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Background Chimeric antigen receptor (CAR) T cell therapy has demonstrated remarkable clinical efficacy in haematological malignancies but limited clinical benefit in treatment of solid cancer. Tumour antigen heterogeneity and antigen escape are obstacles to development of clinically efficacious CAR T for such cancer indications. Additionally, the lack of single clean antigen targets has led to instances of on-target/off-tumour toxicity.Methods To mitigate these issues, we have developed a novel platform called CARKey™ that combinatorially targets multiple tumour antigens. A CAR component consists of a multi-antigen binding domain and primary activating signalling domain, whilst co-stimulatory CAR (CoCAR) component ensures full T-cell activation is restricted to tumour tissues.In parallel, we established a bioinformatics pipeline to analyse a curated ovarian cancer scRNAseq dataset, enabling the identification of optimal antigen combinations for maximal coverage of ovarian tumour cells with CARKey™-engineered T-cells, whilst avoiding the risk of off-tumour toxicity.Results We developed a prototype CARKey™ targeting ovarian cancer and show robust activity against target cells whilst demonstrating predicted tumour specificity.Conclusions This CARKey™ platform is being further developed for clinical evaluation.Acknowledgements Manchester Cancer Research Biobank for acquisition of anonymised patient samplesEthics Approval All samples were collected under the REC approved ethics ID 22/NW/0237 under project 25JBR102