Abstract
Adaptive transfer of engineered T cells promoted tumor regression and objective responses in epithelial cancer.
Major finding: Adaptive transfer of engineered T cells promoted tumor regression and objective responses in epithelial cancer.
Concept: T cells expressing TCR specific for HPV16 E6 were used to target HPV16 positive epithelial cancers.
Impact: Cellular therapy using TCR engineered T cells has therapeutic potential for epithelial cancer.
Genetically engineered T cells expressing a T-cell receptor (TCR) with antitumor specificity are under development as immune cell therapies for cancer. This therapeutic approach has previously shown clinical activity in melanoma and synovial cell sarcoma but has been less effective in epithelial cancers. In a first-in-human phase I/II study, Doran and colleagues evaluated the ability of TCR engineered T cells to regress human papillomavirus (HPV)–associated epithelial cancers, which express E6 and E7 viral oncoproteins not found in normal cells, using a TCR specific to an HLA-A2 restricted epitope derived from HPV16 E6. The primary endpoint was to determine the safety of the HPV16 E6 TCR T cells and the maximum tolerated dose (MTD), and the secondary endpoints were response rate and duration of response. A total of 12 patients with metastatic HPV16-positive epithelial cancer were treated with the TCR engineered T cells: 6 with cervical cancer, 4 with anal cancer, 1 with oropharyngeal cancer, and 1 with vaginal cancer. Two patients, both of whom were in the highest dose cohort, demonstrated objective tumor responses; one of these patients experienced complete regression of one lung metastasis and partial regression of two others. All patients had high levels of E6-specific T cells one month after treatment, and infused T cells had in vitro reactivity against cells loaded with the E6 peptide. One patient with resistance to treatment demonstrated loss of HLA-A2 allele, which is essential for antigen presentation to T cells, and a second patient with refractory disease demonstrated a frameshift deletion in interferon gamma receptor 1 (IFNGR1), which is essential for T-cell activity. A tumor from a patient who responded was negative for those genetic defects. Collectively, the results of this phase I/II trial support further investigation of TCR engineered T-cell therapy against viral antigens as well as for epithelial cancers.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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