Genetic, Immune And Metabolic Endpoints As Biomarkers Of Immune Check- Point Therapy Response

Martin Porebski

Wake Forest University School of Medicine , USA

Biography :

Martin Porebski resident physician in Internal Medicine training at Atrium Health Wake Forest University Baptist Medical Center. My interests include global health as well as medical-entrepreneurship. Ultimately, I hope to specialize further through fellowship and combine my life experiences to bring about comprehensive, empa- thetic, evidenced-based care and develop a career where my impact is felt on more than one patient at a time. Always looking for new and interesting opportunities to diversify my career outside of purely clinical medicine!

Abstract :

The development of immunotherapies represents a significant advance within clinical on- cology, but its efficacy is confined to a subset of patients, and the emergence of acquired resistance is increasingly apparent. Unlike conventional chemotherapy, which often results in measurable changes in tumor size, evaluating responses to immune checkpoint inhibitor ther- apy proves challenging due to its unique mechanism and the frequent occurrence of disease progression before tumor regression. Consequently, identifying biomarkers of therapeutic re- sponse becomes pivotal in formulating strategies to enhance overall response rates. In our current investigation, we conducted a retrospective analysis of peripheral blood mononuclear cells (PBMCs) and plasma obtained from patient blood draws before initiating treatment and then three weeks after the first cycle of therapy for those with metastatic non-small cell lung cancer undergoing immune checkpoint inhibitor therapy; participants are enrolled in an on- going Wake Forest Phase II clinical trial (NCT04253964) that is evaluating the impact of ECOG Performance Status on outcomes in advanced lung cancer. This analysis builds on method- ology from a recently published study centered around patients with metastatic melanoma. To determine biomarkers of response we employed single-cell RNA sequencing (scRNAseq) to study the identity and transcriptional profiles of involved cells within patient PBMCs. Tran- scriptomic clustering consistently identified the major immune cell populations expected in PBMCs: monocytes, natural killers, B cells, and T cells. Graph-based cluster analysis further uncovered transcriptional variations, allowing the identification of multiple immune cell sub- populations within these major clusters. Pathway enrichment analysis of the T cell population revealed that one of the top regulated pathways is oxidative phosphorylation which includes genes related to the mitochondrial electron transport chain and mitochondrial membrane in- tegrity. To determine whether response is related to regulation of this pathways PBMCs were subjected to cellular respiration analysis. Our data demonstrates that patients that respond to immunotherapy have a 2-fold (p