On the 24th of May, 2022, PMM team members, Xuanqi Song and Sam Jarada, 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 in cancer immunotherapy and applications of mRNA technology to the most recent advances in stem cell and gene therapy. 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.
Day 1: Tuesday, May 24th, 2022
Keynote Panel Discussion: State of the Industry, 9:00 – 9:30
Written by Xuanqi Song
The first presentation of the Advanced Therapies Congress began with a discussion about the state of the industry. Cell therapy is defined as the biotechnology involved with engineering cells for a purpose, and it is carried out in vivo (when the cell is the product) or ex vivo (when the vector delivered is the product), said Miguel Forte, the CEO of Bone Therapeutics. According to Miguel Forte said, there is currently a great revolution taking place in the field of cell and gene therapy.
Four professionals from this field shared their opinions on the current progress of cell therapy during the panel discussion. First, Vicki Coutinho from Gammadelta therapeutics mentioned that the current challenge for ATMP (Advanced Therapy Medicinal Products) is the situation regarding GMO (genetically modified organisms). As ATMPs are regarded as GMOs, the process of approvaltakes longer to process as the applications have to go through the European Union commission. Magali Taiel, the Chief Medical Officer of GenSightBiologics, thinks it is already a remarkable achievement to have been able to keep clinical trials running during a pandemic. Jakob Dupont, a tumor immunologist from Atara Biotherapeutics has been working within the cell therapy field for over twenty years, and believes that this field “is coming of age”. Atara Biotherapeutics is developing a T cell platform to address diseases such as multiple sclerosis and cancer. Roy Baynes, the Senior Vice President of global clinical development from Merck Research Laboratories mentioned that the last two years of pandemic has caused great disruption to many companies that are working in this field. It is very challenging to keep operations such as clinical trials running smoothly and monitoring patients under such circumstances can also prove to be difficult. However, as Vicki mentioned, despite all of the hardships presented by the pandemic, great potential has been shown and significant improvements have been made, particularly in ATMP. As Miguel said, “if we want, we can do it.” Cell therapy has exhibited great promise and may have even more applications within the next five or ten years.
ex vivo: medical procedure carried outside of the living body. (https://www.cancer.gov/publications/dictionaries/cancer-terms/def/ex-vivo)
in vivo: testing and experiments with living subjects (https://www.technologynetworks.com/drug-discovery/articles/in-vivo-vs-in-vitro-definition-pros-and-cons-350415)
Removing microenvironmental barriers to cancer immunotherapy success through engineered bacteria – Pedro Correa de Sampaio (Neobe Therapeutics) 10:45 – 11:00
Written by Sam Jarada
The CEO and co-founder of Neobe Therapeutics, Pedro Correa de Sampaio, began his presentation by stating that while immunotherapy has changed the clinical landscape of cancer treatment, unfortunately, only around 15-20% of patients with solid tumors respond to immunotherapy. He then went on to discuss the various reasons behind this lack of response. One of these reasons was the tumor microenvironment (TME), which is a complicated network of cell and non-cell components that initiates cancer progression and invasion and which accounts for resistance to anti-cancer drugs and to immunotherapy.
Neobe Therapeutics believes that bacteria are ideal agents for disrupting tumors as they have an inherent ability to colonize the tumor’s core and can thrive within this oxygen-deficient environment. Bacteria can also trigger an immune reaction using chemicals that they release from their cell surface. The company has proposed the use of genetically engineered bacteria that facilitate tumour microenvironment disruption in order to enhance the delivery of immunotherapy treatment in patients that are currently not responding to treatment. A bacterial engineering platform is used to incorporate certain key features into the bacteria. One of these is features is tumor biosensors which allow the detection of tumors. Another feature is a secretory system that releases chemicals into the microenvironment in order to halt tumor growth. Overall, Neobe Therapeutics has the vision of using its innovative technologies to create a platform for bacterial therapeutics.
New insights into the role of metals in disease – Ivo Timmermans (Pleco Therapeutics) 13:15 – 13:30
Written by Sam Jarada
Ivo Timmermans began his presentation by reminding us that cancer is still one of the leading causes of death globally. While there have been significant advances in our understanding of and treatment of cancer, some cancers that can resist therapy. He mentioned that Maro Ohanian, who published a paper in the American Journal of Hematology in 2020, found that patients with leukemia can have toxic metals present in their bone marrow and serum. The observations suggest a possible correlation between the presence of these toxic metals and lower survival rates.
Ivo also argued that the Industrial Revolution changed the earth’s chemical environment over time, leading to people today having around a hundred times more lead present in their bone marrow than is found in samples recovered from pre-historic people. Some of the essential metal ions that we need are iron, copper, zinc, and magnesium. Toxic metal ions include iron and copper, mercury, and aluminium.
