In this editorial, Aaron D. Levine (Georgia Institute of Technology) reflects on the role manufacturing can play in the commercialization of a cell therapy.
Aaron D. Levine1
1Associate Professor, School of Public Policy, Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology
It’s an exciting time for cell therapy. The recent FDA approval of Novartis’s (Basel, Switzerland) Kymriah — a novel treatment that engineers patients’ own T cells to attack their cancer — and the announcement of the US~$12B acquisition of Kite Pharma (CA, USA) by Gilead Sciences (UK) provided regulatory and financial legitimization that the field has long craved.
Yet the future of cell therapy is far from certain. Indeed, cells have long been identified as the future of medicine, poised to complement existing therapeutic approaches (i.e. small molecules, biologics) and help patients suffering from currently untreatable conditions. Despite the clear potential of cells as a therapeutic medium, however, the development of successful cell therapies has been difficult. This reflects a variety of challenges that cell therapy developers must surmount to make use of living cells as a therapeutic intervention.
A couple of years ago, Brittany Dodson — then an undergraduate student at Georgia Tech — and I reviewed a diverse set of cell therapy literature and conducted interviews with experts in the field to identify and analyze key challenges affecting scientists and firms seeking to develop cell therapies. The paper describing this work (available here) classified challenges into pre-market, post-market issues as well as manufacturing challenges, which cut across the pre-market clinical translation and post-market commercialization stages. The work highlighted how interactions among these various challenges made it difficult for firms to address one challenge without creating new difficulties.
Reflecting on this work and recent advances in cell therapy, I’m struck by the emergence of cell manufacturing as a both a central challenge and a key opportunity for the field. Manufacturing of therapeutic cells is critical to both the scientific and commercial success of the field yet research in this area has lagged. This is perhaps understandable — why, after all, should firms invest in improving and optimizing manufacturing when the field’s overall potential is unclear — but it is nonetheless unfortunate.
Cells are orders of magnitude more complex than traditional small molecule therapeutics or even biologics. They are alive, capable of responding to changes in their environment and surroundings, and changing markedly both before and after their therapeutic application. This complexity underlies their potential but also the cell manufacturing challenge and opportunity. Therapeutic cells must be produced reliably, consistently and affordably to enable cell therapies to reach their potential.
Inconsistencies in cell manufacturing pose safety risks to research participants during clinical trials and to patients should a cell therapy product gain market access. They can also compromise efficacy, making it difficult to bring products to market in the first place or limiting the benefit they provide once there. Potential concerns include contaminants or impurities introduced during the manufacturing process, as well as unexpected cell death or differentiation, among a range of other potential changes to cellular morphology or function.
Addressing manufacturing challenges is, of course, key to gaining regulatory approval to bring a cell therapy to market. Furthermore, the manufacturing requirements imposed by regulators provide an important incentive for firms commercializing cell therapy to standardize their manufacturing approaches. Despite this incentive, however, history has shown that transitioning from research-scale production to commercial-scale production is a daunting task made only more challenging by concerns — whether founded or not — that changes in the manufacturing process to scale up, scale out and otherwise optimize manufacturing will invite novel scrutiny from regulators and complicate the path to commercial and medical success.
While regulators, such as the U.S. Food and Drug Administration, are working to streamline and improve oversight of emerging cell and gene therapies, these steps are only part of the solution. Better scientific understanding and improved technology is needed to efficiently and safely grow, modify and monitor cells as they proceed through the manufacturing process, and ensure that the cells physicians use to treat their patients have the precise characteristics needed to maximize the likelihood they will be benefit patients and minimize they chance they will harm them.
Enhanced cell manufacturing is also critical to ensuring access to emerging cell therapies. These promising but complicated therapies cannot truly revolutionize health care unless patients can afford them. Like other high profile emerging therapies, constraints on access to cell therapies look likely to be an issue. Novartis has, for example, announced an initial price of US$475K for its new cell therapy treatment Kymriah in the United States and this is likely only a fraction of the total health system cost associated with the treatment. While this initial price is lower than some analysts expected, it is substantial, likely putting it out of reach for some patients. The complications associated with manufacturing and administering cell therapies can also delay treatment and impose geographic constraints on access.
Improving the manufacturing of therapeutic cells has the potential to reduce costs, speed time to treatment, and make these treatments available to a broader population. Indeed, if cell therapies are to reach their full potential, investment in cell manufacturing is more than a pragmatic necessity. Rather there are strong ethical justifications to invest in the science and technology and in training the workforce necessary to advance cell manufacturing and increase the chance that novel cell therapies are successfully developed and made widely available to treat patients around the world.
This material is based upon work supported by the National Science Foundation under Grant No. 1648035. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.
Aaron D. Levine is an Associate Professor in the School of Public Policy at Georgia Tech where his research focuses on issues at the intersection of bioethics, biomedical research and public policy. He is co-director for Engineering Workforce Development and conducts ethics and policy research for the NSF-funded Engineering Research Center for Cell Manufacturing Technologies (CMaT).