Given recent progress in cell therapy research, it is clear that the engineering disciplines outlined in this Review will play an increasing role in the creation of new product pipelines with improved safety, efficacy and accessibility for patients.

Recent scientific advances have not only demonstrated the potential impact of technologies
developed by each of these fields, but have also identified potential paths for overcoming the grand challenges that currently limit broader commercialization of cell therapies. We anticipate that these technologies will continue to refine autologous cell therapy pipelines (for example,CAR-T therapy), offering improvements in mode of action and manufacturing. However, it is probable that the most impactful advancements towards products will come from innovations that enable greater potency and
viability in allogeneic products that are more readily sourced and manufactured.

Beyond independent contributions made by the engineering approaches outlined in this Review, are
foreseen synergies between the disciplines that have a major role in advancing translation of cell-based therapies. Genome and epigenome editing strategies will continue to be used to improve cell-intrinsic properties, and new Cas protein variants that are uncovered and engineered will create opportunities to generate increasingly larger and more sophisticated genetic perturbations. These capabilities will enable comprehensive, systems-level reshaping of native cellular pathways and alteration of cell phenotype, potentially yielding products that are resistant to apoptotic signals, demonstrate enhanced viability and expansion potential acrossthe spectrum of manufacturing steps, or are capable of secreting higher therapeutic protein titres. Advancing these capabilities will unlock the ability of synthetic biology to engineer functionality that enables dynamic control over these features through complex regulatory
circuitry.

Although these capabilities stand to enhance autologous cell therapies, their impact on therapies that
rely on allogeneic cell sources could perhaps be even greater given the potential for complex, multi-module synthetic programmes that could be used to engineer enhanced efficacy in readily sourced, yet otherwise low-potency products.

Advances in biomaterials have already facilitated the development of several allogeneic encapsulated cell
products, and there are currently several clinical stage companies advancing encapsulated cell products for type 1 diabetes, endocrinology indications and orphan diseases.

Were anticipated future development of encapsulated cell therapies into new indications by leveraging
innovations in genome and/or epigenome editing and synthetic biology, to develop products with greater longevity and enhanced sense-and-respond capabilities that offer more precise spatial and temporal regulation of therapeutic activity in disease states, in a stage- and patient-specific fashion. Such custom programmed cell-based devices could be deployed as sentinels to monitor, modulate and report on fluctuations in patient physiology, enhancing management of chronic indications such as endocrine or autoimmune disorders.

One of the most exciting long-range opportunities for synergizing engineering approaches to address cell
therapy grand challenges lies in the development of therapeutic pipelines that feature stem cell-derived,
off-the-shelf products that can be custom engineered to treat diverse indications. Doses of these ‘universal’ cell therapy products could be generated on demandvia retrieval from storage, expansion and differentiation to mature effector cell types, thereby furnishing a continuously replenishable, disease-specific cell source.

Although formidable basic research barriers must be overcome before realizing this vision, the potential benefits of such an approach are numerous. As pluripotent cells are generally amenable to repeated and large-scale genetic manipulations, genome and/or epigenome editing and synthetic biology approaches could be fully utilized to engineer sophisticated and specialized functionality. In addition to being configured for immune evasion or exact HLA subtype matching, such cells could harbour synthetic regulatory programmes that precisely delineate differentiation to disease-specific effector cells
or that enable residence within a biomaterial chassis.

Additionally, these cells could be programmed with customized sense-and-respond modules that enhance potency and safety, while enabling field-programmable tuning capabilities to flexibly address diverse disease and patient settings.