Escape From Synthetic T Cell Activator Tebentafusp by Genomic HLA Loss: A Case Report

Tebentafusp, a T-cell receptor-bispecific molecule targeting glycoprotein 100-derived peptide presented by HLA class I molecule and CD3, is standard of care for patients with unresectable or metastatic uveal melanoma who are positive for HLA-A*02:01. Mechanisms of resistance to tebentafusp are unknown. We report a patient with metastatic uveal melanoma who acquired resistance to tebentafusp after 30 months of treatment. Genomic loss of the HLA-haplotype carrying the HLA-A*02:01 restriction element was detected in a progressive metastasis, resulting in loss of presentation of tebentafusp's target antigen. Understanding mechanisms of resistance against synthetic cancer immunotherapies will be key to monitoring disease control and development of early intervention strategies towards cure.