Opportunities and Challenges in Cell and Gene Therapy Development
Genuine progress is being made in the long-standing battle to effectively treat and control disease. The National Cancer Institute projects that nearly five million more U.S. citizens are expected to survive cancer in 2026 than in 2016. Therapeutic tools like next-generation sequencing and advances in immunotherapy are just two ways that fundamental scientific breakthroughs and innovative thinking are moving the potential for cancer treatment forward.
One of the most revolutionary advances in this new era is cell and gene therapy. At its most basic definition, gene therapy （also called human gene transfer） is the therapeutic delivery of nucleic acid into a patient's cells as a drug to treat disease. According to The Journal of Gene Medicine, just over 2,700 gene therapy clinical trials have been undertaken in 38 countries around the world as of 2018.
Genuine potential for success
These clinical trials demonstrate that the recent attention being paid to gene and cell therapy is not just hype. Although initial approvals have been for relatively small patient groups, the significant pipeline of gene therapy studies for diseases such as hemophilia and various forms of blindness will significantly expand the impact of these treatments. It's exciting to see the number of trials grow, especially when one considers this technology's ability to impact patients' lives.
It's true that the number of patients receiving treatment is relatively small compared to other therapeutic regimens, but that's to be expected. Many of the biopharmaceutical researchers and manufacturers started with smaller, defined patient populations as, for example, those with relapsed pediatric refractory acute lymphoblastic leukemia. In part, these early efforts were directed at this type of cancer because the researchers wanted to deal with small populations that they understood well and, in many cases, had few or no other options for treatments.
The success of these initial cell therapy efforts has led to broader programs targeting larger populations—starting with leukemia and now lymphomas. Ultimately, the most challenging opportunity, and the one with the greatest potential for beneficial outcomes, is multiple myeloma. If these patients begin to see benefits from cell and gene therapies, it will justify the incremental approach the industry has been taking.
Promise of personalized medicine
The genuine, almost unprecedented potential for cell and gene therapy cannot be understated. For the first time, people are talking about curing these ruthless, relentless diseases. In a way never before possible, we're taking control of and harnessing the patient's own immune system to fight these cancers. At the recent Alliance for Regenerative Medicine Cell and Gene Therapy on the Mesa meeting, the significant response and survival rates from patients with Diffuse Large B-Cell lymphoma, Acute Lymphoblastic Leukemia, Non-Hodgkins Lymphoma, and Spinal Muscular Atrophy were noted and discussed.
The game changer here is that cell and gene therapy use the body's own systems, either the cellular immune system or the ability to repair and replace defective or missing genes. CAR-T cell therapy is arguably among the most personalized medicines one can consider. The patient's own T cells are extracted, modified, activated, expanded, purified and returned to the patient.
The promise of personalized medicine has been held out for a long time, and now we're actually beginning to see real, tangible effects from decades of research into the genetics of the human genome and cancer, giving us an understanding of how the disease develops and how patients respond.
The changing industry landscape
Significant growth is underway in the size and sophistication of companies and organizations entering the cell and gene therapy markets. Many of the early movers in cell and gene therapy were small biotech startups. In some cases, their treatments were supported by major hospital centers.
Now, we've seen a significant interest from the major biopharma industry. Novartis, in particular, has been active and led the way in securing approval for Kymriah. Novartis's focus in this area continued with the acquisition of AveXis and securing the approval of Zolgensma to treat spinal muscular atrophy (SMA). Since last year, we've also seen several important acquisitions by Gilead snatching Kite Pharma, Roche adding Spark Therapeutics, Bristol-Myers Squibb acquiring Celgene, and other companies in China driving large strategic partnerships with major biopharma companies. As companies of this size get involved, the hope is that they will leverage their increased breadth and depth to develop new labels, new trials and find ways to manufacture these therapies at scale.
Scalability and manufacturability are the two, closely-related challenges the industry faces, especially if cell and gene therapies are to fulfill their clinical potential. At first, the questions to be answered appear quite daunting: Can we manufacture cell and gene therapies at scale? If we can manufacture these treatments at scale, then can we do so safely? Can we do so at a reasonable cost so the populations that are affected by these diseases can access treatments?
And the problems presented are new. With autologous cell therapy, one must think about drug product in a different way. There is no inventory; the patient is waiting, and the risk/reward balance is different.
