enabling kit causes fewer side effects such as colds. The inexpensive materials utilized, also make the kit more ideal for widespread use in emerging nations. No COVID symptoms have been reported in trials as yet, and the kit is currently entering into a phase III trial.
10:30-11:00 – Learnings from the COVID outbreak and how to move forward into a brighter 2022 – Peter Marks, Troels Jørdansen, Miguel Forte and Amir Hefni
Written by Shannon Hylton
It’s April 2020, and you are scrolling through the newsfeed flooded with headlines of COVID-19. You’re feeling overwhelmed and confused but continue to scroll with the hope that somehow, somewhere, an article will relieve your sense of confusion. If this was your experience of last year, fear not, for you are not alone.
2020 was a year where everything halted due to the COVID-19 pandemic. From routine commutes to the office to Zoom meetings in sweatpants, and for schools, energetic playgrounds turned to deserted concrete, hopscotch, and online learning. Our lives were turned upside down because of Covid-19. So, what did the COVID-19 pandemic teach the science and pharmaceutical industries, and how will they advance for the future?
“The success behind the development of the COVID-19 vaccines was due to the collaboration and teamwork amongst scientific and regulatory agencies,” says Amir Hefni (VP, Novartis). Regulation is a sizeable barrier to the successful delivery of pharmaceutical products and can be long and frustrating. Worldwide, there are currently 180-200 pharmaceutical agencies whose role is to ensure the safety and efficacy of medicinal products.
With the fast-tracking of COVID-19 vaccines, there could be possible changes made to regulatory frameworks to guarantee a smoother transition from bench to market, believes Peter Marks of the FDA. One possible method could be to homogenize the language that is used when assessing regulatory checkpoints. Homogenization will help to streamline global regulatory processes, but requires collaboration between different economies, making this process much easier said than done. A further possible change would be to provide multiple methods of drug testing rather than a single, unilateral approach. As different patients respond differently to the same drug, this strategy aims to be more patient-centered rather than focusing solely on being commercially viable (using a single testing method).
´Pricing strategy´was also a buzzword for the discussion. “What is the cost of x-disease to society if there was no x-drug?” questioned Troels Jørdansen (CEO of Glycostem Therapeutics). There are various factors to be considered when determining the price of a medication. However, despite the need for an innovative pricing model that everyone can agree on, and research shows that countries and companies have varied interests, each with different priorities. Therefore, until there is a resolution of differences, or compromission, the pricing strategy will continue to present a significant challenge to both businesses and economies as a whole.
So, where does the future of cell and gene therapies lie? As a consensus, each speaker agreed that the chronic disease market is the golden ticket. Developing CAR-T therapies to treat diseases such as Huntington’s and Parkinson’s disease will be game-changing. Miguel Forte (CEO of Bone Therapeutics) stated CAR-T therapy is currently a service. Provided that innovation can turn CAR-T therapy into a product rather than a service, many more patients will have the chance to receive CAR-T treatment using fewer resources.
These speakers spoke with an air of certainty. It wasn’t a question of if these changes will happen, it’s a question of when.
11:00-11:30 – Tackling large-scale, commercial regulatory challenges – Peter Marks and Janet Glassford
Written by Celeste Cohen
Peter Marks of the FDA and Janet Glassford, Senior Quality Assessor at Medicines & Healthcare products Regulatory Agency (MHRA), gave us a glimpse via Zoom, of the main challenges and prospects being faced by the regulatory industry. The main focus of the discussion was a need for collaboration between regulators, sponsors, and developers. The speakers particularly encouraged developers to use available resources ranging from specific measures to guidelines on regulatory requirements. The use of these resources would increase the success of products and speed up the process of regulatory approval, maximizing approvals as the ultimate goal.
Peter Marks and Janet Glassford also underlined a need for more resources within regulatory institutions, citing 25-50% of understaffing in cell & gene therapy branches. The pandemic had a significant impact on this, making recruiting particularly challenging.
COVID-19 has encouraged the regulatory industry to consider developing more efficient online systems for processes such as patient follow-up during clinical trials. Although some patient follow-ups must be in person, many can be carried out just as efficiently online, representing signifcant savings in terms of both time and cost. If clinical trials for a novel therapy are being conducted in several different countries, the use of such systems could facilitate faster product approvals. The pandemic also allowed for conducting large-scale trials and increased funding for the development of mRNA vaccines. These factors have resulted in significant advances in the field of mRNA vaccines, showing us just how much can be achieved with the proper resources and incentives.
