The landscape of gene and cell therapies is undergoing a significant transformation as regulatory bodies across different countries are actively improving their practices, guidelines, and human resources to accommodate the surge of new product submissions. In a recent Q&A session with Georges Rawadi, CEO at Celyad Oncology, we explored the pathways to effectively mainstream the adoption of these revolutionary interventions within the healthcare sector.

#LBS: What specific innovations or breakthroughs in cell and gene therapies have shown the most promise in recent years, and what challenges must be overcome to bring them to widespread clinical use?

Georges Rawadi: In recent years, several gene and cell therapies have either received regulatory approval or are advancing through advanced clinical trials, showcasing their potential. For instance, AAV-based gene therapies, such as Luxturna and Zolgensma, or CAR-T therapies, such as Yescarta or Kymriah, continue to demonstrate promising results.

This progress is driven by various innovative technologies:

• CAR-T Therapies: CAR-T cell therapies have achieved remarkable successes, with regulatory approvals for eight autologous CAR-T cell therapies targeting hematological malignancies. These therapies, including those directed against CD19 and BCMA, are extending their reach from blood cancers to solid tumors like breast cancer and glioblastoma. Moreover, there's growing interest in applying CAR-T therapies to autoimmune diseases, supported by a robust clinical rationale. Researchers are actively refining CAR-T designs to enhance their efficacy and safety.

• Gene Editing Advancements: Gene-editing tools, such as CRISPR-Cas9, have evolved significantly. Techniques like base editing and prime editing are actively being studied for treating a wide array of genetic diseases. While no gene-editing drug has been approved thus far, multiple advanced clinical trials employing various gene-editing technologies are in progress.

• Regenerative Therapies: The long-standing goal of using stem cells to regenerate and repair tissues is closer to realization. Mesenchymal stem cells (MSCs) and induced pluripotent stem cells (iPSCs) have been explored for various conditions, particularly in the realm of neurological disorders and heart disease. While large-scale clinical success remains a challenge, the field holds immense promise, especially for neurodegenerative diseases and diabetes.

• mRNA-based Therapies: The success of mRNA vaccines during the COVID-19 pandemic highlighted the potential of this technology. Numerous research programs, biotech, and pharma companies are now developing mRNA-based approaches for vaccines and disease treatment. mRNA applications have expanded into various areas, including cancer therapy, infectious diseases, metabolic disorders, and genetic diseases. Future innovation will center on manufacturing, scalability, and tissue delivery.

#LBS: How are regulatory bodies and governments adapting to the rapidly evolving landscape of cell and gene therapies, and what policies or initiatives are being implemented to ensure safe and equitable access for all?

Georges Rawadi: The development of cell and gene therapies faces several significant challenges, including safety concerns, efficacy issues, and obstacles related to quality and scale-up. Often, the pace of innovation outstrips regulatory and policy developments. Nevertheless, regulatory bodies in major regions like the US, Europe, and Japan have been actively improving their practices, guidelines, and human resources to accommodate the surge in cell and gene therapy product submissions. For instance, projections indicate that more than 60 cell and gene therapy products may be approved by 2030.

The novelty of cell and gene therapy products has led regulatory bodies to push the boundaries of existing medicinal product regulations. Despite this, variations persist between countries with distinct regulatory frameworks, resulting in complexity for sponsors as they navigate different markets. To address these challenges, there's a pressing need for greater regulatory convergence among countries. This includes harmonizing expedited pathways for cell and gene therapy product development and approval, as well as adapting preclinical toxicology, pharmacokinetics, pharmacodynamics, and other study requirements to the unique nature of living human cells and viruses. Moreover, revised manufacturing, batch release, stability testing, and other standards are necessary, especially when dealing with small batch sizes intended for single patients. Finally, regulatory bodies should implement new regulations to support innovative clinical trial designs, especially for rare or orphan diseases, by further promoting post-market confirmatory studies.

#LBS:  In what ways are biotechnology and personalized medicine intersecting, and how might this convergence revolutionize the development and delivery of cell and gene therapies?

Georges Rawadi: The convergence of biotechnology and personalized medicine presents a unique opportunity to revolutionize the development and delivery of cell and gene therapies in several ways. Here are some key intersections and their potential impact:

• Tailored Treatments: Personalized medicine, empowered by advances in genomics and molecular profiling, enables the identification of specific genetic or molecular targets associated with a patient's disease. Biotechnology is leveraged to develop cell and gene therapies targeting these individualized disease markers.

• Patient Stratification: Personalized medicine facilitates the identification of patient subgroups most likely to respond to specific therapies, potentially leading to more efficient clinical trials and improved patient outcomes.

• Real-Time Monitoring: Biotechnology tools, including wearable devices and remote monitoring, provide real-time data on patient responses to treatment, enhancing patient monitoring and enabling treatment adjustments.

