Cell and gene therapies have caused huge waves in drug development. FDA approval of Kymriah – developed by Novartis and researchers at the University of Pennsylvania – demonstrated that these therapies could be successfully commercialized, opening the door to many more. In this feature, experts discuss why cell and gene therapies are such an important disruptor in the industry.
We asked: What has/have been the key disruptor(s) driving the industry over the past ten years, and how will this change in the next 10 years?
Here, we include views related to the science and development of advanced therapies. Read about other areas of pharma drug development here.
Appreciating the Potential of Cell Therapy – with Victor Levitsky, CSO, Circio
Cells are the fundamental units of our bodies and their proper functioning is crucial. Diseases in humans often result from cell death, improper growth control, or functional impairments. Each cell relies on a complex array of molecules organized into subcellular structures to carry out its role. The main challenges in drug development often arise because molecules act differently depending on the cell type and context. This means that interfering with a specific molecule can produce a variety of unpredictable and often harmful effects.
There are two potential solutions to this: highly specific drug delivery and cellular therapy. Currently, highly specific drug delivery methods face significant hurdles and may not fully address the complexities of biological systems, whereas cellular therapy offers a promising, almost untapped, alternative. Cells can be pre-modified using various molecular and genetic techniques before being reintroduced into the body.
Many investors and those in the industry view dealing with cellular products as a temporary inconvenience, despite the impressive results of relatively straightforward therapies like CAR-T treatments. Once it becomes widely recognized that the expertise and infrastructure required for delivering cellular products provide substantial opportunities and a competitive edge, however, the pharmaceutical and biotech industries may experience significant changes.
The Future Belongs to Allogeneic CAR-Ts – with Syed Rizvi, Chief Medical Officer, Poseida Therapeutics
Over the course of my 20+ years in the biopharma industry, I have been fortunate to spearhead innovative advances in medicine, including the development and commercialization of several autologous CAR-T therapies. These medicines use a patient's own immune cells to fight cancer and have been life changing. However, access remains a big challenge for many patients.
Today, we are on the cusp of a true revolution in biotechnology. Innovative cell and gene-based therapeutics have the potential to be the third leg of the stool, next to small molecules and biologics, that could greatly impact patient outcomes. In the years to come, I believe an expansion of access will be at the forefront of transforming the standard of care in oncology and beyond.
The future belongs to off-the-shelf allogeneic CAR-Ts, which are made from healthy donor cells and therefore readily available to patients. The allogeneic approach promises to bring new and potentially life-saving therapies to broader patient populations, while reducing the time and cost barriers associated with currently available autologous options. Within the next 10 years, I would expect a wide use of allogeneic cell therapies and genetic medicines in oncology, immunology and beyond.
The Power of Genetics – with Gary Herman, Senior Vice President and co-head, Regeneron Genetic Medicines Clinical Development Unit
Drug discovery and development is incredibly difficult under any circumstances, but more so when the biology underpinning disease is unknown and the approaches taken are largely empirical. Having the ability to understand the human genome is one of the greatest forces that changes the odds of making breakthrough discoveries. As such, the biopharma industry is increasingly focusing R&D on understanding the role of genetics in health and disease. The explosion in our understanding of human genetics and disease biology – combined with advanced technology – may hold the key to addressing some of the most intractable diseases at their very source and truly gives us a fighting chance.
R&D in genetic medicines creates a real opportunity to develop a thorough understanding of disease biology, which involves identifying and characterizing both disease-causing and -preventing (protective) genetic changes. Integrating genetic data into drug development continues to accelerate the discovery process, starting with sequencing genomes at scale, which allows for the identification of novel targets that are key drivers of disease. Alongside this, new technologies are now enabling us to modify these genes – silencing or deleting, adding, or editing – that have the potential to not only better address diseases with high unmet needs, but also yield potentially curative treatments.
While genetic medicines have come a long way in transforming our approach, challenges remain, including ensuring therapeutic agents reach their intended targets within the body without affecting other tissues. Many current approaches involve systemic administration of viral vectors carrying a gene of interest. With the liver filtering and intercepting therapeutic agents before they reach their targets, however, this often necessitates higher doses of viral vectors, which could cause toxicity and adverse events.
