Optimising CAR-T efficacy in pancreatic cancer with bioengineered scaffolds and immune agonists

Commercial partner: Oxford BioMedica, Oxford - http://www.oxb.com/

Cancer stem cells (CSCs) can drive tumorigenesis as founder elements or through malignant cells that gain stem cell traits. CSCs are defined as slowly replicating cells, where bulk tumour growth arises from non-CSCs. Therapeutic strategies target fast-replicating cells in bulk tumour, as more quiescent CSCs avoid targeting and contribute to recurrence and metastatic spread by repopulating the non-CSC compartment. Although challenging, due microenvironmental factors and tumour plasticity between CSC and non-CSCs, targeting CSCs is critical in the search for curative cancer treatments. The oncofetal tumor-associated antigen 5T4 (TBGP) has been identified as a CSC marker in several malignancies. OXB have developed immunotherapies targeting 5T4 including a Vaccinia-based vaccine (Trovax) and 5T4-directed chimeric antigen receptor T-cells (CAR-T) (OXB-302) with positive responses in clinical trials.

Although promising, Vaccine and CAR-T cell therapies are less effective in solid tumours due to inefficient tumour targeting, the immunosuppressive microenvironment; and tumour heterogeneity/plasticity. Implantable biopolymer devices can deliver vaccines or CAR-T cells directly to the surfaces of solid tumours (e.g. pancreatic cancer and melanoma), and are moreeffective in tumour targeting than systemic delivery. We aim to adapt this technology to implant biopolymer scaffolds to target 5T4 expressing cells in orthotopic human tumours engrafted in immunocompromised mice. Additionally, combination of CAR-T strategies with the agonists of the STimulator of IFN Genes (STING) pathway (e.g. cyclic di-GMP) can lead to dramatic tumour regression. This is achieved though stimulation of antigens not recognized by the adoptively transferred lymphocytes that could target heterogeneous tumours or CSC and non-CSC compartments.

Thus, we propose a project to understand the role of 5T4 in CSCs, investigate bioengineering scaffold devices that concentrate and localise 5T4-target therapies in solid tumours and combine these with STING agonists to protect against the emergence of escape variants in vivo. We aim to explore the feasibility of these approaches in vivo in mice and in human tissue samples. The candidate will gain experience in cell and tumour biology, bioengineering of scaffolds and in the design, construction and deployment of CAR-T cells in these experimental models.