Cell-based molecularly targeted therapy: targeting oncoproteins with T cell receptor gene therapy.

As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be "druggable," tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation. T cells genetically engineered to express an anti-BRAFV600E T cell receptor (TCR) from the patient demonstrated recognition of an epitope that spanned the BRAFV600E mutation. These findings suggest that BRAFV600E might be targeted therapeutically with adoptive transfer of anti-BRAFV600E T cells. This research supports the emerging therapeutic paradigm of targeting oncogenic drivers with T cell immunotherapy.