A phase I/II clinical trial of E6 T-cell receptor gene therapy for human papillomavirus (HPV)-associated epithelial cancers.

Abstract

3009 Background: Engineered T-cell therapy has shown promise in B-cell malignancies and melanoma, but clinical investigation in epithelial cancers has been limited. Methods: We conducted a phase I/II clinical trial of T cells genetically engineered to express a T-cell receptor that targets an HLA-A*02:01-restricted epitope of E6 (E6 TCR T Cells) for patients with metastatic HPV-16+ carcinoma. The cell dose was escalated in cohorts of single patients (1 x 109, 1 x 1010, and 1-2 x 1011cells). Patients received a nonmyeloablative conditioning regimen of cyclophosphamide and fludarabine, a single infusion of E6 TCR T Cells, and systemic high-dose aldesleukin. Results: Twelve patients were treated, 9 at the highest cell dose, plus one retreatment. The cancer types were 6 cervical, 4 anal, 1 oropharyngeal, and 1 vaginal. No dose-limiting toxicity, autoimmune adverse events, or cytokine storm were observed. Two patients with anal cancer treated at the highest cell dose experienced partial tumor responses lasting 6 and 3 months after treatment. The patient with a 6-month response had complete regression of one tumor and partial regression of two tumors that were resected upon progression; she has no evidence of disease 22 months after treatment. T-cell receptor gene transfer efficiency was 45 and 51% in the responding patients, and 47-76% (median 61%) in the non-responding patients. Responding patients showed robust levels of E6 TCR T cell memory (30 and 46% of circulating T cells 1-month after treatment). Non-responding patients showed wide-ranging levels of E6 TCR T cell memory (range 4-53%, median 29%). Expression of programmed cell death protein 1 (PD-1) by circulating E6 TCR T Cells 1-month after treatment was low in all patients ( < 5%). The patient with a 6-month response had 7% E6 TCR T Cells in a resected tumor 10 months after treatment, 25% of which expressed PD-1. A patient with no response had no detectable E6 TCR T Cells in a resected tumor 3 months after treatment. Conclusions: E6 TCR T-cell therapy was safe at doses up to 2 x 1011 cells. Regression of metastatic HPV+ carcinoma occurred in two patients following treatment, suggesting that TCR T-cell therapy can mediate epithelial cancer regression. Clinical trial information: NCT02280811.

A Phase II Study of Tumor-infiltrating Lymphocyte Therapy for Human Papillomavirus–associated Epithelial Cancers

“…A clinical trial of T cells genetically engineered with a T cell receptor that targets the E6 antigen has shown some clinical activity. 23 A clinical trial with a higher avidity T cell receptor that targets the E7 antigen is actively accruing patients (NCT02858310). 24…”

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

“…Two of 9 patients treated with HPVtargeting TCR-T cells experienced complete tumor responses (4); however, in this study, non-oncoprotein tumor antigens were also targeted, precluding definitive conclusions about which antigens were responsible for tumor regression (5). A recent clinical trial of TCR-T cells that target HPV-16 E6 has provided more direct evidence to suggest that an HPV oncoprotein can be targeted with TCR-T cells (6,7). In this report, 2 of 12 patients with metastatic HPV + cancers experienced tumor responses (2 of 9 patients treated at the highest dose of TCR-T cells).…”

Therapeutic vaccines for high-risk HPV-associated diseases

“…In another study, T cell receptors against E6 were introduced into CTLs, which killed HPV+ cells from cervical and head and neck cancer cell lines [138] . Most recently, a phase I/II clinical trial ( NCT02280811 ) targeting several HPV-associated cancers (cervical, anal, vaginal and oropharyngeal) showed regression of metastatic HPV+ carcinoma in 2 out of 12 patients, suggesting that T cell receptor therapy can facilitate epithelial cancer regression [139] . A phase I trial using T cells genetically engineered with T cell receptors targeting HPV-16 E7 with or without programmed cell death protein 1 (PD-1) blocking drugs (PD-1 is an inhibitory receptor on T cells), in patients with cervical, vaginal, anal, penile or oropharyngeal cancers, is currently recruiting participants ( NCT02858310 ).…”

“…HPV cancers evade the immune system and treatment of solid tumours remains a challenge. Effective T cell therapy will need to improve and address concerns such as tumour heterogeneity, antigen escape, an immunosuppressive microenvironment, inhibition of T cell localisation [139] , [140] , [141] and methods to improve the state of leaky and fragile blood vessels that supply tumour cells [143] , [144] .…”