Application of synthetic gene circuits to novel NK cell immunotherapy

We propose to use synthetic biology principles to develop a next-generation therapeutic approach for cancer, in particular carcinomas and focussing on Ovarian Cancer (OC) for our proof-of-principle work. Several different forms of immunotherapy including CAR-T cells and Checkpoint Inhibitors have had important success treating cancer. However, these approaches have had little or no therapeutic benefit for OC due to lack of tumour-antigen availability, T-cell exhaustion or major safety issues e.g. cytokine storms and autoimmune responses. Access is also limited by their cost and complexity. Here we aim to develop a universal platform for cancer immunotherapy based on Natural Killer (NK) cells. This will be based on a universal platform to lower cost and increase accessibility, whilst targeting the currently poor outcomes for OC.

We will enhance and modify an existing gene circuit model to be deployed as a novel immunotherapy via NK cell activation, which can directly kill tumour cells. The circuit will trigger tumour cell-specific expression of molecules that can enhance the activation of endogenous Natural Killer (NK) cells within the tumour or attract more NK cells into the tumour. NK cells play a key role in early tumour clearance without requiring pre-existing immunity or tumour-antigen targeting. The clinical potential for NK cell therapy has already been demonstrated, (Shimasaki et al. Nature Reviews Drug Discovery 2020) without toxicity or need for logistically challenging and expensive autologous production, as in the case of CAR-T cell therapy.

We will develop an adaptable RNA-mediated genetic logic circuit based on that previously described in Nissim et al., 2017. The key component of this genetic circuit is a Boolean AND gate that generates an output signal only if both input signals are present together. The genetic circuit is transferred by viral vectors into cancer cells, in the first case to be tested, ovarian cancer cells. Only a small proportion of the ovarian cancer cells need to be transduced with the complete circuit to lead to output and hence NK activation. This is a major USP of the system. In a clinical context, only a small proportion of the cancer cells within a tumour would need to be transduced to have a significant therapeutic effect by producing the potent output molecules to activate nearby NK cells.

The 2016 UK Roadmap Bio-design for the Bio-economy highlighted the substantial impact that synthetic biology can bring to the UK and global economies by developing: frontier science and technology; establishing a healthy innovation pipeline; a highly skilled workforce and an environment in which innovative science and businesses can thrive. Synthetic biology promises to transform the UK Bio-economy landscape, bringing bio-sustainable and affordable manufacturing routes to all industrial sectors and will ensure society can tackle many contemporary global Grand Challenges including: Sustainable Manufacturing, Environmental Sustainability Energy, Global Healthcare, and Urban Development. Whilst synthetic biology is burgeoning in the UK, we now need to build on the investments made and take a further lead in training next generation scientists to ensure sustained growth of a capable workforce to underpin the science base development and growth in an advanced UK bio-economy.
This training provided by this CDT will give students from diverse backgrounds a unique synthesis of computational, biomolecular and cellular engineering skills, a peer-to-peer and industrial network, and unique entrepreneurial insight. In so doing, it will address key EPSRC priority areas and Bioeconomy strategic priorities including: Next-generation therapeutics; Engineered biomaterials; Renewable alternatives for fuels, chemicals and other small molecules; Reliable, predictable, and scalable bioprocesses; Sustainable future; Lifelong health & wellbeing.
Advances created by our BioDesign Engineering approach will address major societal challenges by delivering new routes for chemical/pharma/materials manufacture through to sustainable energy, whilst providing clean growth and reductions in energy use, greenhouse gas emissions and carbon footprints. Increased industry awareness of bio-options with better civic understanding will drive end-user demand to create market pull for products. The CDT benefits from unrivalled existing academic-industry frameworks at the host institutions, which will provide direct links to industrial partners and a direct pathway to early economic and industrial impact.

This CDT will develop 80-100 next-generation scientists and technologists (via the funded cohort and wider integration of aligned students at the three institutions) as adept scientists and engineers, instilled with technical leadership, who as broadly trained individuals will fill key skills gaps and could be expected to impact internationally through leadership roles in the medium term. Importantly the CDT addresses key skill-gaps identified with industry, which are urgently required to create and support high value jobs that will enable the UK to compete in global markets. Commercialisation and entrepreneurship training will equip the next generation of visionaries and leaders needed to accelerate and support the creation of new innovative companies to exploit these new technologies and opportunities.

The UK government identified Synthetic Biology as one of the "Eight Great Technologies" that could be a key enabler to economic and societal development. This CDT will be at the forefront of research that will accelerate the clean growth agenda and the development of a resilient circular bioeconomy, and will align with key EPSRC prosperity outcomes including a productive, healthy and resilient nation. To foster wider societal impact, the CDT will expect all students to contribute to public outreach and engagement activities including: open days, schools visits, and science festival events: students will participate in an outreach programme, with special focus on widening participation.

This CDT will contribute to the development of industrial strategy through the Synthetic Biology Leadership Council (SBLC), Industrial Biotechnology Leadership Forum (IBLF), and wider Networks in Industrial Biotechnology and Bioenergy and Professional Institutes.