The achievements of cell-based therapeutics over the last decades have bolstered efforts in recent years to bring more of these products to market and across an ever more diverse range of applications. These advanced therapeutics offer promising potential to treat conditions which, to date, have defied traditional treatment modalities. Interest and investment in this sector are at an all-time high and whilst many are hopeful of a boom in the number of approved therapies in the coming years, the industry still faces significant challenges, particularly with regard to the manufacture and regulation of these cell-based products. In this article, we will provide an overview of some of the key applications of cell therapies as well as look more closely at the challenges facing the evolution of this field.
To date, the applications of cell therapies have largely fallen into two broad categories; tissue regeneration and immuno-modulation. With regard to the former, cell therapy has been viewed as one of the most promising techniques for the repair of damaged tissue, with applications in cardiovascular disease, neurodegenerative disease (for example, Parkinson's and Alzheimer's), musculoskeletal injury or degeneration and endocrine dysfunction (for example, type I diabetes).
Cell therapies have proven particularly effective in the repair of articular cartilage, for which the intrinsic capacity for repair is low. The most established of these therapies have employed the patient's own cells, i.e. autologous cells. In brief, harvested chondrocytes are expanded ex vivo, seeded into a collagen matrix and then re-implanted into cartilage defects in joints. Such products have been available for around a decade now (ChondroCelect, developed by TiGenix was first approved in the EU in 2009) and have shown considerable efficacy, although use of these advanced options is still low when compared to traditional treatment modalities (for example, joint replacement and analgesics). Whilst cartilage repair applications have tended to employ the terminally differentiated chondrocyte, bone repair applications have made use of the regenerative capacity of stem and progenitor cells. Bone marrow-derived mesenchymal stem cells (MSCs) have been proven in a range of orthopaedic applications over recent decades, including in the treatment of infants with osteogenesis imperfecta and in the repair of non-union fractures. Unfortunately, obtaining sufficient yields of pure MSC populations from bone marrow has proven difficult and there has been a switch in recent years to utilise MSCs derived from other sources, such as adipose tissue.
Autologous cell therapies like those discussed above all depend on obtaining sufficient cell numbers from the donor patient and the ability to expand functional cells ex vivo. Off-the-shelf cell therapies, which clinicians can employ for a range of patients, as and when needed, without concerns over yield or expansion protocols, are likely to represent the future of cell therapy. UK-based biotech, ReNeuron, is one such company forging ahead with allogeneic cell therapies. Interestingly, ReNeuron's neural stem cell line for the treatment of the disabling effects of stroke were cryopreserved prior to utilisation in the PISCES I (Phase I) clinical trial. Cryopreservation is just one of a number of advancements which will be necessary to bring off-the-shelf cell products to reality.
Whilst the regenerative applications of cell therapies have, at the very least, been researched for some time now, the immuno-modulatory applications of cell therapy, in particular, chimeric antigen receptor (CAR) T cells, is a more recent development. Indeed, it was only in the early 90s when first-generation CAR T cells (which contained an antibody/T cell receptor fusion molecule) were developed and around the same time researchers were investigating adoptive transfer of patient-derived virus-specific T cells. Since these early days, significant leaps forward have been made. In 2017, Novartis' Kymriah (tisagenlecleucel) became the first CAR T cell therapy to be approved by the FDA, with Kite Pharma's Yescarta (axicabtagene ciloleucel) following shortly thereafter. Data from the UK's Cell and Gene Therapy Catapult clinical trials database indicates that there were around 22 clinical trials investigating the safety and efficacy of CAR T cells in the UK alone in 2018. The success of CAR T cells to date has largely been shown for haematological malignancies (indeed, Kymriah and Yescarta are approved for the treatment of acute lymphoblastic leukaemia and large B-cell lymphoma respectively). In contrast, despite extensive research, CAR T cell therapy for solid tumours hasn't had the same impact, not least because of the challenges of targeting solid tumours including identifying a suitable target antigen and homing the cells to the hostile, tumour microenvironment. Nonetheless, strides are being made by combining CAR T cell therapy with other biologic agents, specifically checkpoint inhibitors such as pembrolizumab and nivolumab which target programmed cell death protein 1 (PD-1) a key regulatory protein found on T cells. The University of Pennsylvania, for example, is recruiting for a Phase I clinical trial assessing the safety of a CAR T cell/pembrolizumab combination therapy for the treatment of glioblastoma. This follows preliminary evidence from the Memorial Sloan Kettering Cancer Center that showed both safety and efficacy of a mesothelin targeting CAR T cell and pembrolizumab combination therapy in patients with malignant pleural disease. Thus, the use of CAR T cells for the treatment of solid tumours appears to be progressing.
Immuno-modulatory cell therapies other than CAR T cells are also being investigated in the clinics. By way of example, Fate Therapeutics is currently assessing the safety of its off-the-shelf Natural Killer (NK) cell therapy. Unlike traditional CAR T cells, Fate's NK cell therapies are derived from an induced pluripotent stem cell (iPSC) line allowing the production of large numbers of well-defined cells without relying on a patient's own immune cells (which are often depleted in many cancers). Preclinical studies showed the efficacy of these cells in the treatment of checkpoint inhibitor resistance tumours. At present, Fate has a pipeline of at least five different NK cell therapies.
