T-Cell Receptor Gene Therapy in HPV-Associated Epithelial Cancers
In a first-in-human phase I/II study reported in the Journal of Clinical Oncology, Doran et al found that autologous genetically engineered T cells expressing a T-cell receptor directed against the human papillomavirus (HPV)16 E6 oncoprotein were capable of inducing tumor regression in metastatic, HPV-associated epithelial cancers.
Study Details
The proof-of-principle study, performed at the National Cancer Institute, included 12 patients with metastatic HPV16-positive cancer (primary tumor sites: cervical = 6 patients, anal = 4, oropharyngeal = 1, and vaginal = 1) who had received prior platinum-based therapy. Patients received a nonmyeloablative, lymphodepleting preparative regimen (cyclophosphamide and fludarabine) for 5 days followed the next day by a single infusion of E6 T-cell receptor T cells and systemic aldesleukin dosed to tolerance.
Patients received E6 T-cell receptor T cells at doses of 1 × 109, 1 × 1010, 1 × 1011, and 1 to 2 × 1011 cells. Overall, 9 of 12 patients received the highest dose level.
Outcomes
No dose-limiting toxicities were observed in the phase I accelerated dose-escalation phase. Overall, no autoimmune adverse events or off-target toxicities attributable to E6 T-cell receptor T cells were observed, and no acute toxicities from cell infusion or cytokine storm were reported. The most common toxicities were transient cytopenias associated with the lymphodepleting regimen.
Objective responses were observed in two of nine patients receiving the highest E6 T-cell receptor T-cell dose level. One patient with three lung metastases exhibited complete regression of one tumor and partial regression of two tumors that were subsequently resected; this patient has shown no evidence of disease at 3 years after treatment. Another patient exhibited a 3-month partial response with subsequent progression in a nontarget lesion. Four patients exhibited stable disease.
Most patients exhibited target tumor regression, with variability observed in extent and duration. All patients exhibited peripheral blood engraftment with E6 T-cell receptor T cells at 1 month after treatment (median = 30%, range = 4%–53%).
A resistant tumor in one patient who did not respond to treatment showed a frameshift deletion in interferon gamma receptor 1, a receptor essential for T cell–mediated antitumor activity. A resistant tumor in another patient exhibited loss of HLA-A*02:01, the antigen presentation molecule required for E6 T-cell receptor T-cell therapy. A tumor from a patient who responded to treatment had no identified genetic defects in interferon gamma response or antigen presentation. Another potential mechanism of resistance was expression of programmed cell death protein 1 (PD-1) by tumor-infiltrating E6 T-cell receptor T cells and expression of programmed cell death ligand 1 (PD-L1) by tumor-infiltrating immune cells, which was observed in residual tumor of a patient with partial response.
The investigators concluded, “Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed [cell] death [protein] 1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.”
Christian S. Hinrichs, MD, of the Experimental Transplantation and Immunology Branch, Center for Cancer Research, National Cancer Institute, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by the National Institutes of Health Intramural Research Program and by a Cooperative Research and Development Agreement with Kite Pharma, a Gilead Company. For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
