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Synthetic biology, genetic circuits and machine learning: a new age of cancer therapy
Krishneel Prasad1, Ryan S Cross1, Misty R Jenkins1,2,3
1Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Vic., Australia.
Abstract:
Synthetic biology has made it possible to rewire natural cellular responses to treat disease, notably demonstrated by chimeric antigen receptor (CAR) T cells as cancer immunotherapy. Building on the success of T-cell activation using synthetic receptors, the field is now investigating how induction of noncanonical signalling pathways and sophisticated synthetic gene circuitry can enhance the antitumour phenotype of engineered T cells. This commentary explores two recently published studies that provide proof of concept for how new technologies achieve this. The first demonstrated that non-naturally occurring combinations of signalling motifs derived from various immune receptors and arranged as a CAR drove unique signal transduction pathways in T cells and improved their tumour killing ability. Here, machine learning complemented the screening process and successfully predicted CAR T-cell phenotype dependent on signalling motif choice. The second explored how synthetic zinc fingers can be engineered into controllable transcriptional regulators, where their activity was dependent on the presence or absence of FDA-approved small-molecule drugs. These studies are pivotal in expanding the design choices available for gene circuits of the future and highlight how a single cellular therapy could respond to multiple environmental cues including target cell antigen expression, the tumour microenvironment composition and small molecule drugs.
Insights
Synthetic biology advances engineered T cells for cancer therapy. New research shows custom signaling motifs and drug-controlled gene circuits enhance T cell anti-tumor activity, paving the way for smarter cellular therapies.
Area of Science:
- Synthetic biology
- Immunotherapy
- Cellular engineering
Background:
- Chimeric antigen receptor (CAR) T cells represent a significant advancement in cancer immunotherapy.
- Current research focuses on enhancing engineered T cells using synthetic biology approaches.
- Sophisticated gene circuitry and noncanonical signaling pathways are key areas of investigation.
Purpose of the Study:
- To explore recent studies demonstrating novel methods for enhancing engineered T cell anti-tumor activity.
- To highlight the potential of synthetic biology in creating more responsive and effective cellular therapies.
- To showcase advancements in designing gene circuits for future therapeutic applications.
Main Methods:
- Engineering novel chimeric antigen receptors (CARs) with unique signaling motifs.
- Utilizing machine learning to predict CAR T cell phenotype based on signaling motif selection.
- Developing synthetic zinc finger-based transcriptional regulators responsive to small-molecule drugs.
Main Results:
- Novel CAR designs with specific signaling motifs improved T cell tumor-killing capabilities.
- Machine learning successfully predicted CAR T cell responses linked to signaling motif choice.
- Engineered zinc finger regulators demonstrated drug-dependent control over gene expression.
Conclusions:
- These studies provide proof of concept for advanced engineered T cell therapies.
- Expanded design choices for synthetic gene circuits enable multi-responsive cellular therapies.
- Future therapies can integrate responses to tumor antigens, microenvironment, and drugs.
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