Targeting of HPV-16+ Epithelial Cancer Cells by TCR Gene Engineered T Cells Directed against E6

LM Draper, MLM Kwong, A Gros, S Stevanović… - Clinical Cancer …, 2015 - AACR
Clinical Cancer Research, 2015AACR
Abstract Purpose: The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in
principle ideal immunotherapeutic targets, but evidence that T cells specific for these
antigens can recognize and kill HPV+ tumor cells is limited. We sought to determine whether
TCR gene engineered T cells directed against an HPV oncoprotein can successfully target
HPV+ tumor cells. Experimental Design: T-cell responses against the HPV-16 oncoproteins
were investigated in a patient with an ongoing 22-month disease-free interval after her …
Abstract
Purpose: The E6 and E7 oncoproteins of HPV-associated epithelial cancers are in principle ideal immunotherapeutic targets, but evidence that T cells specific for these antigens can recognize and kill HPV+ tumor cells is limited. We sought to determine whether TCR gene engineered T cells directed against an HPV oncoprotein can successfully target HPV+ tumor cells.
Experimental Design: T-cell responses against the HPV-16 oncoproteins were investigated in a patient with an ongoing 22-month disease-free interval after her second resection of distant metastatic anal cancer. T cells genetically engineered to express an oncoprotein-specific TCR from this patient's tumor-infiltrating T cells were tested for specific reactivity against HPV+ epithelial tumor cells.
Results: We identified, from an excised metastatic anal cancer tumor, T cells that recognized an HLA-A*02:01–restricted epitope of HPV-16 E6. The frequency of the dominant T-cell clonotype from these cells was approximately 400-fold greater in the patient's tumor than in her peripheral blood. T cells genetically engineered to express the TCR from this clonotype displayed high avidity for an HLA-A*02:01–restricted epitope of HPV-16, and they showed specific recognition and killing of HPV-16+ cervical, and head and neck cancer cell lines.
Conclusions: These findings demonstrate that HPV-16+ tumors can be targeted by E6-specific TCR gene engineered T cells, and they provide the foundation for a novel cellular therapy directed against HPV-16+ malignancies, including cervical, oropharyngeal, anal, vulvar, vaginal, and penile cancers. Clin Cancer Res; 21(19); 4431–9. ©2015 AACR.
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