Grants and Contracts per year
Grants and Contracts Details
BACKGROUND: Human papillomavirus (HPV), the most common sexually transmitted infection in the United States, is implicated as the causative agent in over 70% of oropharyngeal squamous cell carcinomas (OPSCC). HPV induces carcinogenesis by integrating its own DNA into the host cell’s genome, causing the host cell to express the viral E6 and E7 proteins. These proteins are ideal targets in the development of immunotherapeutics as they are conserved epitopes that are required for malignant conversion but do not have a human correlate in non-cancer cells. Pre-clinical studies on promising the HPV E6 and E7 therapeutic vaccines have been conducted at this institution and has identified a number of HLA-restricted peptide epitopes which stimulate strong CD8+ T-cell responses and potent tumor regression in mouse models. While these peptides show promise as part of an HPV cancer vaccine and are part of an upcoming phase II clinical trial in cervical cancer, (a closely-related but unique entity also caused by HPV via similar mechanisms) it has not been extrapolated as to which HPV antigens are important in OPSCC patients in inducing tumor infiltrating CD8+ cytotoxic T-cells. OBJECTIVE/HYPOTHESIS: The CD8+ T-cell epitopes present on HPV-induced cancers consist of 9 amino acid peptides derived from HPV E6 and E7. Because different HLA class I (A and B) will present distinct peptides, it is unclear which peptides will be important antigenic targets in any given patient. The objective of this pilot proposal is to establish a work-flow for the identification of E6 and E7 epitopes presented by OPSCC cells which in turn are recognized by patient tumor infiltrating CD8+ T-cells. OPSCC HPV+ tumors are expected to have peptide signatures that are immunogenic for the patient’s own CD8+ T-cells, which can ultimately be exploited as a potential therapeutic vaccine target. For the peptide sequences that elicit the strongest CD8+ T-cell response, single cell T-cell receptor sequencing will be undertaken in order to begin development of targeted T-cell receptor-based therapies for OPSCC. STUDY DESIGN: A small portion of tumor from patients undergoing standard-of-care surgery for HPV+OPSCC will be set aside for rapid T-cell expansion, HLA typing, and testing against a verified panel of synthetic E6 and E7 peptides by ELISPOT assay. The correlation between HLA subtype and this specificity will be validated with binding assays to define the most immunogenic peptide sequences and the associated T-cell receptor sequences will be determined. CANCER RELEVANCE: Elucidating the peptide sequences of HPV+ OPSCC is a critical first step toward development of a therapeutic vaccine with neoadjuvant or potentially curative applications. Additionally, the application of recently developed single-cell sequencing techniques to the development of targeted T-cell receptor-based therapies, not only for OPSCC but possibly other solid tumors, is a novel and powerful approach to developing new treatment modalities. Institutional Research Grant American Cancer Society – January 2019 Principal Investigator: Alexandra E. Kejner, MD FACS 18.3 PLANS FOR FUTURE EXTRAMURAL SUPPORT: Successful execution of this project will provide the necessary preliminary data for the first 10 patients to enable a strong NIH immunotherapy grant application for HPV-related cancers by early-stage investigator, Dr. Kejner. Currently, the plan for funding has a three-pronged approach. If funded, this mechanism will allow the accrual of early pilot data that will then be used as a springboard to apply for KL2 and R01 funding. The KL2 mechanism will support both the next phase in the development of this work toward a therapeutic agent as well as career development for Dr. Kejner, with mentored training in immunology and bioinformatics with Dr. Woodward. The preliminary data from this work will also support an R01 application to develop and refine T-cell based therapies and a therapeutic vaccine based on the most immunogenic peptides and TCR sequences identified in this work. These applications work together thematically to support development of a safe and effective treatment and therapeutic vaccine for HPV-associated neoplasia and cancers as a neoadjuvant or a standalone therapy, potentially reducing the morbidity associated with standard treatment of HPV+ cancers.
|Effective start/end date||6/1/20 → 8/31/22|
- American Cancer Society
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