A novel T cell receptor targeting mutated KRAS identified in the peripheral blood of a pancreatic cancer patient
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease which remains refractory to most available therapies. As 95% of PDACs express KRAS mutations, the therapeutic potential of creating a vast off-the-shelf T-cell receptors (TCRs) library targeting the common KRAS mutations is immense. We recently initiated a clinical trial at Sheba Medical Center using engineered T-cells expressing mutated KRAS-specific TCRs, in which two patients were treated. This work aims to identify and isolate novel TCRs targeting KRAS driver mutations, and to explore their potential use to treat PDAC patients. We have used a non-invasive method to probe tumor-specific T-cells in the peripheral blood of four PDAC patients by in vitro stimulation with the mutated KRAS peptide presented by autologous antigen-presenting cells.
Unprecedentedly, in the case of pancreatic cancer, we have identified circulating mutation-specific T-cells in one patient harboring a tumor KRASG12R mutation. TCR sequencing revealed one dominant clone, which we cloned and retrovirally transduced into autologous T-cells, confirming a specific recognition of the KRASG12R mutation. We have also determined the reactive TCR`s HLA restriction (DQA1*05:05/DQB1*03:01). In this study, we demonstrated the presence of mutation-specific T-cells in the peripheral blood of a PDAC patient and confirmed the feasibility of their isolation. We have also identified a novel KRASG12R-specific, HLA-DQA1*05:05/DQB1*03:01-restricted TCR, which will be used in our recent clinical trial at Sheba Medical Center to treat pancreatic cancer patients.