On November 10, 2022 Repertoire Immune Medicines reported that conducted with the company’s proprietary DECODE platform, which characterizes the cellular response to disease, identifying novel therapeutic targets in human papillomavirus (HPV) 16 and HPV 33-positive tumors (Press release, Repertoire, NOV 10, 2022, View Source [SID1234623775]). This research is part of Repertoire’s collaboration with Dana-Farber Cancer Institute to advance discovery and development of treatments for HPV-positive oropharyngeal (head and neck) cancers and was presented at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper) (SITC 2022) 37th Annual Meeting, in Boston.

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"One of the growing challenges in HPV-positive cancer treatment is that we are observing an increase in the prevalence of HPV high-risk genotypes associated with worse outcomes," said Glenn J. Hanna, M.D., director of the Center for Salivary and Rare Head and Neck Cancers at Dana-Farber Cancer Institute.1 "The research we conducted with the DECODE platform suggests that current treatments may not be targeting some key antigens active in these genotypes, which has significant implications for patient treatment. Importantly, we now have data that point to antigens active in driving these malignancies, which we can use to develop novel targeted medicines."

The DECODE platform is a suite of integrated experimental and computational technologies designed to decipher the immune synapse, the complex interface between T cells and the epitopes they recognize. DECODE is being used to assess the immunogenicity profile of HPV 16 and HPV 33-positive tumors in oropharyngeal squamous cell carcinoma (OPSCC). By characterizing the cellular response to these cancers, it is possible to identify the specific epitopes eliciting the strongest T cell activity in tumors and the associated T cell receptors (TCRs) binding those epitopes, identifying what may be ideal targets for immunotherapies.

"Using the DECODE platform, we have a window into the mechanisms involved in the immune surveillance of cancer, which offers us the ability to develop highly selective immune-based medicines," said Anthony Coyle, Ph.D., President, Research and Development, Repertoire Immune Medicines. "The data we presented today from our DECODE platform illustrate the immunogenic profile of HPV 16 and HPV 33-positive tumors, providing us with insights into the specific epitopes that are drivers of these cancers and are targets for new immunotherapies."

HPV infection is a risk factor for several cancers, including OPSCC. Many therapeutic approaches for OPSCC target the epitopes from E6 and E7 antigens of HPV; however, these treatments are not successful for every patient and new approaches based on highly prevalent immunodominant epitopes in both early-stage and relapsed/refractory patients may offer more effective treatment for certain genotypes of HPV-positive OPSCC.

DECODE Discovery in HPV 16 and HPV 33-Positive Oropharyngeal Squamous Cell Carcinoma

In order to better characterize the cellular response to HPV-positive OPSCC across common human leukocyte antigen (HLA) haplotypes, biopsies were collected from patients with HPV 16-positive or HPV 33-positive OPSCC. All samples were assessed using the DECODE platform.

In patients with HPV 16-positive tumors, effective cytotoxic responses were induced by antigens E1 and E2 of HPV, which were substantially greater than the response driven by E5, E6 and E7. These findings suggest HPV 16 E1 and E2-directed immunotherapy may be effective among patients with HPV 16-positive OPSCC expressing these antigens.

HPV 33-positive OPSCC is characterized with an inferior survival rate compared to HPV 16-positive head and neck cancers. To better understand the potential reasons for this difference in outcomes, a comparison of the immunogenic profile of HPV 16 and HPV 33-positive tumors was conducted with DECODE.

HPV 33-positive tumors in this research had fewer cytotoxic CD8+ T cells and fewer activated antibody-secreting B cells compared to HPV 16-positive tumors. In addition, the HPV 33-positive tumors had poor antigen presentation and deficient HPV E7 recognition by T cells. Both genotypes of OPSCC are typically treated with the same standard of care, but the differences observed in the HPV 33-positive tumor composition and cellular phenotype would be expected to lead to a poor immune response and may be the cause of the inferior treatment outcomes observed in the population of patients with this tumor genotype.

Additional detail from this ongoing research is included in Poster #86, HPV16 E1 and E2 elicit a robust cytotoxic immune response in virally driven Oropharyngeal Squamous Cell Carcinoma, and in Poster #1404, HPV33-driven Oropharyngeal Squamous Cell Carcinomas are increasing in prevalence and are characterized by low CD8 infiltration and epitope presentation deficiencies.

These data, as well as the company’s early research in targeting interleukin-2 (IL-2) to solid tumors, will be presented during the poster session at the SITC (Free SITC Whitepaper) congress on Thursday, November 10, through Friday, November 11, 2022, 9:00 a.m. – 9:00 p.m. EST.

About the DECODE Platform

The DECODE platform is a powerful discovery engine that characterizes essential elements of the immune synapse. In particular, the platform identifies T cell receptor-antigen pairs in the context of other important features of the immune synapse, such as T cell function and how antigens are presented by molecules on antigen-presenting cells, known as major human leukocyte antigen, or HLA, molecules. Repertoire intends to utilize these insights into key drivers that govern immune function to design and develop novel immune product candidates.