12:00-13:00 – Roundtable 1: Gene therapy manufacturing, patient associations and market access – Angela Columbano
Written by Celeste Cohen
Angela Columbano, Head of Business Development and Partnership at Genethon, started by presenting the company as a non-profit organization created 30 years ago by the French patient association, AFM Telethon. Genethon develops gene therapy for rare diseases from the bench to patients, with a development team and a clinical team.
The main challenge that was highlighted by Genethon as well as other companies that participated in the roundtable discussion, was the cost of gene therapy manufacturing. Some treatments currently cost upwards of a million euros per dose. What is the solution to this? Collaboration between patient associations, charities, and market providers is urgently needed to increase access to gene therapy by patients. There is also the hope of reducing manufacturing costs by increasing productivity. However, the economic viability of investing in expensive treatments for ultra-rare diseases is not known.
By working with charities and patients, gene therapies are becoming more widely promoted and incentivized, increasing production and potentially reducing costs. Patient associations play an essential role in helping to improve access to gene therapy innovations as they can educate patients and lobby pharmaceutical companies to encourage investment. This is particularly true when it comes to ultra-rare conditions where affected populations may be too small to incentivize investment into the development of treatments. Angela Columbano expressed the importance of patient associations as a bridge between the pharmaceutical industry and patients.
14:00-14:30 – Precision medicine informed immune-oncology – Roy Baynes
Written by Aaron Logsdon
That title sounds like a mouthful, but precision medicine is simply a treatment that is tailored to a patient’s specific characteristics and needs. Immune-oncology is an approach to the treatment of cancer that uses the patient’s own immune system to help to fight and elminate cancer cells from their body. Merck Sharp & Dohme (MSD) is one example of a pharmaceutical company that is using precision medicine to inform their immune-oncology.
Dr Roy Baynes, the Senior Vice President of MSD, spoke extensively of MSD’s research into pembrolizumab. Pembrolizumab is an antibody that prevents interactions between the molecules, PD-1 and PD-L1, on immune cell and cancer cell surfaces. When such interractions are left uninterrupted, they can result in the shutting down of our immune cells.
MSD often found patient’s whose tumours had many mutations responded better to pembrolizumab therapy than patient’s whose tumours had fewer mutations. Dr Baynes stated that such MSD uses this genetic information to help them to determine which cancer patients are more likely to benefit from pembrolizumab than others, thereby personalizing treatment.
MSD’s characteristic informed approach of immune-oncology has led to 41 US-based approvals of pembrolizumab treatment to date.
14:30-15:00 – Base editing – An innovative and safer gene editing solution for advanced cell and gene therapy – Jesús Zurdo
Written by Celeste Cohen
Horizon Discovery is a company that develops products and techniques for use in research and therapies. Dr Zurdo (Head cell, Gene therapy & Bioproduction at Horizon Discovery) addressed the current challenges faced in the field of gene editing and its application to cell and gene therapy.
Cell and gene therapies make use of gene modulation technologies, which temporarily modify gene expression, as well as gene editing technologies, which permanently alter genes. Better technology leads to better treatments, and therefore Horizon has focused on developing novel techniques for gene modification.
When it comes to gene modulation, Horizon has developed and combined the SMARTvectorTM and shRNA technologies. These technologies are used together, to insert engineered DNA into cells in order to express shRNA, which is an artificial RNA molecule that targets particular sections of mRNA molecules, silencing the expression of specific genes and thereby preventing the translation of particular proteins.
Horizon’s answer to current gene editing challenges is their Pin-point TM base editing technology, which is a more precise and predictable alternative to existing technologies such as CRISPR. While CRISPR breaks both strands of the DNA molecule in order to edit genes, base editing generates point mutations – specific, single base-pair changes – without creating a double-strand break. This specificity reduces the risk of undesired movements of DNA fragments when editing multiple genes. Base editing also makes gene editing simpler by simultaneously knocking-in and knocking-out genes in a one-step process.
Researchers have used base editing in T cell engineering for CAR-T therapy, a tyep of therapy that uses T cells ( a type of immune cell) to recognize and destroy cancer cells. This method generates more viable T cells with better cell replication and T cell functions than CRISPR does. Researchers have also used base editing in Induced Pluripotent Stem Cell (iPSC) engineering. iPSCs are stem cells that are engineered from differentiated cells that have been collected from patients. The use of base editing yielded higher cell viability and pluripotency (the ability to differentiate into most cell types) than when using CRISPR. Base editing may also be used directly on patients for in vivo gene therapies in the future.
