"Transcriptomic-Guided Tumor Infiltrating Lymphocyte Therapy for Immune-Resistant Cancers"

Abstract: Most patients with metastatic cancer do not respond to immunotherapy using checkpoint inhibition, and thus alternative treatments are necessary. Metastatic uveal melanoma is a prototypic solid tumor with resistance to checkpoint inhibition. Our group has previously shown that a subset of uveal melanoma patients harbor tumor-reactive tumor infiltrating lymphocytes (TIL) in their metastases and that adoptive cell transfer (ACT) of these TIL could mediate a 35% objective response rate. Our goal is to further improve upon these clinical results and extend this therapeutic approach to other immune-resistant cancers.

In this talk we will describe the discovery of a novel transcriptomic biomarker for TIL anti-tumor reactivity based upon extensive multiomic profiling of a large cohort of surgically resected UM metastases. This will be followed by in depth studies involving TCR repertoire analysis and single-cell RNA sequencing of metastatic UM tumors. Finally, we will discuss adaptation of this uveal melanoma biomarker to a pan-cancer biomarker (TILScore) with semi-supervised machine learning. We are now prospectively evaluating TILScore in the context of multiple ongoing TIL therapy trials at UPMC and for screening patients using core biopsies.