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Culturing of Human Nasal Epithelial Cells at the Air Liquid Interface
Published on: October 8, 2013
T-Cell Receptor Gene Therapy for Human Papillomavirus-Associated Epithelial Cancers: A First-in-Human, Phase I/II
Stacey L Doran1, Sanja Stevanović1, Sabina Adhikary2
1National Institutes of Health, Bethesda, MD.
Purpose:
Genetically engineered T-cell therapy is an emerging treatment of hematologic cancers with potential utility in epithelial cancers. We investigated T-cell therapy for the treatment of metastatic human papillomavirus (HPV)-associated epithelial cancers.
Methods:
This phase I/II, single-center trial enrolled patients with metastatic HPV16-positive cancer from any primary tumor site who had received prior platinum-based therapy. Treatment consisted of autologous genetically engineered T cells expressing a T-cell receptor directed against HPV16 E6 (E6 T-cell receptor T cells), a conditioning regimen, and systemic aldesleukin.
Results:
Twelve patients were treated in the study. No dose-limiting toxicities were observed in the phase I portion. Two patients, both in the highest-dose cohort, experienced objective tumor responses. A patient with three lung metastases experienced complete regression of one tumor and partial regression of two tumors, which were subsequently resected; she has no evidence of disease 3 years after treatment. All patients demonstrated high levels of peripheral blood engraftment with E6 T-cell receptor T cells 1 month after treatment (median, 30%; range, 4% to 53%). One patient's resistant tumor demonstrated a frameshift deletion in interferon gamma receptor 1, which mediates response to interferon gamma, an essential molecule for T-cell-mediated antitumor activity. Another patient's resistant tumor demonstrated loss of HLA-A*02:01, the antigen presentation molecule required for this therapy. A tumor from a patient who responded to treatment did not demonstrate genetic defects in interferon gamma response or antigen presentation.
Conclusion:
Engineered T cells can induce regression of epithelial cancer. Tumor resistance was observed in the context of T-cell programmed death-1 expression and defects in interferon gamma and antigen presentation pathway components. These findings have important implications for development of cellular therapy in epithelial cancers.
Insights
Genetically engineered T-cell therapy shows promise for treating metastatic human papillomavirus (HPV)-associated epithelial cancers. This approach led to tumor regression in some patients, highlighting its potential despite observed resistance mechanisms.
Area of Science:
- Oncology
- Immunotherapy
- Cellular Therapy
Background:
- Genetically engineered T-cell therapy is an emerging treatment for hematologic cancers.
- Its potential utility in epithelial cancers is under investigation.
Purpose of the Study:
- To investigate T-cell therapy for metastatic human papillomavirus (HPV)-associated epithelial cancers.
- To evaluate the safety and efficacy of engineered T cells targeting HPV16 E6.
Main Methods:
- Phase I/II, single-center trial.
- Enrolled patients with metastatic HPV16-positive cancer post-platinum therapy.
- Treatment: autologous T cells engineered with E6 T-cell receptor (TCR), conditioning, and aldesleukin.
Main Results:
- Twelve patients treated; no dose-limiting toxicities.
- Two patients achieved objective tumor responses, including complete regression.
- High peripheral blood engraftment of engineered T cells observed.
- Tumor resistance linked to interferon gamma pathway defects and HLA-A*02:01 loss.
Conclusions:
- Engineered T cells can induce regression of epithelial cancers.
- Tumor resistance mechanisms identified include T-cell PD-1 expression and defects in interferon gamma and antigen presentation pathways.
- Findings inform the development of cellular therapies for epithelial cancers.
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