15:00-15:30 – Tackling solid tumours: how do we move forward? – Marco Alessandrini, Sven Kili, Jarema Kochan, Avery Posey
Written by Aaron Logsdon
Dr Kili (CEO of Antion Biosciences) asked, “what are the key challenges for developing cell and gene therapy for solid tumours”. Dr Posey (Assistant professor at Perelman School of Medicine) expressed the view that we must target tumour-specific antigens for cell therapy like CAR-T treatment rather than targeting tumour-associated antigens. Tumour-specific antigens are molecules that are found uniquely on the surfaces of tumour cells. Tumour-associated antigens are over-expressed on the surface of tumour cells, but seen on the sureface of only a subset of normal cells. Treatment based on tumour-associated antigens targets cells with tumour-associated antigens on their surface.
After the summit, I reached out to Dr Posey for further comment on his view. Dr Posey´s view is that there is a small list of tumour-associated antigens that have been attractive for use. Dr Posey believes that the dosage range of tumour-associated antigen-based CAR-T treatment does not justify the risk of toxicity. This toxicity is due to the therapy targeting normal cells that display the tumour-associated antigen, leading to damage of normal tissue. In the past, this led to lethal damage in a number of patients that received CAR-T therapy.
Dr Posey feels that the technologies currently available for understanding the genetic modifications that generate tumour-specific antigens is relatively new. It may be that the time for tumour-specific antigen discovery is here.
However, Dr Alessandrini (CTO of Antion Biosciences) expressed the view that we should improve the engineering of CAR-T treatment. I also reached out to Dr Alessandrini after the summit. He mentioned that scientists have tried to find novel tumour-specific antigens on tumour cells with little luck as when those identified they tend to be present on only a minority of tumour cells and in a minority of patients. Therefore, targeting these antigens is unlikely to be effective in eradicating the tumour, in most cases.
Dr Alessandrini believes we should engineer the CAR-T cells to behave like natural T cells. CAR-T treatments have been developed based on our knowledge of the biology of natural T cells. Dr Alessandrini would like to focus on improving the avidity of CAR-T cells binding to antigen rather than on on affinity. Avidity is the accumulated strength of many binding interactions, while affinity is the strength of one interaction.
Dr Alessandrini believes that fine-tuning the avidity of CAR-T treatment, rather than finding high-affinity interactions with tumour-specific antigens is the way forward to successfully achieve this natural behaviour. Essentially, Dr Alessandrini promotes improving the engineering of CAR-T treatment with the tissue-associated antigens that we already have. This may help us to circumvent some of the current challenges being faced when it comes to the effectiveness of cell and gene therapies for treating solid tumours.
16:30-16:45 – Harnessing cell death for regenerative medicine – Francesco Dazzi
Written by Celeste Cohen
Francesco Dazzi, Vice Dean (International) and Head of Regenerative Medicine at King’s College London, presented the use of apoptosed mesenchymal stromal cells (MSCs) in healing and regenerative medicine. MSCs are multipotent cells that can differentiate into several cell types, including bone, cartilage, and fat cells. Apoptosis is a process by which cells die due to a range of factors including cell damage.
The normal biological response to tissue injury is inflammation and healing by tissue repair or fibrosis, where tissue does not properly heal and results in excessive scarring. The goal, however, is to promote tissue repair rather than fibrosis in the case of post-traumatic injuries, heart attacks, autoimmune diseases, transplants, and lung injuries.
Francesco Dazzi outlined the importance of MSCs in repairing bone, cartilage, and fat tissue and modulating the body’s immune response. MSCs are effective in repair, do not require donor-recipient matching, and have a broad range of action. However, MSCs can target specific disease sites and can be used, for instance, in cases of graft-versus-host disease (GvHD) and Inflammatory bowel disease (IBD). GvHD and ID occur due to undesired immune responses, with donor cells attacking recipient cells in GvHD, and chronic inflammation of the digestive tract in IBD. MSCs can be use to treat such immune-mediated degenerative conditions by controlling inflammation without compromising the immune system.
Francesco Dazzi nonetheless specified that clinical responses to MSC therapy are often unpredictable. MSC treatments are most efficient in patients with higher levels of cytotoxicity, which is a release of agents that are toxic to MSCs and cause MSCs to undergo apoptosis. Apoptosis of MSCs induces immunosuppression and tissue repair. Therefore, a treatment that uses artificially apoptosed MSCs (ApoMSCs) has been proposed, resulting in efficient treatments for all patients regardless of cytotoxicity levels. For instance, ApoMSCs have successfully treated asthma in mice where the use of MSCs was not effective. ApoMScs can also reduce inflammation in the joints of arthritis patients with effectiveness that is comparable to that obained with steroids. Francesco Dazzi outlined ApoMSC therapy as a potentially life-changing allogeneic (using donor cells) cell therapy with broad applications.