It will be critical to leverage multiple technologies to tackle persistent delivery challenges. As one example, at Regeneron, we're leveraging our legacy in protein therapeutics and the development of fully human, highly specific antibodies to develop targeting strategies to guide genetic medicines directly to the specific cells or tissues that are underpinning the disease. This is accomplished by attaching antibodies against cell- or tissue-specific receptors (e.g. a muscle specific receptor for a disease driven by an abnormal protein expressed in muscle) to the viral delivery vectors, allowing therapeutic payloads to be introduced into desired cells with high precision – thereby bypassing the liver and allowing for lower therapeutic doses, potentially reducing unwanted toxicity and side effects.
Over the next ten years, the refinement of delivery systems will be crucial in propelling gene editing technologies into the mainstream, addressing a broader range of diseases, with increased selectivity and reduced off-target effects. This is especially critical to those affecting complex systems, such as the central nervous system, where precise targeting is paramount. Ultimately, the marriage of multiple tools and technologies within the platform of genetic medicines, combined with careful and rigorous clinical investigation, holds the potential to transform the healthcare landscape, offering more personalized, targeted treatments once thought to be out of reach.
Engaging the Immune System – with Martin Main, Chief Scientific Officer, Medicines Discovery Catapult
Engaging our body’s immune system to act as a treatment represents a revolution in cancer therapy. However, this is just the tip of the iceberg in terms of the pivotal role the immune system plays in a wide range of diseases – and in how we might be able to modulate it to generate novel therapeutic approaches.
Aberrant inflammatory response is at the root of a diverse range of pathologies, affecting any organ in the body, from central nervous system disease to lung and liver fibrosis. It is also likely to be a key component in age-related diseases because of the reduced immune function as we age. Immune homeostasis is critical as both underactive and hyperactive immune response can drive pathology and lead to a wide range of different symptoms and conditions depending on the organ or tissue affected. This makes the immune system both a complex systems-based drug target and medicine.
There are some blunt tool medicines to suppress the immune system, such as steroids, and CAR-T therapies. However, we have very few immune modulators that can tune the response specific to a disease in a sophisticated manner to prevent a destructive side effect profile observed with current therapeutic approaches. The next ten years will see a wide range of ‘off the shelf’ CAR-T therapies, making this cell therapy class more accessible. Behind this will be novel approaches of immune modulation and immune ‘trainers’ that will enable the advent of disease remission rather than only symptom management.
Solid Tumors and Unmet Needs – with Brian Gastman, EVP of Medical Affairs, Iovance Biotherapeutics
In the next decade, I envision a transformative shift in drug development and manufacturing, particularly in individualized T cell therapies. These groundbreaking therapies could revolutionize treatment for solid tumors, which constitute over 90 percent of cancers in the US, and are characterized by a lack of commonly shared antigens among patients.
Approved and individualized T-cell therapies will be a significant stride forward in helping address the substantial unmet needs for advanced melanoma treatment, considering that approximately half of metastatic melanoma patients treated with immune checkpoint inhibitors require additional therapy within a year. And this is just the beginning.
There are still significant unmet medical needs for multiple solid tumor cancers. We need to see an ongoing commitment to expanding the reach of T-cell therapy with robust pipelines that show promising clinical data across multiple solid tumor cancers, including frontline advanced melanoma, non-small cell lung cancer, and head and neck cancer. Frontline therapies to enhance the rate and depth of responses, while maintaining manageable long-term safety for patients with solid tumors, could improve outcomes over current checkpoint inhibitor mono- or combination therapies.
Collaboration will forge a path forward. Transformation combines taking what we know works and investing in its potential to advance innovation. I see a future where solid tumor therapy development and manufacturing is enhanced, streamlined, and increasingly more available with the goal of creating fuller and longer lives for cancer patients across the globe.
