Background: Engineered T-cell therapy is an emerging treatment for hematological cancers. In epithelial cancers, its study has been limited. Human papillomavirus (HPV)-16+ epithelial cancers constitutively express the HPV E6 oncoprotein. We investigated treatment of metastatic HPV-16+ cancers with T cells that target E6 by an engineered T-cell receptor (E6 T cells). Methods: A phase I/II, single-center, clinical trial was conducted. Eligible subjects had a metastatic HPV-16+ cancer from any primary tumor site and had received prior platinum-based therapy. Treatment consisted of a one-time, intravenous infusion of E6 T cells. A lymphocyte-depleting conditioning regimen and systemic aldesleukin were also administered. Results: Twelve subjects were treated on this protocol. Dose-limiting toxicity was not encountered (maximum dose was 1.7 x 10¹¹ T cells). Transduction efficiency range was 45-76%. Infused E6 T cells demonstrated engraftment at one month post-treatment in all patients (range 4-53%). Two of nine subjects in the highest dose cohort experienced tumor responses. A subject with a 6-month partial response had complete regression of one lesion and partial regression of two lesions, which were subsequently resected; the subject has no evidence of disease three years after treatment. Resected tumor from this subject demonstrated infiltration by E6 T cells that showed increased expression of the inhibitory molecule PD-1 as compared to E6 T cells in the peripheral blood (26% vs 2%). Genomic analyses were performed on the tumors of two subjects who did not respond to treatment. One subject displayed a frameshift deletion in the interferon-gamma response gene, IFNGR1. Another demonstrated loss of heterozygosity (LOH) in chromosome 6 with deletion of HLA-A*02:01, the necessary restriction element for this therapy. A subject who responded to treatment did not demonstrate genomic alterations in these pathways. Conclusions: Engineered T cells targeting E6 can induce regression of HPV+ epithelial cancers. Treatment resistance may be related to T-cell inhibition by PD-1, tumor evasion by antigen processing and presentation loss, and defects in interferon-response pathways. Clinical trial information: NCT02280811