On down the E6.

Top Line: Could the human papillomavirus (HPV) E6 and E7 proteins be targets for engineered T-cells?

The Study: While we’ve been waiting for someone to figure out how to CRISPR E6 or E7 out of HPV-mediated tumors, engineered T-cells have now entered the game as a potential therapeutic option. As a reminder, E6 and E7 are the key oncogenic products of the human papilloma virus (HPV). E6 interferes with the tumor suppressor p53. E7 binds to the Rb protein and interferes with it’s normal suppression of the transcription factor E2F. The great thing about E6 and E7 as targets is that they aren’t human--meaning they shouldn’t exist outside infected cells. In this proof of concept study, a T-cell receptor (TCR) was developed with a high affinity for E6 and administered via genetically engineered autologous T-cells. Patients had to have metastatic HPV16-positive cancer of any primary site and have failed or declined prior therapy. After conditioning chemotherapy, they were administered a one-time infusion of the E6 TCR T-cells followed by aldesleukin (recombinant IL-2). Twelve patients were treated with half of them having metastatic cervical cancer. No significant dose limiting toxicities from the E6 T-cells (particularly auto-immune toxicity or off-target effects) were observed. Two patients had objective tumor responses, both of whom had anal cancer primaries. The responses are perhaps more modest than would be expected for such a specific target, however ongoing trials are testing a higher affinity TCR for the E7 protein.

TBL: Genetically engineered autologous T-cells with receptors for the HPV16 oncogenic protein, E6, have been safely tested in patients with metastatic HPV16-positive cancers. | Doran, J Clin Oncol 2019