Moving Beyond Blood Cancers – with James Lim, CSO at Xcell Biosciences
For all the excitement around cell therapies to treat cancer, the reality is that most cell therapies today are only effective for hematological malignancies. The greatest improvement for pharma would be translating the success of cell therapies to solid tumors, which make up the vast majority of cancers. This would be a game-changer for the industry, and a literal life-saver for patients.
The fundamental reason cell therapies are stymied by solid tumors is their near-toxic microenvironment. Rife with immunosuppressive mechanisms, low oxygen levels, and high interstitial pressure, tumors thrive in an environment that’s hostile to most cells. Evaluations of therapeutic cells that have been delivered to solid tumors found them to be depleted and dysfunctional. Tumor infiltrating lymphocyte therapy, the only class of cell therapies currently approved for a solid tumor indication, has existed for decades, and yet the challenges of manufacturing these cells to dose while maintaining their potency has stymied progress.
But there is hope. Mounting evidence suggests that growing cell therapies under conditions more like the tumor microenvironment can make them hardier. Metabolic conditioning with advanced incubators that allow users to fine-tune more parameters, including oxygen and pressure levels, can help acclimate cells, preparing them to survive in an environment that might otherwise kill them. This approach is at odds with the conventional wisdom that therapeutic cells should be grown in conditions that keep them as happy as possible in vitro. Yet it is supported by more and more studies showing that metabolic conditioning can lead to more potent and more abundant cell therapies. This new avenue could dramatically expand the use of cell therapies across a wide range of cancers.
Further Advancing Cancer Research – with John Scarlett, Chairman of the Board, President and CEO, Geron
I believe the continued momentum around new modalities and new classes of medicines for the treatment of hematologic malignancies could dramatically improve the industry as our understanding of the biology in this area continues to improve significantly. Today, CAR-Ts, immunotherapies and other novel treatment approaches have the potential to revolutionize care for the millions of Americans impacted by blood disorders.
However, despite these advances, there are still a number of hematologic disorders with substantial patient populations that continue to have unmet medical needs. This is why we were thrilled to bring the first FDA-approved telomerase inhibitor to certain lower-risk MDS patients, a serious blood cancer that has seen only modest drug development innovation over the past decade, with the approval of Rytelo (imetelstat) earlier this year.
Additionally, I believe these further advancements in cancer research and new classes of medicines can unlock innovation more broadly across our industry. For example, CAR-Ts have shown promising early results for the treatment of a small set of patients with the autoimmune disease lupus. I look forward to what new modalities can be addressed tomorrow with the science we are leveraging today.”
The Importance of AI and Machine Learning – with Alexander Seyf, CEO, Autolomous
The integration of digital technology has dramatically refined our approach to scientific data collection, enhancing the precision and efficiency of research. I believe that AI and ML are set to take the capabilities of cell and gene therapies to unprecedented heights. By harnessing AI to analyze vast datasets, researchers can uncover patterns and predict outcomes much more rapidly than traditional methods allow. This integration of AI and ML could not only accelerate the development process, but enhance the precision of cell and gene therapies, leading towards a more robotized and automated future in medicine.
Imagine a world where cutting-edge therapies are not only developed in distant, centralized labs, but are seamlessly integrated into a “lab-by-the-bed” setting. Such a model could leverage digital data, collaborative platforms, and standardized processes to drastically reduce costs and expand access to personalized, effective treatments. By adopting global standards and fostering international collaborations, CGT can be made available universally, ensuring equitable healthcare outcomes across all demographics.
Sharing unsuccessful outcomes will also be as crucial as celebrating breakthroughs. By openly discussing what doesn’t work, the scientific community can avoid repeating past mistakes, thereby preventing potential setbacks and disasters in cell and gene therapy development. A transparent approach to failure will help foster a culture of continuous improvement and safety.
The Far-Reaching Benefits of Genomic Medicine – with Seng H. Cheng, SVP Research and Product Development, Alexion, AstraZeneca Rare Disease
Establishing a healthcare ecosystem that fosters the R&D and delivery of genomic medicines, including gene therapy and gene editing, will be transformative in the years ahead. Decades of research in this space is finally bearing fruit, with technological advancements, an evolving regulatory landscape, and clinical successes driving momentum in the development of this innovation that confers the potential for a curative therapy.
