Abstract
Engineered mammalian cells for medical purposes are becoming a clinically relevant reality thanks to advances in synthetic biology that allow enhanced reliability and safety of cell-based therapies. However, their application is still hampered by challenges including time-consuming design-and-test cycle iterations and costs. For example, in the field of cancer immunotherapy, CAR-T cells targeting CD19 have already been clinically approved to treat several types of leukemia, but their use in the context of solid tumors is still quite inefficient, with additional issues related to the adequate quality control for clinical use. These limitations can be overtaken by innovative bioengineering approaches currently in development. Here we present an overview of recent synthetic biology strategies for mammalian cell therapies, with a special focus on the genetic engineering improvements on CAR-T cells, discussing scenarios for the next generation of genetic circuits for cancer immunotherapy.
Highlights
Engineered mammalian cells for medical purposes are becoming a clinically relevant reality thanks to advances in synthetic biology that allow enhanced reliability and safety of cell-based therapies
CAR, where the extracellular part of the TGFβRII is fused to the endodomain of 4-1BB or that link a TGFβ-specific scFv to the CD28-CD3ζ intracellular signaling domains, have been engineered (Figure 1), activating rather than inhibiting CAR-T cells by TGFβ stimulation [53,54]
In this two-steps approach, the binding of the SynNotch receptor to the first tumor-associated antigens (TAAs) triggers the release of an intracellular transcription factor, which drives the expression of a CAR specific to a second TAA
Summary
Cancer immunotherapy has the goal of improving anti-tumor immune responses reducing off-target effects typical of chemotherapies and other state-of-the-art treatments. Different classes of immunotherapies have already been approved for cancer treatment and some others are in clinical trials [1] intending to facilitate the recognition of cancer cells by the immune system [2,3] These include checkpoint inhibitors, lymphocyte activating cytokines, agonists for co-stimulatory receptors, cancer vaccines, oncolytic viruses, bispecific antibodies and T cell-based adoptive immunotherapy (ACT) [2,3]. Several issues including the pleiotropic function of many cytokines, which can act both as immunosuppressors or activators depending on the cellular context, the redundancy of cytokine signaling, and the short half-life of these molecules make the efficacy of these treatments difficult This therapy often consists of the administration of high doses of cytokines that can cause vascular leakage and cytokine release syndrome (CRS) [9]. Advances in synthetic biology allowed engineering safer and more effective vectors, DNA or RNA–based implemented on bacterial or viral backbones, carrying genetic components, and functional resources [12]
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