Standardizing processes and systems
One issue is process standardization. With cell therapy, the single biggest point of variability is the patient's own cells. And by its very nature, this is specific to the patient and specific to the health of the patient at the time of leukapheresis.
Variables and failure modes must be taken out of the manufacturing process. And innovations in process technology can make a real difference. We can standardize and close production systems so they're less exposed to failure modes. Processes can be miniaturized to drive cost efficiencies and, perhaps, better clinical outcomes. We can employ better workflow technologies, such as single-use sterile-fluid transfer. Fill/finish requirements will surely be different for cell and viral products and improved excipient technologies will play a large part in better patient experience and response. Different analytical standards will apply, particularly in relation to adventitious agents during cell expansion.
In particular, the numbers around virus production for gene therapy and ex-vivo cell therapy just don't add up. Adherent process and packaging systems are inefficient. Given the high viral titer numbers indicated in recent approvals, it will be difficult to scale these manufacturing operations. Either something must change, or massive manufacturing future capacity will need to be built. In the meantime, there will be significant reliance on CMOs for capacity.
Across the board, improvements in raw material inputs and innovations in manufacturing technology are now required if we are to see the deployment of these therapies economically and at scale.
To address these challenges, cell and gene therapy producers and the supply companies that support them need to develop stronger partnerships. In areas such as cell culture components, production chemicals, single-use technologies, sterile fluid transfer, excipients, and the technology surrounding those process components, there is value to improving collaboration and trying new solutions to address the issues of manufacturability and scale.
We need to better analyze and understand the variability that comes from the research data, even at the early stages of these trials, and use it to correlate with clinical and process outcomes. Taking out manual steps as early as possible is important, as well as creating closed systems using sterile fluid transfer technologies.
One of the most significant challenges is finding solutions around side effects. As we understand how to provide a more efficacious dose, perhaps using less cells, some of the side effects of these drug therapies may improve. Furthermore, we must find scalable ways to address costs which are far too high. Ultimately, these drugs must be developed in a more cost-effective manner. That's an area where technology providers and suppliers can play a significant role, by closing and automating systems and by understanding the contribution of labor and overhead and possible economies of scale from reducing processes.
Improving regulatory support
There have been encouraging improvements in the way various global regulatory groups have supported gene and cell therapy. To a certain degree, there was a perception of an “arms race” between different regional bodies—the U.S., Europe and the UK, China, and Japan and in different ways within different specialties.
More recently, it appears that regulatory bodies have been open and collaborative in acknowledging that cell and gene therapy is different from more mature biopharma cancer treatments. They are willing to put the appropriate regulatory system into place to enable these drugs to get to market and to monitor them going forward.
The U.S. FDA's support on CAR-T technologies is a good example. Regulators are allowing flexibility in the normal hierarchy of how clinical trials are performed, particularly in phase II and III trials, but the companies must still address the FDA's post-marketing comments and safety issues.
The future of cancer treatment
Undoubtedly, cell and gene therapies will have a significant role to play in disease treatment, given the personalized and precise nature of the treatments. But this will be against the backdrop of many existing and emerging therapy paradigms.
Both large molecules and small molecules will continue to provide trusted, effective solutions with each type of drug product finding its niche. For example, we have seen recent encouraging news in the area of monoclonal drugs for neurodegenerative diseases. And emerging fields such as nucleic acid based drugs are showing strong potential thanks to improvements in formulation and delivery.
It's worth remembering that monoclonal-based therapies and biopharmaceuticals have really only started to make a significant impact in the last 15 to 20 years. Cell and gene therapies are just emerging and have yet to make a significant market impact. With that consideration, who's to say what's next? Expanded programs in basic research to develop, understand and characterize drug targets; an exciting program of clinical development and improvements in process technologies should ensure this will be a constantly evolving landscape. And there will be many patient treatment options going forward.
All these developments are exciting and offer a great deal of hope. Gene and cell therapies work and save lives, and the challenge now is to scale the opportunity they offer to their full potential. It's clear that cell and gene therapy can succeed as one more healing tool. As with other treatments that moved from theoretical possibility to real results, we see the issues that need to be addressed more clearly, and we're ready to get the next stage of development in motion.
1.Cancer Statistics, National Cancer Institute, 2018.
2.Ginn S et al, Gene therapy clinical trials worldwide to 2017: An update, Journal of Gene Medicine: doi.org/10.1002/jgm.3015, 2018.