Targeting of HPV-16⁺ epithelial cancer cells by TCR gene engineered T cells directed against E6

Purpose: The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV⁺ tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV⁺ tumor cells. ExperimentalDesign: T-cell responses against the HPV-16 oncoproteins were investigated in a patient with an ongoing 22-month disease-free interval after her second resection of distant metastatic anal cancer. T cells genetically engineered to express an oncoprotein-specific TCR from this patient's tumor-infiltrating T cells were tested for specific reactivity against HPV⁺ epithelial tumor cells. Results: We identified, from an excised metastatic anal cancer tumor, T cells that recognized an HLA-A∗02:01-restricted epitope of HPV-16 E6. The frequency of the dominant T-cell clonotype from these cells was approximately 400-fold greater in the patient's tumor than in her peripheral blood. T cells genetically engineered to express the TCR from this clonotype displayed high avidity for an HLA-A∗02:01-restricted epitope of HPV-16, and they showed specific recognition and killing of HPV-16⁺ cervical, and head and neck cancer cell lines. Conclusions: These findings demonstrate that HPV-16⁺ tumors can be targeted by E6-specific TCR gene engineered T cells, and they provide the foundation for a novel cellular therapy directed against HPV-16⁺ malignancies, including cervical, oropharyngeal, anal, vulvar, vaginal, and penile cancers.