16:30-17:00 – The development of gamma delta T-cells for cell therapy in oncology – Kate Rochlin
Written by Shannon Hylton
Dr Kate Rochlin is the Assistant Vice President of Operations and Innovation at IN8bio, a clinical-stage biopharmaceutical company. IN8bio focuses on the discovery, development, and commercialization of gamma-delta (γδ) T cell therapies in cancer treatment. Their DeltEx platform aims to engineer γδ T-cells to be chemo-resistant, while still allowing them to recognize stress signals. γδ T-cells possess a unique ability to differentiate between healthy and diseased tissue and are the most correlative with solid and liquid tumours. The T-cells operate in the damage DNA repair pathway (DDR pathway) instead of targeting a specific antigen, and are therefore applicable to a wide range of disease treatments.
Glioblastoma (GBL) is a type of cancer that still has many unmet needs. Almost all patients relapse within centimetres of resection, making it near impossible to remove GBL tumours. IN8bio, therefore, aims to direct γδ T-cells to target the GBL cells. Dr Rochlin further explained that in8bio have also selected GBL as their proof of concept. This selection was based on the analysis of 15 years’ worth of data. Radiation therapy (Temozolomide/TMZ) has been used to treat GBL patients for the last 15 years.
The end goal for DeltEx therapy is to ‘outrun’ the tumour by using multiple dosing. Research has shown that after TMZ therapy, there is generally a 30% reduction in the size of GBL tumours. However, after 50 days, the tumour doubles in size. With multiple dosing, IN8bio aims to reduce tumour size to a minimum to reduce the chance of patient relapse.
17:15-17:30 – New techniques for adherent cell assays – Semarion – Jeroen Verheyen
Written by Celeste Cohen
Semarion, presented by its Co-Founder and CEO, Jeroen Verheyen, is a company which has the goal of miniaturizing adherent cell assays. Unlike suspension cells (cells that can grow and replicate in suspension in a liquid medium), to date, there has been little innovation in the development of adherent cell manipulation techniques. These techniques require a solid surface for cells to grow. The adherent cell assay is a technique that is used to study cells and their properties.
Currently, existing adherent techniques are lengthy processes that are difficult to reproduce. The techniques do not make it possible to study several different cell samples simultaneously (cell multiplexing). Also, the techniques have limited miniaturization capacity, meaning that large amounts of cells are required.
The solution proposed by Semarion is a SemaCyte® cell screening platform, which is a platform to which cells adhere, after being placed in a liquid reagent. This placement makes it easier to manipulate and requires smaller amounts of cells. When the cells are needed, a magnetic holder is used to attract the platform to the bottom of the well, orienting cells correctly. This technique may allow for the use of up to 2,000 times fewer cells in assays, the possibility of assaying 50-100 cell types in one well, and overall, a simpler automated assay process.
17:15-17:30 – Safety and proof of Concept data of a new allogeneic cell therapy for treatment of orthopaedic disorders – André Gerth
Written by Shannon Hylton
As someone who is particularly sporty, this discussion jumped out to me on the agenda. André Gerth is the CEO of BioPlanta GmBH, a pharmaceutical company that is developing cell therapeutic products from mesenchymal stems cells (MSCs) for clinical application in humans. Cell therapy is undergoing a paradigm shift from autologous to allogeneic therapy. Autologous therapies come from the patient and are therefore highly specific. Allogenic treatments are not derived from the patient themselves, and are therefore not compatible with their immune system. The shift from autologous to allogenic therapies is more economically viable as more patients can be treated using fewer resources.
BioPlanta treats more than 10,000 patients a year. Most of these patients have inflammation of the ankle and knee post-surgery. Gerth explains that BioPlanta’s role is to provide immunosuppressive effects using MSCs. Umbilical cord tissue-derived MSCs are suited to autologous and allogenic approaches as they are easily available. The MSCs are simple and non-invasive and have ethically uncritical recoverability.
BioPlanta treated patients with cartilage defects in knee joints during knee arthroscopy and gave them pre-and post-treatment scores assessing physical function, pain, and range of motion. 89% of patients returned to the normal knee function within the first year.