TCR-engineered T cells targeting E7 for patients with metastatic HPV-associated epithelial cancers

In a first-in-human phase 1 trial of patients with HPV-associated metastatic epithelial cancers, T cells targeting HPV-16 E7 were well tolerated, with one observed dose-limiting toxicity, and elicited objective clinical responses in 6 of 12 treated patients. Genetically engineered T cell therapy can induce remarkable tumor responses in hematologic malignancies. However, it is not known if this type of therapy can be applied effectively to epithelial cancers, which account for 80-90% of human malignancies. We have conducted a first-in-human, phase 1 clinical trial of T cells engineered with a T cell receptor targeting HPV-16 E7 for the treatment of metastatic human papilloma virus-associated epithelial cancers (NCT02858310). The primary endpoint was maximum tolerated dose. Cell dose was not limited by toxicity with a maximum dose of 1 x 10(11) engineered T cells administered. Tumor responses following treatment were evaluated using RECIST (Response Evaluation Criteria in Solid Tumors) guidelines. Robust tumor regression was observed with objective clinical responses in 6 of 12 patients, including 4 of 8 patients with anti-PD-1 refractory disease. Responses included extensive regression of bulky tumors and complete regression of most tumors in some patients. Genomic studies, which included intra-patient tumors with dichotomous treatment responses, revealed resistance mechanisms from defects in critical components of the antigen presentation and interferon response pathways. These findings demonstrate that engineered T cells can mediate regression of common carcinomas, and they reveal immune editing as a constraint on the curative potential of cellular therapy and possibly other immunotherapies in advanced epithelial cancer.

Automated summary

In a first-in-human phase 1 trial, T cells targeting HPV-16 E7 showed promising results in treating metastatic epithelial cancers, with objective clinical responses observed in 6 out of 12 patients. This suggests that genetically engineered T cell therapy may be effective in treating common carcinomas, but further studies are needed to understand the resistance mechanisms in advanced epithelial cancer.