Toxic metals that are ingested can get stored in the body and are difficult to clear from the body. To address this problem, Pleco Therapeutics has designed plecoid agents, which utilize chelators and antioxidants to aid in the removal of toxic metals from the body and reduce detrimental effects on cancer patients. The plecoid agents function by cleansing the tumor’s micro-environment prior to treatment. Ivo also mentioned that it will be necessary to further study the most relevant toxic metals such as mercury and lead to determine whether they play an active role in disease or whether they are metal ´bystanders´.
A further challenge is to determine which plecoid agent should be used to treat which patient and condition. In the future, there will be a focus on the use of broad-spectrum chelators that can remove certain toxic metals from the body while allowing certain essential metals to remain. Pleco Therapeutics has carried out animal studies in a rat model. In these studies, the rats were given a mix of 8-12 critical metals via oval gavage for one week and were then kept without any further treatment for one month. The results of these studies demonstrated that the animals endured the treatment and had no adverse effects, as assessed by examining standard weight gain patterns as well as by conducting hematological and biochemical analyses . The results provide experimental support and justification for the use of chelation treatment in cancer and support the proposed mode of action, which is that the metal mix alone is sufficient to counteract chemoresistance, and that different chelators can reverse chemoresistance in cells that have been exposed to metals.
Panel Discussion: Immunogenicity for gene therapy, 14:30 – 14:50
Written by Xuanqi Song
In the panel discussion on the immunogenicity for gene therapy, Paul Gissen from UCL, Sean Armour, who is the head of discovery from Spark Therapeutics, and Pedro Gonzalez-Alegre, the head of gene therapy research of Spark Therapeutics, have discussed and given their opinions on what immunogenicity of gene therapy is and how it can be addressed.
The speakers think that immunosuppression, re-dosing, and in-utero dosing could be the challenges for immunogenicity of gene therapy. Also, the choice of animal model could be a significant challenge as well because animal models don’t seem to translate the data from the clinic, but the clinical data is required to support whether the product is improved or not. As animals such as mice are obviously very different biologically from humans, certain risks and side effects due to toxicity may not be observed or accurately reflected in animal models. Furthermore, the underlying medical conditions of human patients may affect their immune responses, and this will only be evident at the clinical stage. This highlights the importance of dose serum relationship and also the role of complement activation. Complement is part of the innate immunity, playing the role of first defense against foreign cells. It is a group of serum proteins expressed on cell surface, including C1 to C9. Those complement proteins corporate when bound to a foreign cell and will induce a cascade event of killing the pathogen. The process is known as opsonization.
(https://www.frontiersin.org/articles/10.3389/fimmu.2015.00262/full).
Although there are many challenges when developing gene therapy, many of them could be solved together with joint effort.
Day 2: Wednesday, May 25th, 2022
Track 4: Gene Therapy: Leveraging an mRNA platform in the context of rare diseases, 11:00 – 11:20
Written by Xuanqi Song
Paolo Martini, introduced Moderna´s mRNA platform and the features and potential of mRNA in his presentation. Moderna uses mRNA in different applications for different diseases not only for vaccines. Now, with messenger RNA, Moderna has found a variety of solutions targeting different diseases, for instance, autoimmunity or genetic diseases.
The properties of mRNA are drug-like, and with Moderna’s development, it has a very precise dosage, “It needs to be applied in the exact amount of mRNA and the exact amount of dosage.” Said Paolo Martini. Moderna can dose patients chronically, not like normal gene therapy, and if any safety issues occur, the administration can be cancelled at any time.
Paolo also introduced the process of developing an mRNA platform. According to Moderna’s website, where more information about the mRNA platform is available, there are still certain biological barriers that must be overcome to deliver mRNA medicines and maximize their clinical potential. In most cases, the effective delivery of mRNA-based medicines is enabled by encapsulating the mRNA in tiny lipid (fat) droplets, known as lipid nanoparticles (LNPs). This is done in order to protect it against degradation and facilitate uptake by cells. Moderna announces advances in developing numerous proprietary LNPs, each suited to target different cell types and optimized for different routes of administration. Moderna has invested in the development of LNPs for systemic, intramuscular, intratumoral, and pulmonary delivery of mRNA.
The platform has special features such as the longevity of mRNA is stabilized and the mRNA platform increases the affinity by 20x compared to the affinity of endogenous mRNA used for the treatment of disease. In addition, the mRNA undergoes certain key modifications in order to eliminate immunogenicity. Paolo also talked about the factors that could influence the process of protein progression. There are ways to make RNA tissue-specific. However, Moderna is currently focusing on developing their mRNA platform. Moderna´s clinical trial which began in April, 2021 involved a 12-week repeat dose study to assess the treatment of propionic acidemia (PA) in hypomorphic mice to support the preclinical proof-of-concept for the project of mRNA-3927 started on April, 2021.
