Friday, May 10, 2024
5/10/2024
PROJECT SUMMARY Human papillomavirus (HPV) is the causative agent of a growing proportion of incident cases of head and neck squamous cell carcinomas (HNSCCs). HPV type 16 is responsible for over 90% of HPV+ HNSCCs diagnosed in the United States. The HPV16 E7 antigen is an attractive immunotherapeutic target for HPV-associated cancers since it is a unique virus-specific oncoprotein constitutively expressed by all cancer cells. T cells that are genetically engineered to express an HLA-A*0201-restricted T cell receptor (TCR) that recognizes the HPV16 E711-19 epitope can mediate regression of HPV16-associated cancers in a preclinical model.1 A phase 1, first-in-human (FIH) multi-center study demonstrated the safety and efficacy of an autologous HPV TCR- engineered T cell (TCR-T) therapy which targets the HPV16 E7 binding epitope in HLA-A*0201-expressing HPV+ cancer patients (NCT03912831).2 However, the realized challenges with adoptive cell therapy (ACT) are: i) the high costs associated with manufacturability and monitoring and managing the toxicities from the supra- physiological bolus of ACT products which are combined with systemic IL-2 administration, and ii) the limited in vivo persistence due to the lack of appropriate antigen-specific stimulation due to poor intra-tumoral T cell recruitment into solid tumors. Herein, we propose innovative proof-of-concept (PoC) experiments to determine whether a low dose of adoptively transferred HPV16 E711-19 TCR-T cells can be exponentially expanded in situ by administering a novel biologic fusion protein, CUE-101, which delivers the HPV16 E7 antigen-specific stimulation with localized delivery of high doses of IL-2.3-5 Furthermore, we determine whether HPV16 E7 TCR- T cell persistence translates into an enhanced anti-tumor effect in preclinical HPV+ tumor models (Aim 1). Lastly, we build upon our team’s discovery of the role of the CXCR6:CXCL16 axis in the recruitment of peripheral circulating CD8+ T cells to perivascular niches of the tumor populated by CXCL16-expressing CCR7+ DC3s, which can sustain the survival of tumor-specific CD8+ T cells.6 Thus, we assess whether the efficacy of HPV16 E7 TCR-T cells can be improved through engineering strategies that introduce CXCR6 to the TCR-T cells, which can facilitate intra-tumoral recruitment, proliferation, and survival in situ (Aim 2). The completion of these aims will generate the supporting rationale for a future clinical trial administering HPV16 E7 TCR-T cells and CUE- 101 in HPV+ cancer patients. These efforts can potentially transform our current approaches to adoptive cell therapy.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