Among the most notable applications for genomic medicines are rare diseases, which impact the lives of 400 million people around the world. Today, there are 10,000 known rare diseases, 80 percent of which are believed to have a genetic cause. As patient populations for individual rare diseases are inherently small (sometimes numbering fewer than 100), advancing these medicines can be challenging and requires collaboration across the entire healthcare ecosystem. This includes early engagement with patient communities and regulatory authorities, as well as ongoing dialogue with payers to ensure patients around the world have access to these innovative treatments.
While the unmet need is significant for rare diseases, genomic medicine also has the potential to deliver far-reaching benefits if applied to more common diseases that impact larger patient populations. This scientific advancement holds the possibility to not only transform the lives of patients and their families but the biopharmaceutical industry as a whole.
Engineering With Gene Editing – with Nicholas Siciliano, Co-Founder & CEO of Vittoria Biotherapeutics
Over the past decade, gene editing has emerged as a centurial disruptor in biotechnology, reshaping our approach to research and accelerating our understanding of disease. In the next evolution of its application in drug development, gene editing technologies are now being applied to enhance cellular function, and more directly, as a strategy to engineer the next generation of cell therapies.
We have seen the tremendous promise of cell therapy through the achievement of curative outcomes in certain patients with B cell malignancies, but their broader application has been hindered by significant challenges in targeting, durability, and safety.
Through gene editing, we can fundamentally redesign T cells and address functional limitations. Initial efforts are already underway through the targeting of inhibitory signaling pathways to enhance effector function and improve tumor clearance. However, as we refine our approaches and continue to build a better understanding of T-cell biology, we could potentially layer on additional modifications to create an entirely new class of cell therapies. Beyond the direct benefit of improving patient outcomes, increasing proliferative capacity and all-around stemness could lower dosing requirements and streamline manufacturing, leading to reduced costs and improved accessibility.
Looking ahead to the next decade, I anticipate that gene editing will power the continued evolution of cell therapies. These next generation cell therapies will boast greater efficacy and safety, but will also be engineered to treat a broader range of diseases, transforming treatment paradigms across oncology, autoimmune diseases, and beyond.
CRISPR Meets AI – with Monika Paule, CEO of Caszyme
I envision a future where CRISPR gene editing revolutionizes healthcare through personalized gene therapies tailored to individual genetic profiles. By precisely correcting underlying mutations, CRISPR has the potential to surpass traditional therapies, offering superior treatment outcomes across a wide range of conditions. To realize its full potential, the development of novel Cas nucleases with advantages over existing CRISPR tools is crucial. Expanding the selection of available CRISPR nucleases with diverse characteristics is essential for creating therapies tailored to each individual’s genetic profile. CRISPR gene editing also accelerates drug discovery by swiftly generating and validating disease models, expediting the identification of therapeutic targets, and facilitating the development of innovative treatments, while promising shorter timelines from discovery to market, enhancing efficiency, and increasing accessibility of novel therapeutics.
Integrating other innovative approaches, such as AI, with CRISPR technology amplifies the potential impact of gene editing even further. AI can optimize CRISPR gene editing systems, accurately predict editing outcomes, and refine therapeutic strategies, enhancing treatment effectiveness and safety. This synergistic integration could not only transform genetic disease treatments, but also revolutionize global drug development processes.
I also think that mRNA-based delivery technologies promise to bring significant changes to the therapeutics field. The SARS-CoV-2 pandemic accelerated development and validation of mRNA vaccines, showcasing the immense potential of mRNA with longer-lasting expression of therapeutic proteins leading to prolonged clinical benefits. With further optimization of mRNA composition and established quality control, mRNA technology could revolutionize the field.
Over the next decade, I anticipate more targeted therapies tailored to individual genetic variations, facilitating faster cycles of innovation and improving patient outcomes across diverse diseases. Unlocking the full potential of new technologies such as CRISPR gene editing, mRNA, and AI will lead to significant changes in therapeutic development and manufacturing.
Read more about the future of pharma here.
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