editorial Towards advanced cell therapies For cell therapies to transition from promises to products, increased eforts need to be put into the identifcation of the factors and biological mechanisms that afect safety and efcacy, and into the design of cost-efective methods for the harvesting, expansion, manipulation and purifcation of the cells.

he properties and functions of cells can be harnessed to identify and treat Tdisease. For example, injecting stem cells into diseased tissue — such as cardiac muscle after myocardial infarction — can promote tissue regeneration. Yet despite the promises of cell therapies, very few cell products have been approved for clinical use. One main reason is that cell therapies have failed to provide sufficient safety and efficacy guarantees, in part owing to a lack of understanding of the intracellular factors and biological pathways that determine cell expansion and differentiation. As our understanding of cell phenotype and differentiation deepens, it becomes increasingly possible to manipulate cells for the generation of effective therapeutic products for regenerative medicine and for cell-based immunotherapy, and in the form of cell vaccines. Although mechanistic understanding is necessary, it is insufficient. To take full advantage of the therapeutic potential of cell It highlights the need for interdisciplinarity, the survival and therapeutic efficacy of the products with enhanced or new capabilities, from developmental biology to materials transplanted cells. beneficial cellular functions need to be engineering to cell-product manufacturing, Cell therapies are transforming repurposed or reinforced, for instance by in order to overcome the hurdles that oncology. From cell-based vaccines to re-engineering signalling circuits. Take, for prevent many advanced therapies from engineered T cells, encouraging results example, T-cell-mediated cancer therapy: reaching the clinic. Indeed, despite decades from multiple clinical trials in patients the engineering of T cells bearing artificial of advances in cell therapies for cardiac with haematological cancers chimeric antigen receptors (CARs) — each regeneration, evidence of efficacy from are setting new efficacy goals. In a Review of them a collage of molecular components clinical trials has been underwhelming. Article, Crystal Mackall and colleagues that links the recognition of a specific In a Perspective, Eduardo Marbán highlights provide an overview of the many tumour antigen to T-cell activation — has the importance of designing therapies that CAR-design strategies used in clinical led to unprecedented clinical efficacy are deeply rooted in understood biological trials and reported in preclinical studies, in patients with haematological cancers mechanisms, and posits that cell-secreted including the use of new genetic modules, (as exemplified by the recent approvals, exosomes could become next-generation co-stimulatory domains and suicide by the United States Food and Drug therapeutics for cardiac regeneration, with switches that improve the specificity, Administration, of the two first CAR-T advantageous efficacy and safety profiles. efficacy and safety of these engineered cell products, Kymriah and Yescarta). Yet In cardiovascular regenerative medicine, T cells. They also discuss the design protein engineering is just one of the many research on the biology of stem cells has of CAR-T cells for treating solid fields contributing to the rise of tailor-made largely focused on the characterization of tumours — which are harder to tackle cell constructs for clinical applications. stemness and on differentiation factors owing to their immunosuppressive The path towards effective cell therapies that enable the differentiation of stem microenvironment and to the paucity of also involves mastering the manipulation, cells into functional cardiomyocytes and targetable tumour-specific antigens — and expansion, purification and preservation of other cell types found in diseased cardiac outline what would be needed for the the cells to establish standardized and robust tissue. In a Review Article, Joseph Wu development of off-the-shelf CAR-T cells. cell-product manufacturing processes. and colleagues discuss the critical factors Cells can also provide a source of tumour This focus issue dedicated to the limiting the therapeutic efficacy of stem antigens for immunization. Similarly to the prospects of cell therapies provides an cells transplanted to the heart, delineate how use of traditional vaccines for preventing overview of the current state of the art, with non-myocyte cells may be reprogrammed infectious diseases, dead tumour cells can be emphasis on cardiac regenerative medicine for cardiovascular regenerative applications, injected to kick-start an immune response and immunotherapy, and explores the and emphasize the importance of against tumours; alternatively, the antigen- challenges that lie ahead. cell-delivery strategies that do not impair presentation functionality of dendritic cells

Nature Biomedical Engineering | VOL 2 | JUNE 2018 | 339–340 | www.nature.com/natbiomedeng 339 © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. editorial can be hijacked to present specific tumour in biomedicine. Today, it is possible to discuss the need for robust infrastructure antigens to the immune system for the create synthetic gene circuits in cells that, that enables all the necessary steps to activation of tumour-killing T cells. In a via intracellular computational modules manufacture clinical-grade cell products. Comment, Nina Bhardwaj and colleagues and effector agents, ‘upgrade’ the cells to Biomanufacturing and commercialization posit that dendritic cells can make highly make them fully autonomous therapeutic challenges can be daunting, yet need efficacious tumour vaccines. Multiple antigen machines. The repurposing of endogenous dedicated efforts if next-generation cell- compositions, dendritic-cell formulations proteins or the de novo design of protein based therapies are to see widespread and delivery methods are currently being building blocks controlled by tailored genetic application. tested in clinical trials, including some in networks allows for cell customization, with The rise of powerful and easy-to-use which vaccine efficacy is being assessed exquisite targeting specificity, controlled tools for the molecular manipulation of in combination with potent antitumour timing and therapeutic activity. Martin cells is opening up wide prospects for cell immunotherapies such as checkpoint- Fussenegger and colleagues provide in a therapy. Yet one should not forget that the blockade inhibition. Review Article an overview of developments route to clinical success is paved by the As biotechnologies evolve at an ever in synthetic biology that enable the acquisition of deep biological knowledge faster pace, the toolkit for manipulating programming of cells to sense environmental and by thorough preclinical and clinical mammalian cells for therapeutic applications triggers and identify, eliminate or prevent the testing, and facilitated by the painstaking keeps expanding. The ability to modify development of pathologies. optimization of production protocols and a cell’s DNA with precision, enabled by Irrespective of disease type, the processes. ❐ methods based on clustered regularly production of cell-based therapeutics interspaced short palindromic repeats needs standardized, safe and cost-effective (CRISPR), has paved the way for a degree of scale-up production processes. In a Review Published online: 11 June 2018 cell customization that is without precedent Article, Biju Parekkadan and colleagues https://doi.org/10.1038/s41551-018-0256-4

340 Nature Biomedical Engineering | VOL 2 | JUNE 2018 | 339–340 | www.nature.com/natbiomedeng © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved. © 2018 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.