Journal Article

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

Bagheri, Mohammad Hadi, Meyer, Thomas J., Stroncek, David, Schweitzer, Colleen, Trimble, Cornelia L., Doran, Stacey L., Faquin, William C., Nagarsheth, Nisha B., Astrow, Stephanie H., Bot, Adrian, Highfill, Steven, Adhikary, Sabina, Ferraro, Erin, Gkitsas, Nikolaos, Lack, Justin B., Kanakry, Jennifer A., Norberg, Scott M., Stevanović, Sanja, Korrapati, Soumya, Hinrichs, Christian S., Sinkoe, Andrew L., Warner, Andrew C.

2021

Overview

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 × 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. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/67 / 631/67/1059 / 631/67/1517 / 631/67/1536 / 631/67/580 / Antigen presentation / Antigens / Biomedical and Life Sciences / Biomedicine / Blood cancer / Cancer / Cancer Research / Carcinoma / Cell Line, Tumor / Cell therapy / Complications and side effects / Critical components / Genetic aspects / Genetic engineering / Health services / Human papillomavirus / Humans / Immunotherapy / Infectious Diseases / Interferon / Letter / Lymphocytes / Lymphocytes T / Metabolic Diseases / Metastases / Metastasis / Molecular Medicine / Neoplasm Metastasis / Neoplasms, Glandular and Epithelial - metabolism / Neoplasms, Glandular and Epithelial - pathology / Neoplasms, Glandular and Epithelial - virology / Neurosciences / Ovarian cancer / Papillomaviridae - metabolism / Papillomavirus E7 Proteins - metabolism / Papillomavirus infections / Papillomavirus Infections - metabolism / Patients / PD-1 protein / Receptors, Antigen, T-Cell - metabolism / Regression / Risk factors / Robustness (mathematics) / Solid tumors / T cell receptors / T-Lymphocytes - metabolism / Therapy / Toxicity / Tumors