As well as the immuno-oncology applications, cell therapies are also being trialled for immuno-regulatory applications such as in the treatment of autoimmune disease and graft versus host disease. These trials have largely involved the use of autologous, expanded, regulatory T cells (Treg cells) which, through a range of mechanisms, are able to suppress a variety of immune cells. Treg cells used in studies to date have been isolated from both umbilical-cord blood and peripheral blood. A variety of Phase I studies have been completed or are in the process of assessing the safety of Treg cells for the treatment of type I diabetes. Although in the early stages of development, data to date is showing that Treg cells are well tolerated in patients and the ex vivo expansion methods are capable of generating sufficient numbers of stable and functional Treg cells. Future Phase II/III trials will of course be needed to reveal the true potential of these cells.
Global investment in cell-based therapies increased to US$7.6 billion in 2018, a 64% increase from the previous year. In spite of this, the sector still faces a number of significant challenges before these advanced therapeutics become widely used.
Research and development in this sector is undeniably booming, though difficulties in expanding, manufacturing and transporting cell products may be hampering the commercial viability and ultimate availability of these products. Achieving the quantity of cells needed with current production methods, especially if uptake of these therapies becomes more widespread, is one of the major hurdles facing the industry. By way of example, the recommended dose of ChondroCelect is 1 million cells/cm2 of cartilage defect. CAR T cell therapy Yescarta is dosed at a staggering 2 million cells per kg (around 140 million cells for an average adult male). The issue is magnified somewhat by the focus of today's research on the cell product per se; emerging biotech companies with innovative cell therapies should, at an early stage, consider the processes that will be necessary to achieve the desired cell numbers for later Phase II/III trials and beyond. These challenges also bring opportunities however, and there are now a number of innovative companies seeking to develop solutions for the industry, to simplify, accelerate and improve cell therapy manufacturing and supply.
Automation of the manufacturing processes is currently of significant interest to the community. At present, the manufacturing processes employed in the generation of cell therapies largely resemble those utilised in other biopharmaceutical areas (for example therapeutic antibodies). Unlike therapeutic antibodies production, however, cell therapies (especially those relying on patient or donor cells) vary significantly from batch to batch, requiring complex and adaptive processes to generate consistent products within the regulatory confines. Through the implementation and training of a variety of mechanisms, e.g. sensors, robotics and image acquisition as well as processing software, researchers believe variability and reliability of current manufacturing processes can be improved.
Whilst improvements in the manufacturing processes will hopefully lead to a reduction in the costs associated with the production of cell therapies, it should be noted that, unlike traditional therapeutic modalities, cell therapies are often a one-off treatment option for patients. Biotech companies must bear this in mind when attempting to recoup their research and development costs and, as such, costs are always likely to be higher than traditional biologics. As it stands, the high costs associated with these therapies is proving challenging for healthcare providers to justify.
The cost of these therapies is at least in part due to the convoluted path from bench to bedside. Cell therapies are considered differently to the conventional biopharmaceutical agents and have to undergo even more rigorous regulatory and quality assessments. This of course ensures public safety, but has also put the brakes on the number of cell therapies actually being approved (despite the ample number of trials). As is so often the case, the regulatory frameworks in place have not been able to keep up with the unprecedented scientific advances in this field. What's more, the absence of harmonisation across jurisdictions has placed undue burden on the smaller players in this field. The lengthy timescales involved in obtaining regulatory approval (even after showing clinical efficacy) are exemplified by Holclar, an autologous cell therapy (comprising human corneal epithelial cells and limbal stem cells) for the repair of damaged cornea, which despite having shown clinical efficacy as early as 1997, only obtained regulatory approval in 2015.
Regulation is of course paramount to ensure the safety of patients receiving advanced therapeutics (including cell and gene therapies) which have long been shrouded in safety concerns. These concerns are not without basis. Indeed, safety has been a major sticking point for stem cell therapies. The primary concern regarding stem cell therapies is unwanted differentiation, as has been shown in the cardiovascular setting, where calcifications have been identified in the myocardium of patients treated with MSCs following infarction (MSCs, of course, give rise to cells of bone and cartilage as well as muscle). Tumorigenesis has also been a concern for stem cell therapies, although this appears to have been unwarranted based on current data. In the immuno-oncology field, CAR T cells have also been associated with safety concerns including the development of cytokine release syndrome in patients receiving CAR T cell therapies, the engagement of target antigens on non-pathogenic tissues and host immune response to the specific recombinant proteins found in these cells. Pleasingly, the industry is seeking solutions to these problems and research is ongoing to improve the safety profile of these therapies. In the CAR T cell space, the incorporation of suicide or elimination genes into delivered cells is being investigated as a means to selectively deplete these cells in the body when necessary. The approved cell therapies are largely still in their infancy and data from future Phase IV clinical trials will be indispensable in assessing the long-term safety of these therapies.
The number of cell therapies actually approved for clinical use remains small. This highlights that, despite the significant scientific advances and investment, the sector is largely still at the research and development stage. Having said that, the industry appears to have reached a critical mass and with the number of clinical trials in this field growing steadily, we can only assume that we will be seeing more and more of these therapies in the clinics. The industry seems to have clicked and more emphasis is now being placed on the challenges of efficiently, yet safely, manufacturing these products. Improvements in this key area could pave the way for wider implementation and access to these therapies. A multidisciplinary approach will be essential in the coming years to increase the number of approved therapies whilst still ensuring affordability and, importantly, patient safety.
Originally published in IBI (https://issuu.com/mark123/docs/2019-ibi_winter-web_compressed).
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