Development of synthetic RNA-based gene circuits to enhance NK cell based immunotherapy

Biotechnological advances in DNA synthesis and molecular cloning have given rise to synthetic biology, a discipline that seeks to implement different engineering principles to biological systems, enabling programming of cellular behaviours. Genetic circuits made of different modular biological components can be designed to perform logical functions such as feedback loops, toggle switches or Boolean logic gates.

Recently, an RNA-based immunomodulatory gene circuit has been developed as a highly innovative approach to T-cell based cancer immunotherapy1. Working analogously to Boolean AND-gate, a digital logic gate that generates an output signal only if all input signals are in present in conjunction; this gene circuit, delivered to target cancer-cells through a lentiviral vector, only activates in presence of two distinct cancer-specific promoters. Activation of the genetic circuit result in synthetises of different immunomodulatory proteins such as cytokines, chemokines and immune checkpoint inhibitors. Most importantly, this system achieved robust therapeutic efficacy in mice models, with no more than 15% of tumour cells being transduced with the genetic circuit.

While T-cell based immunotherapies have proved their importance in fighting cancer, the intrinsic immunosurveillance and tumour killing capabilities make natural killer (NK) cells excellent candidates for cancer immunotherapy; and recent developments have shown (NK) cell-based immunotherapies to be among the most promising. Furthermore, NK-cells present multiple advantages over T-cells: in terms of biosafety as NK-cells have a different cytokine profiles than T-cells, which do not present a risk for cytokine release syndrome; and cancer immunoevasion via MHC class I molecule downregulation, as NK-cell activation is dependent of an off-balance of multiple activator and inhibitory signals.


The ultimate goal of this project is to develop a new immunomodulatory gene circuits for NK-cell cancer immunotherapy, where cancer-specific promoters drive the expression of immunomodulatory proteins such as cytokines IL-12, IL18 and IL21. As well as develop a platform to adapt this gene circuits to different cancer types by changing to other cancer-specific promoters.

References
Nissim, L. et al. (2017) 'Synthetic RNA-Based Immunomodulatory Gene Circuits for Cancer Immunotherapy', Cell. doi: 10.1016/j.cell.2017.09.049.