The American Society of Gene and Cell Therapy (ASGCT) brings together pioneers, trailblazers, and trainees of the field annually for four days of engaging and insightful presentations. This year was slightly different given the virtual format. Nevertheless, the jam-packed agenda proved to be as exciting as promised.
The science of gene and cell therapies has advanced tremendously throughout the last decade such that their product markets are among the fastest-growing within the pharmaceutical industry. With an estimated market value of $2.5 billion in 2020 and a projected value of $25 billion by 2027, the future of this field is brighter than ever. Just last year, Jennifer Doudna and Emmanuelle Charpentier won the Nobel Prize in Chemistry for “the development of a method for genome editing" with CRISPR/Cas9, scoring a major accomplishment for the field, as their discoveries made possible many of the therapeutic products and processes being tested today. Cell and gene therapy has already disrupted the scientific world this year with the fastest roll-out of a modernvaccine in human history and the approval of the first non-CD19 cell therapy targeting the B-cell maturation agent (BCMA).
In this article, we highlight the major themes and advancements in the field of cell and gene therapy presented at ASGCT 2021 during one of the most exceptional years of our lives.
Paving the Way for SARS-CoV-2 mRNA Vaccines
What could accelerate a field more than the urgent need to develop a vaccine against the greatest threat to global health of our time? The emergence of the novel SARS-CoV-2 virus threw the biotech industry/scientific world into high gear as it sought to rapidly develop vaccines and novel therapeutics to combat COVID-19. Advancements in gene therapy paved the way for the technology used to design the mRNA vaccines deployed by BioNTech/Pfizer and Moderna. The technology underlying the mRNA nanoparticles and recombinant adenoviruses used to develop the latest vaccines has been in development for many years by RNA researchers such as Dr. Katalin Kariko and Dr. Drew Weissman of the University of Pennsylvania. The RNA therapy field has also increased dramatically over the past years with 647 RNA therapies in the clinical pipeline and the most common targets being COVID, melanoma, Duchenne muscular dystrophy, and neurological diseases (ASGCT Gene, Cell, & RNA Therapy Landscape, Q1 2021 Quarterly Report).
The rocky yet resilient history of gene therapy as seen through the lens of the beta-globin gene was described by Michel Sadelain, MD, Ph.D. of Memorial Sloan Kettering Cancer Center. During his ASGCT 2021 presentation, he highlighted the efforts taken to advance precision vector engineering of gene therapy for beta-thalassemia and sickle cell disease. The groundwork laid by Dr. Sadelain and others, such as the use of lentiviral vectors for the precise expression of the beta-globin gene, have paved the way for the mRNA vaccine technology employed today,including the use of the cap site and polyA tail derived from beta or alpha-globin gene. Presentations by Ugur Sahin, Ph.D. of BioNTech, and Scott Hensley, Ph.D., University of Pennsylvania, showcased the potential of mRNA-based vaccines to revolutionize modern vaccinology. They discussed how the next major applications of mRNA vaccines will be in improving the flu vaccine, developing personalized cancer vaccines, and vaccines against autoimmune disease.
Advances in Gene Editing Propel Cell Therapy Technologies
Today, physicians are increasingly prescribing 'living drugs', also known as genetically modified immune cells, for the treatment of blood-based cancers. Current efforts in the field of cell therapy aim to improve the efficacy and safety of next-generation cell therapies and overcome the barriers of targeting solid tumors. Precise genetic engineering of clonal cells for the fine-grained selection of custom edits in clonal cells is required to effectively improve patient outcomes. Solid tumors are notoriously difficult to treat, but through precision targeting with modified immune cells, tumor microenvironments inaccessible to other conventional therapeutic products may now be accessible by cell-based therapies.
Particularly exciting is the use of induced pluripotent stem cells (iPSC) for deriving cells of interest such as T cells and Natural Killer (NK) cells. The "holy grail" of cell therapies is the use of a master cell bank of genome-edited iPSCs with unlimited expansion and replication to produce consistent, well-characterized cell products that can be developed on a clinical and commercial scale. Fate Therapeutics presented an example of how to use CRISPR-mediated genome editing by introducing modifications into invariant natural killer cells (iNKs) that addresschallenges such as NK persistence, enhanced antibody-dependent cellular cytotoxicity, decreasing toxicity, and pan-tumor targeting. Caribou Biosciences, co-founded by Jennifer Doudna, presented their work utilizing CRISPR hybrid RNA-DNA (chRDNAs) technology designed to exhibit high on-target editing efficiency and reduce off-target editing relative to the first-generation CRISPR technology. chRDNA has been used for the development of the CB-010, an allogeneic anti-CD19 CART therapy recently approved for Phase I clinical trials, making it the first allogeneic cell therapy with PD1 deleted by CRISPR editing.
Cell and Gene Therapy Product Development
Considerations for the development of products and processes were critical reoccurring topics throughout pre-meeting workshops and industry-sponsored symposia. The science of cellular and genetic manipulations continues to advance rapidly in the laboratory, but how those emerging technologies penetrate the marketplace requires addressing some unique and unprecedented challenges. Mitigating risks and maximizing efficacy are critical to the success of any new therapeutic product, though cell and gene therapies present the added cost of personalized development. The added cost associated with product development, especially that of autologous cell therapies, demands continuous examination and re-examination of processes to maximize efficiency. Alternative cell types have been explored, especially NK cells, to broaden the range of efficacious products, and pluripotency was also a major topic aimed at developing off-the-shelf products that can be tailored to patients. Given the staggering speed at which these technologies change, it was evident at ASGCT that new companies, and even those with existing entities entering this field, require flexible partnerships with collaborators, CROs, and vendors in which those organizations possess the knowledge base and agility to evolve in concert with the needs of companies.
Investment into cell and gene therapies entails immense risks. Craig Gordon, MD, of Capital Group denoted the rigid attention to efficiency in regulating the application of technologies that should be a continuous learning process. Data management and integration are crucial components contributing toward meeting regulatory requirements of changing technologies and ensuring minimization of lost efforts and resources. Megan Liles, of Precision for Medicine, pointed out that organizations and vendors must grow with one another. Expertise in analysis or data management in one therapeutic area may not necessarily translate to all possible products. With each new cell type, for instance, or modified sequence, new unique considerations for data modalities are required. Some 2800 clinical trials are currently underway for cell and gene therapies and adapting the infrastructure of companies to monitor the wealth of information from the complex scientific and clinical outcomes to enable real-time decision making is absolutely essential. Co-evolution is key to success. By sharing knowledge within the domain, cell and gene therapy companies will not only go fast but also go far.
At Genedata, we are committed to supporting companies in unlocking the full potential of their cell and gene therapy R&D data through the digitalization of internal and external processes. We partner with biopharmaceutical companies to advance translational and clinical research by providing an off-the-shelf platform for data management, integration, analysis, and visualization. Genedata Profiler enables the ability to leverage all data and knowledge from pre-clinical to clinical trials while providing a secure and controlled GxP environment for efficient collaboration across research teams and external partners. The Genedata Profiler platform advances interoperability and agility, allowing organizations to optimize R&D processes and automate complex scientific workflows that remove data silos and harmonizes scientific data streams.
Mention of companies or research organizations in this article does not indicate their endorsement of Genedata or its products. Presentations mentioned here have been selected based on our opinion of their scientific and technological interest.