Use of cord blood as starting material for cell therapy – Marcie Finney (Cleveland Cord Blood Centre) 11:20 – 11:40
Written by Sam Jarada
Marcie Finney, the Executive Director at the Cleveland Cord Blood Center Cleveland Cord Blood Centre, began her presentation by outlining a brief history of cord blood banking. 1988 was the year of the first umbilical cord blood (UCB) transplant in France into a 5-year-old child suffering from Fanconi anemia. This patient is alive and remains disease-free today. 1993 was the year of the first UCB transplant and first CB bank in the US (at Duke University), while the National Cord Blood Program was created in the New York Blood Centre (NYBC). In 2005, the US Congress passed the Stem Cell Research & Therapeutic Act, creating a national inventory including 150,000 high-quality CB samples. In 2021, over 35,000 patients received CB transplants and over a hundred clinical trials were performed to assess the various applications of Cord Blood.
Marcie identified several uses of cord blood in cell therapies, regenerative medicine, and research and even in the development of treatments for COVID-19 infections. She mentioned ten different applications for the use of cord blood as a starting material for cell therapy, with one being that cord blood has unique biological properties. As a result, cord blood stem cells have no environmental or viral exposure since they are fresh from the baby and multipotent, meaning that they can only differentiate into specific cell types such as red blood cells, white blood cells, and platelets.
Another reason is that cord blood banks have a lot of capacity as they continuously collect, store, qualify and process more cord blood units yearly, with current blood usage being over 2,000 units. In comparison, 4,000 units were added in the US in 2020. Cord blood is highly regulated and accredited by organizations such as the Human Tissue Authority (HTA) in the UK and Australia’s Therapeutic Goods Administration (TGA).
There are eight US public cord blood banks with licensed products which are as follows: ClinImnume Labs (Colorado), Carolinias CB Bank, St. Louis CB Bank, LifeCord (Florida), BloodworksNW (Washington), Cleveland CB Center and MD Anderson CBB. The loading of CB is supported by storage at -150 degrees Celsius or colder and can be stored for 21-23.5 years without losing its function.
Furthermore, the CB inventory is ethnically diverse, with over 136,000 units originating from non-white donors on the registry. The supply chain for CB banks is established with transport from CB collection site to CB bank, then transport from CB bank to transplant centre, which is stored for use.
There is a plentiful supply of CB (over 800,000 units), which means that CB is readily available for a variety of applications. A final reason is that the procedure involved in rerieving CB presents a low risk to the donor as it takes place after the baby is born. The cord is cut (typically removed as medical waste). Therefore, collecting CB does not impact the delivery.
In response to my question to Marcie, regarding why, despite there being plenty of cord blood units available, the use of this product not more widespread, she explained that there is a natural progression in research, where such products are initially used as an autologous product. An autologous product is obtained from an individual and then used to treat that same individual. She then went on to say that the product will eventually become more allogenic, where it will be possible to use the CB derived from one individual as the starting material for the development of a cell therapy to be used to treat a different individual.
Curing Corneal blindness with stem cells – Laura Koivusalo (StemSight) 13:45 – 14:00
Written by Sam Jarada
CEO of StemSight, Laura Koivusalo, began her presentation by comparing some of the types of corneas that can affect a person’s eye. A normal cornea is vital for clear vision. Corneas are one of the more common transplanted organs from the human body and limbal stem cell deficiency (LSCD) is a disease in the cornea that primarily impacts young and working-aged people. Endothelial dystrophy (ED) is an inherited disease in the cornea that justifies corneal transplants.
Laura also explained that 18,000 patients with LSCD require treatment in the US and EU, while 13.5 million patients with ED are in need of therapy in the US and EU. According to Laura, the average age of onset for LSCD is 34, while ED is 40 and the cost to cure LSCD per eye is €250,000 or $578,000. For ED, it is $265,000 per eye, as evaluated by the Lewin Group in 2013. She informed the audience that using corneal transplants from deceased donors is not necessarily the best way to treat LSCD and proposed an alternative of using induced pluripotent stem cells (iPSCs) to treat corneal blindness, by using natural materials obtained from an external company’s cell bank.
StemSight intends to use laboratory methods to ensure the iPSCs grow into limbal stem cells and corneal endothelial cells. Even though there are many competitors tackling corneal blindness, she stated some advantages of StemSight. The cells being used were the only line of therapy that was found to restore corneal function completely. The limbal stem cells used are of a high purity (80%), which helps to ensure a high therapeutic potential. The final product is convenient for corneal surgeons to use as the carrier membrane is easy to handle and fits well with their current surgical techniques.
The company claims that their product can provide life-long restoration of vision. The iPS-derived cells have longer lifespans than donor-derived cells. StemSight has proven their concept by conducting a long-term continuing study to assess their product on rabbits with intense chemical burns on their corneas. Results obtained after week following the treatment, demonstrated an improvement in vision.