• Data Integration and Artificial Intelligence: Biotechnology, in conjunction with AI, can analyze extensive datasets, encompassing genomic and clinical data. This analysis informs treatment decisions, enabling healthcare providers to make more precise and personalized recommendations for cell and gene therapies.

#LBS:  What ethical considerations and public discussions surround the use of CRISPR and other gene-editing technologies in the context of cell and gene therapies, and how are these shaping the direction of research and implementation?

Georges Rawadi: Gene editing and our ability to surgically manipulate the human genome represent a revolutionary concept with profound implications for research, drug discovery or disease treatments. While the concept of DNA manipulation is not new and dates back to the discovery of DNA in 1953, several subsequent discoveries, including transposons and restriction enzymes, paved the way. High-precision gene editing tools became possible with the development of engineered nucleases such as Zinc-Finger Nucleases (ZFNs in 1996) and Transcription Activator-Like Effector Nucleases (TALENs in 2009). However, the pivotal breakthrough came in 2012 when the CRISPR-Cas9 system was demonstrated for precise gene editing in various organisms. I nature it is used by prokaryotes to fight against mobile genetic elements like viruses, the CRISPR-Cas9 technology quickly gained widespread adoption, with numerous advancements in precision and efficiency. The method based on CRISPR-Cas9 received the Nobel Prize in Chemistry in 2020.

But like many groundbreaking discoveries, such as embryonic stem cells, the rapid development of gene-editing technologies has raised significant ethical concerns. These concerns primarily revolve around germline editing and the potential for genetic selection or modification of human embryos. Notably, the controversial work of Jiankui He in China, who edited human embryos with CRISPR-Cas9, leading to the birth of genetically modified babies Lulu and Nana, and the intention of highlighted these ethical challenges. The scientific community widely condemned these interventions, prompting calls for a moratorium on inheritable genomic manipulations. This episode underscored the importance of establishing international consensus on the use of gene editing in humans.

Historically, instances of scientific or medical discoveries being misused have led to the establishment of international guidelines on bioethics. Notable examples include the Nuremberg Code (after the trial of Nazi doctors in 1947), the Declaration of Helsinki (1964), and the Belmont Report (1978). Ethical considerations vary widely from one country to another, with some prohibiting the manipulation of embryos and their genetic modification, some allowing it, and many others occupying intermediate or ambiguous positions.

#LBS: How can interdisciplinary collaboration between scientists, clinicians, policymakers, and ethicists be enhanced to navigate the complexities of cell and gene therapy, and what role do public perceptions and education play in this collaboration?

Georges Rawadi: Cell and gene therapies are not just scientific innovations but also encompass significant ethical, social, economic, and regulatory dimensions. Collaborative efforts involving scientists, clinicians, policymakers, ethicists, and the public are vital for the responsible development and application of these therapies. Achieving this requires open dialogues, joint research projects, and robust public engagement. Through such initiatives, the complexities surrounding these therapies can be addressed by striking a balance between scientific progress and ethical and societal values.

To enhance interdisciplinary collaboration among scientists, clinicians, policymakers, and ethicists, it is imperative to encourage collaborative research projects that span these disciplines. These projects deepen our understanding of the complexities and ethical considerations of cell and gene therapies and promote wider adoption. Additionally, the establishment of interdisciplinary ethics committees, comprised of ethicists, clinicians, scientists, and policymakers, is essential to set ethical guidelines and ensure that policies align with evolving technology. Engaging the public early in these discussions allows diverse perspectives to shape the ethical framework for cell and gene therapies.

Public awareness and patient involvement are paramount to the success and adoption of cell and gene therapies. Urgent public education campaigns should transparently inform the public about the potential benefits, risks, and ethical considerations associated with these innovations. Engaging patient advocacy groups and patient representatives in collaborative discussions ensures that patient perspectives and concerns are integral to the development and implementation of these therapies.

#LBS: London Biotechnology Show offers a wider platform for the deep exploration of the advanced therapies, the present and potential future applications? How significant are events of this nature?

Georges Rawadi: Organizing regular workshops and conferences that convene experts from various fields provides a valuable platform for discussion, idea exchange, and collaborative problem-solving. These events serve as a nexus for experts, including scientists, clinicians, policymakers, and industry leaders, to share knowledge and insights. This knowledge exchange fosters a deeper understanding of the latest biotechnological advancements and the potential applications of advanced therapies.

Such gatherings offer critical networking opportunities, showcasing innovative technologies, providing education and training, and engaging the public in discussions about the impact of advanced therapies on healthcare, society, and the ethical considerations surrounding their use.

In the context of events like the London Biotechnology Show, as with other similar global gatherings, they serve as essential hubs for the biotechnology and cell and gene therapy community. Here, experts come together to collaborate, share, and collectively advance the field.