Quick Take: T-Cell Receptor Gene Therapy for Human Papillomavirus–Associated Epithelial Cancers: A First-in-Human, Phase I/II Study

Genetically engineered T-cell therapies, such as chimeric antigen receptor T-cells (CAR T-cells), have been approved for the treatment of hematologic malignancies, however, there are limited data to support this approach in the management of epithelial cancers. Human papillomavirus (HPV)-associated epithelial cancers express viral E6 and E7 oncoproteins, which are absent from healthy tissues, making them appealing targets for T-cell therapies. In this phase I/II single-center trial, 12 patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy received autologous genetically engineered T-cells expressing a T-cell receptor (TCR) directed against HPV16 E6 to assess safety, with secondary end points of objective tumor response rate and duration of response. The TCR was a high-avidity TCR directed against an epitope of HPV16 E6 presented by HLA-A*(02:01). Autologous genetically engineered T-cells were created by transducing peripheral blood mononuclear cells with E6 TCR retrovirus, and the conditioning regimen consisted of cyclophosphamide and fludarabine. At baseline, 6 patients had cervical cancer, 4 had anal cancer, 1 had oropharyngeal cancer, and 1 had vaginal cancer. Three of the cervical cancers were adenocarcinomas, and the remainder of the tumors were squamous cell carcinomas (SCC). The median age was 50 years (range 32 to 70 years), and two patients had previously received immunotherapy (one received checkpoint blockade with an anti-PD-1 agent, and one received adoptive T-cell therapy with tumor-infiltrating lymphocytes). Researchers observed no autoimmune adverse events or off-target toxicities attributable to E6 TCR T cells. Two of 12 patients attained objective tumor responses, both of whom had anal SCC (patients 5 and 10). Patient 5 ultimately underwent resection of lung metastases that had regressed with E6 TCR T-cell treatment, and had no evidence of disease 3 years after treatment. This patient was also the only patient with E6 TCR T-cells detected in a post-treatment tumor biopsy. Patient 10 experienced a partial response lasting 3 months before progression of a non-target lesion. All patients demonstrated peripheral blood engraftment with E6 TCR T-cells one month after treatment (median 30%, range 4% to 53%). Whole-exome sequencing of the post-treatment tumor biopsy in a patient who did not respond to treatment revealed a frameshift deletion in IFNGR1, and a tumor of a patient who experienced rapid cancer progression after treatment was found to have allelic imbalance with loss of HLA-A*02:01. Neither of these mutations occurred in Patient 5, and thus they represent potential mechanisms of resistance. Overall, this study indicates that genetically engineered T-cells with virus-specific TCRs are safe and can induce regression in HPV-associated epithelial cancers.

Click to read the study in Journal of Clinical Oncology

Image: PD

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