One of the company´s fundamental value drivers is to focus on the eyes, which are a primary target for stem cell therapy as they are easily accessible and can be monitored safely. Laura expressed the view that while a number of other companies are focusing on retinal cells, are corneal cells are not being investigated enough. Laura concluded the presentation by stating that StemSight’s vision is to become the leading developer and manufacturer of stem cell-based therapies for the treatment of corneal blindness.
Driving the advanced therapy processing revolution, a biocomputer based therapy development kit – Colin Barker (BiologIC Technologies) 14:40 – 15:00
Written by Sam Jarada
The Chief Scientific Officer at BiologIC Technologies, Colin Barker, introduced his company saying that their aim is to overcome global challenges by using biology to make advanced therapies more accessible and sustainable.
He stated that McKinsey: The Bio Revolution, May 2020, said that “60% of the physical inputs into the global economy could be produced biologically”. This means that biology can feed people, create fuels, heal people, build using biopolymers and bioconcretes and compute using DNA as data storage.
He asked, “why are we not using biology even though it is possible?” and concluded that using biology for the global economy requires a great deal of bioprocessing power to work, which cannot currently be met using our existing technologies. Therefore, his company came up with the concept of a biocomputer that can be used to automate, optimize, and scale biological processes down by using Bio Processing Units (BPUs) inside the biocomputer.
The Biocomputers are part of a therapy development kit (TDK) for advanced therapy developers who need to speed up biological processes in the clinic. They can be configured depending on what approach the buyer needs to perform with analytics included in the system such as cell count, viability, and PCR. Compared to classic systems that use different equipment, the TDK can be used at each stages of the therapy life cycle (research, development, and production).
Track 5: Manufacturing: Closed system manufacturing to create a CAR (chimeric antigen receptor) T for brain tumors, 16:20 – 16:40
Written by Xuanqi Song
Shabnum Patel is currently the Director of Process Development & Manufacturing at Stanford Cancer Institute. They are currently working on a project involving the use of CAR-T cell therapy. CAR-T cell therapy is a type of immunotherapy that uses CAR-T cells to target specific protein on the surface of cancer cells and subsequently kill the cancer cells. The CAR-T therapy is being developed to treat a type of brain cancer called Diffuse Midline Glioma (DMG). DMG is a type of brain tumor that can develop in the pons or spinal cord and over 70% of these tumors are correlated with mutations in the histone-3-K27M gene which stimulates an upregulation of GD2. Consequently, GD2 is a promising target for cell therapy.
Shabnum Patel briefly introduced the background to this type of tumor and the current clinical state of cancer. DMG usually has an early onset and there is no treatment available apart from radiotherapy. It is quite an aggressive cancer that has a low survival rate (most patients do not survive longer than eleven months from the diagnosis date). Patients with DMG may experience problems with muscle control or mobility. Shabnum and her teams are working on GD2, a disialoganglioside expressed in tumors such as DMG, DIPG, osteosarcoma, and neuroblastoma. GD2 was chosen as an ideal target for immunotherapy due to some of its specific characteristics. It is known to be highly expressed in tumor tissue, but not in normal tissue. The teams have obtained patient samples that show that GD2 CAR-T cells can cure patient-derived xenograft DIPG in mice. They subsequently designed a drug Dasatinib for clinical manufacturing, which is a type of tyrosine kinase inhibitor.
Shabnum also talked about the advantages of using GD2 in this CAR-T cell therapy, the potential questions about this therapy, and the application of Dasatinib in the clinical setting. An important advantage of using GD2 as the CAR, is that it can prevent damage to the surrounding normal brain tissue. In comparison to T cell receptor (TCR), which is engineered to specifically target cells such as cancer cells, CAR-T appears to be more potent in that it can have a higher affinity to engineered monoclonal antibodies than the TCR does. Also, their mechanisms differ, where CAR-T can combine many factors of normal T cell activation together to activate T cell for immune response, whereas TCR is MHC (major histocompatibility complex)-dependent. During her talk, Shabnum further elaborated on safety issues related to the clinical trials, such as how to reduce the risks of toxicity in the therapy and the development of process parameters. To summarize, Shabnum Patel talked about some of the clinical trial results obtained with Dasatinib treatment. She mentioned that it shows that major tumor regressions in DIPG were observed following the intravenous (IV) and intracerebroventricular (ICV) delivery of GD2-CAR T cells. The results demonstrate that the most effective way of delivering these CAR-T cells may be via ICV infusion.
There are still potential challenges to be addressed with regards to product development and moving the whole process from bench to desk. However, this innovative method of CAR-T cell manufacturing may eventually lead to a more effective method for treating solid tumors. Therefore, future research should continue to look into solving these challenges.