Adoptive T-cell therapy for HPV associated cancers

Long-lasting infections with high-risk human papillomavirus-16 (HPV16) can cause epithelial cancers, which include squamous cell carcinomas (SCC) and adenocarcinomas of the cervix, oropharynx, anus, vulva, vagina, and penis. Oncogenic HPV virus accounts for approximately 600,000 cases worldwide every year and advanced HPV-associated cancers are generally incurable and resistant to chemotherapy. However, T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of HPV associated cancer, targeting viral antigens which are absent in healthy tissues, making them attractive targets for genetically engineered T-cell therapy. We have been working on the oropharyngeal cancer patient’s samples and identified HPV16 antigens specific high-avidity CD4+ and CD8+ TCRs directed against different HPV16 antigens by single cell TCR sequencing.

• Functional characterisation of HPV specific transgenic TCR T cells, which involves assessing the in vitro efficacy by real time killing assay (Xcelligence assay) and flow cytometry and ex vivo efficacy using HPV xenograft mice model. • Adoptive therapy with ex vivo–expanded genetically modified antigen-specific T cells, which can induce remissions in patients with relapsed/refractory cancer. The clinical success of this therapy depends upon efficient transduction and expansion of T cells ex vivo and their homing, persistence and cytotoxicity following reinfusion. This focuses on the use of different cytokines and metabolic checkpoint inhibitor or epigenetic regulator in ex vivo culture to further enhance the efficacy and quality of genetically modified HPV-specific T cells.

The characterisation of HPV16 specific transgenic TCR T cells through examining their effectiveness and therapeutic applicability contributes to the development of an advanced cellular therapy.