Toward?next-generation advanced therapies: extracellular vesicles and cell therapy – partners or competitors?

摘要

Success in practice with cell-based regenerative immunotherapies has transformed blood cancer care?but underscores challenges in terms of access, affordability?and mixed responsiveness [1]. Accordingly, the regenerative toolkit continues to diversify, aimed to address shortcomings of earlier approaches. Enhancing standardization and scalability, as well as achieving cost-effective outcomes, are drivers for next-generation solutions. In this context, cell-free approaches have generated major interest. Case in point, extracellular vesicles (EVs) are increasingly considered to overcome some of the limitations of cell-based therapies [2–4]. So far, EVs have been used in preclinical trials as cancer vaccines, as vehicles for targeted drug therapy, or to promote regeneration and wound healing in connective tissues, with more clinical studies to come [5–8]. In the present article, we discuss whether the use of EVs is an appropriate treatment strategy, and which regulatory and biological hurdles must be overcome before EVs can be considered as next-generation advanced therapeutics.In the early years, the development of surgical strategies and chemical engineering of pharmaceutical compounds with well-defined pharmacokinetics and efficacy profiles significantly improved outcomes and contributed to higher life expectancy in developed countries [9]. However, only few treatment options were curative, and?in most cases?the higher life expectancy was associated with a prolonged chronic state of the underlying disease [10]. About 30 years ago, the advent of protein engineering further diversified the therapeutic toolbox, ultimately leading to cellular engineering and cell-based approaches around the turn of the century that held the promise of regenerating and curing chronic diseases [11–13]. Today, gene editing and immunotherapies are the most advanced approaches along the translational path, with a selection of products already available in clinical practice [1]. Cell-based therapies were studied intensively over the past 20 years, reflected by more than 150,000 publications in the past 10 years alone. Despite these tremendous efforts, only few cell-based products received market approval by the EMA and/or the US FDA (Tables 1–3). Some of these approved therapeutics, such as Provenge, Tecartus?or Kymriah, are based on the ex vivo modification of immune cells to trigger an immune response against certain cancer cells. In this context, autologous cell preparations were either genetically modified to express chimeric antigen receptors?or were primed with tumor antigens (Table?1). In the field of regeneration, cell-based products such as Alofisel and Holoclar have received market approval (Table?2), and the growing interest in gene therapy has led to the EMA- and FDA-approved products Luxturna and Zolgensma (Table?3). In contrast, despite conducting more than 50 clinical trials using adult progenitor cell preparations for cardiovascular disease therapy, none resulted in an EMA- or FDA-approved drug [14]. One explanation for such a low commercialization is the complexity of the mechanism of action of cell preparations [15]. Compared with pharmaceuticals, which act as ligands for specific receptors, the mechanism of action of cell-based products is much more difficult to characterize. Due to their plasticity, the large number of nucleic acids and proteins that cells contain, there is an indefinite number of possible interactions with the host after cell transplantation [16]. Deciphering the mode of action of such a complex therapeutic requires a higher degree of collaboration than is currently practiced in many academic institutions [17–19]. The conceptualization of such a research approach, from the first in vitro experiments to preclinical large animal experiments, requires a well-coordinated work plan and the collaborative, multidisciplinary effort of scientists and clinicians. This?in turn?requires an environment and infrastructure that is