Ger Brophy, PhDExecutive Vice PresidentBiopharma ProductionAvantor

Genuine progress is being made in the longstanding battle to effectively treat and control cancer. The National Cancer Institute projects that nearly five million more U.S. citizens are expected to survive cancer in 2029 than in 2019.1 Therapeutic tools such as next-generation sequencing and advances in immunotherapy are just two ways that fundamental scientific breakthroughs and innovative thinking are realizing the potential for new cancer treatments.

One of the most revolutionary breakthroughs 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 patients cells as a drug to treat disease. According to a paper published in the Journal of Gene Medicine, somewhere around 2600 gene therapy clinical trials had been undertaken in 38 countries around the world as of November 2017.2

These clinical trials demonstrate that the recent attention being paid to gene and cell therapy is not just hype. Some have noted that a select number of approved cell and gene therapies are for relatively small patient groups. However, its exciting to see the number of trials grow, especially when one considers this technologys ability to impact patients lives.

Its true that the number of patients receiving treatment is relatively small compared to other therapeutic regimens, but thats to be expected. Many of the biopharmaceutical researchers and manufacturers started with smaller, defined patient populations and, in particular, those with pediatric relapse 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 efforts has led to broader programs targeting larger populationsstarting with leukemia and lymphoma. Ultimately, the most challenging opportunityand the one with the greatest potential for beneficial outcomesis 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.

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, were taking control of and harnessing the patients own immune system to fight these cancers. Among the first patients treated for acute lymphoblastic leukemia, several are alive and thrivingfour, five, and six years later.

The game changer here is that cell and gene therapy uses the bodys 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 patients own T cells are extracted, modified, activated, expanded, purified, and returned to the patient.

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.

Increasingly, weve all seen a greater interest from the major biopharma companies. Novartis was probably the biggest; it started earliest and was successful in getting approval for Kymriah. Since last year, weve seen several important acquisitions by Gilead and Bristol-Myers Squibb, and major biopharma companies are participating in large strategic partnerships in China. As companies of this size get involved, the hope is that they will leverage their increased breadth and depth to develop novel products, instigate new trials, and find ways to manufacture therapies at scale.

If the cell and gene therapy industry is to succeed, it must overcome challenges of two kinds: scalability and manufacturability. These challenges may be summarized in a set of questions: 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?

With cell therapy, the single biggest point of variability is the patients own cells. By their very nature, these cells are individual to the patient, and their health implications for the patient should be considered as an integral part of cell processingat least as far back as the time of leukapheresis.

Variables and failure modes must be taken out of cell processing systems. We can standardize and miniaturize these systems, and we can enclose them so that theyre not exposed to failure modes. Also, we can improve technologies, like sterile fluid transfer, if we use excipient technology to further stabilize production. Finally, we can use analytical technology to understand the factors that contribute to a therapys success or failure.

Cell therapy producers and the companies that support and supply them need to become more innovative. In areas such as cell culture components, production chemicals, single-use technologies, sterile fluid transfer, and excipientsand the technology surrounding those process componentsthere 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 fewer cells, some of the side effects of these drug therapies may improve. Furthermore, we must find scalable ways to reduce costs.

Ultimately, these drugs must be developed in a more cost-effective manner. Thats 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.

There have been encouraging improvements in the way various regulatory groups have supported gene and cell therapy. To a certain degree, groups representing different regionsNorth America, Europe, and Asiahad been perceived to be setting precedents independently. More recently, it appears that regulatory bodies have been very open and collaborative in acknowledging that cell and gene therapies differ from more mature treatments such as biopharma drugs for cancer. The regulatory bodies have shown that they are willing to put the appropriate regulatory system into place to streamline the approval process and institute the ongoing monitoring of cell and gene therapies.

The U.S. FDAs support on CAR T-cell 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 FDAs postmarketing comments and safety issues.

Some have suggested that, ultimately, almost all cancer treatments will be based on gene and cell therapy approaches since they represent the most personalized form of treatment, which is, theoretically, the one with the highest potential for success.

Thats probably overly ambitious. Both large molecules and small molecules will continue to provide trusted, effective solutions with each type of drug product finding its niche. For example, large molecules are being developed for areas like neurodegeneration and are still offering great potential.

Its 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 starting and have yet to make a significant market impact. But considerable effort is going into developing, understanding, and characterizing drug targets, as well as the development of technology to make targeted drugs in production-level volumes.

All these developments are exciting and offer a great deal of hope. It is clear that gene and cell therapies work and save lives. The challenge now is to scale their production. It is also clear that cell and gene therapies can emulate other therapeutic approaches that have transitioned from theoretical possibility to practical reality. As a similar transition occurs for cell and gene therapies, the production issues that need to be addressed will be seen more clearly, prompting action that will bring us to the next stage of development.

References1. Bluethmann SM, Mariotto AB, Rowland, JH. Anticipating the Silver Tsunami: Prevalence Trajectories and Comorbidity Burden among Older Cancer Survivors in the United States. Cancer Epidemiol. Biomarkers Prev. 2016; 25: 10291036.2. Ginn SL, Amaya AK, Alexander IE, et al. Gene therapy clinical trials worldwide to 2017: An update. J. Gene Med. 2018; 20(5): e3015.

Ger Brophy, PhD, is Executive Vice President, Biopharma Production at Avantor

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Opportunities and Challenges in Cell and Gene Therapy Development - Genetic Engineering & Biotechnology News