To investigate the efficacy and safety of genetically engineered T cells designed to target solid tumors
Beta-catenin, which is encoded by the catenin Beta 1 (CTNNB1) gene, contributes cell proliferation and differentiation by transporting extracellular signals to the nucleus. Mutations of the CTNNB1 gene alter the spatial characteristics of the beta-catenin protein, leading to drastic reprogramming of the nuclear transcriptional network. CTNNB1 is altered in 3.10% of all cancers with endometrial endometrioid adenocarcinoma, lung adenocarcinoma, colon adenocarcinoma, prostate adenocarcinoma, and hepatocellular carcinoma having the greatest prevalence of mutations. Among all kinds of mutations, S37F mutation lies within the ubiquitination recognition motif of the CTNNB1 protein and occurs at a Gsk3b phosphorylation site on the CTNNB1 protein. S37F confers a gain of function to the CTNNB1 protein as demonstrated by nuclear accumulation of CTNNB1, increased activity in a reporter assay, and increased cell invasion and migration in the context of an EGFR activating mutation. Our preliminary data indicates T cells expressing CTNNB1 specific TCRs recognize target cells with the S37F mutation but not those with wild type protein.
This provides a possibility for modified cytotoxic T cells to distinguish and kill tumor cells without disturbing normal healthy cells. We find that under in vitro conditions, CD8+ cytotoxic T cells expressing CTNNB1 specific TCRs exhibit robust killing of cancer cell lines with the S37F mutation. To test therapeutic effect of these T cells in vivo, we plan to engraft them to immunodeficient NOD scid gamma (NSG) mice after inducing tumor growth and observe tumor progression at different time points after injection. We are further aiming to address one of the most common tumor escape mechanisms observed during TCR T cell therapy: downregulation of HLA class I molecules. This will be achieved combining TCR T cell administration with transient upregulation of HLA class I molecules using an mRNA-based therapeutic vaccine approach. This study would demonstrate the efficacy of these specific T cell in vivo and indicate the safety for clinical trial in the future.
This provides a possibility for modified cytotoxic T cells to distinguish and kill tumor cells without disturbing normal healthy cells. We find that under in vitro conditions, CD8+ cytotoxic T cells expressing CTNNB1 specific TCRs exhibit robust killing of cancer cell lines with the S37F mutation. To test therapeutic effect of these T cells in vivo, we plan to engraft them to immunodeficient NOD scid gamma (NSG) mice after inducing tumor growth and observe tumor progression at different time points after injection. We are further aiming to address one of the most common tumor escape mechanisms observed during TCR T cell therapy: downregulation of HLA class I molecules. This will be achieved combining TCR T cell administration with transient upregulation of HLA class I molecules using an mRNA-based therapeutic vaccine approach. This study would demonstrate the efficacy of these specific T cell in vivo and indicate the safety for clinical trial in the future.