Genetic determination of T-cell activity in adjuvant immunotherapy
Novel immunotherapies have recently been applied in the adjuvant setting, substantially improving clinical benefits for patients at earlier stages of cancer, with a high propensity for potential metastatic progression.
In our lab, we have developed a novel approach of examining genetic control of T-cell activation to elucidate the contribution of genetic determinants of host immunity on the success of immune-checkpoint inhibition in patients at earlier stages of melanoma.
In a well-controlled clinical trial involving patients with stage III melanomas, treated by anti-PD1 and anti-CTLA4 therapies, we study the dynamic epigenetic and genetic mechanisms of T-cell activation to develop novel biomarkers and therapy targets of immune-checkpoint inhibition in the adjuvant melanoma setting.
Recently, these studies were awarded funding from the National Cancer Institute (NCI), as part of the NYU Melanoma SPORE grant.
Genetic control of transcriptional regulatory networks in immunotherapy-treated metastatic melanoma
A substantial number of patients do not benefit from promising new immune checkpoint blocking (ICB) therapies that stimulate the immune system to target melanoma. Our study seeks to discover the factors that influence response to these novel therapies, providing an opportunity to significantly improve treatment outcomes for patients with metastatic melanoma.
We hypothesize that circulating CD8+ T cells, a primary target of ICB therapies, are controlled by germline genetic variation in the CD8+ non-coding regulatory genome (regulome), and that this genetic variability modulates ICB efficacy and toxicity. Using whole-genome sequencing, whole-transcriptome sequencing, and analysis of open chromatin states, we will identify inherited genetic and epigenetic signatures that predict response to ICB therapy in these patients.
For the first time, our study will elucidate the effect of inherited anti-tumor host immunity on ICB outcomes and may identify transcriptional networks in CD8+ T cells affecting ICB resistance, which may serve as novel drug targets for improved ICB therapies in melanoma and other cancers.
International Germline Immuno-Oncology Melanoma Consortium (IO-GEM)
Melanoma is a deadly form of skin cancer with extremely poor prognosis when diagnosed late. This is largely because there is no effective clinical strategy that can reliably predict the likelihood of recurrence for individual patients at early stages of the disease. Our study aims to identify novel germline genetic markers for improved clinical strategies to tailor the prediction of melanoma prognosis to individual patients.
We are conducting comprehensive genetic profiling (whole-genome and whole-transcriptome sequencing) of germline and tumor specimens of 7,000 melanoma patients ascertained at 45 clinical centers across the world to identify novel germline genetic loci associated with the risk of melanoma recurrence. These variants will then be incorporated into a prognostic melanoma model to improve subsequent treatment outcomes.
The findings generated through this international collaboration will not only reveal novel markers of melanoma prognosis with more personalized clinical potential, but our comprehensive exploration of their biological role may point to novel molecular pathways in melanoma progression. Besides improved clinical follow-up care of patients at early stage of melanoma, the study's impact is in the discovery of putatively novel targets of more personalized adjuvant therapies tailored for those patients with early disease but high risk of recurrence.
This work is funded through a Team Science Award from the Melanoma Research Alliance (MRA).