Abstract
T cells engineered to recognize and kill tumor cells have emerged as powerful agents for combating cancer. Nonetheless, our ability to engineer T cells remains relatively primitive. Aside from CAR T cells for treating B cell malignancies, most T cell therapies are risky, toxic, and often ineffective, especially those that target solid cancers. To fulfill the promise of cell-based therapies, we must transform cell engineering into a systematic and predictable science by applying the principles and tools of synthetic biology. Synthetic biology uses a hierarchical approach—assembling sets of modular molecular parts that can be combined into larger circuits and systems that perform defined target tasks. We outline the toolkit of synthetic modules that are needed to overcome the challenges of solid cancers, progress in building these components, and how these modules could be used to reliably engineer more effective and precise T cell therapies.
Highlights
Challenges in Engineering T Cells to Treat CancerT cells modified to express chimeric antigen receptors (CARs), which redirect cytotoxicity toward tumor cells (Figure 1a), have proven to be remarkably effective for treating B cell malignancies
CAR T cells and challenges facing them for solid tumors. (a) Diagram of CAR T structure, which includes an extracellular recognition domain bound to the cancer antigen and fused to intracellular T cell receptor (TCR) signaling domains (CD3ζ ) and costimulatory domains (e.g., CD28 or 4-1BB). (b) There are three major challenges for CAR T cells when treating solid tumors
We propose that synthetic biology efforts to engineer T cells should be driven by three major needs: (a) enhancing the tumor recognition precision to prevent healthy tissue cross-reaction/toxicity, (b) boosting the ability to overcome suppressive tumor microenvironments (TMEs), and (c) enabling user control over engineered cells to enhance safety in patients (Figure 1b)
Summary
Engineering T Cells to Treat Cancer: The Convergence of Immuno-Oncology and Synthetic Biology. Cellular immunotherapy, synthetic biology, engineered immune cells, T cells, solid tumors
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