Transient TCR-based T-cell therapy in a patient with advanced treatment-resistant MSI-high colorectal cancer.

We previously demonstrated the anti-tumor effectiveness of transiently TCR redirected T cells recognizing a frameshift mutation in TGFβRII. We here describe a clinical protocol using mRNA TCR modified T cells to treat a patient with progressive, treatment-resistant metastatic MSI-H colorectal cancer. Following 12 escalating doses of autologous T cells electroporated with in vitro transcribed Radium-1 TCR mRNA we assessed T cell cytotoxicity, phenotype and cytokine production. Tumor markers and growth on CT scans were evaluated and immune cell tumor infiltrate at diagnosis assessed. At diagnosis tumor infiltrating CD8+ T cells had minimal expression of exhaustion markers, except for PD-1. Injected Radium-1 T cells were mainly naïve and effector memory T cells with low expression of exhaustion markers, except for TIGIT. We confirmed cytotoxicity of transfected Radium-1 T cells against target cells and found key cytokines involved in tumor metastasis, growth, and angiogenesis to fluctuate during treatment. The treatment was well tolerated, and despite his advanced cancer, the patient obtained a stable disease with 6 months' survival post treatment. We conclude that treatment of metastatic MSI-H colorectal cancer with autologous T cells electroporated with Radium-1 TCR mRNA is feasible, safe, well tolerated and warrants further investigation in a Phase I/II study.