Developing Tumor-Infiltrating Lymphocyte Therapy for Immune-Resistant Cancers

Presenter: Dr. Shravan Leonardi-Murali (Mentor: Dr. Udai Kammula)

Most metastatic solid tumors are resistant to checkpoint inhibition and are in need of alternate immunotherapies. Metastatic uveal melanoma is a prototypic immune-resistant cancer with uniform resistance to checkpoint inhibition. Dr. Leonardi-Murali's group previously showed that a subset of UM metastases harbor tumor-reactive tumor-infiltrating lymphocytes (TILs) and that adoptive cell transfer (ACT) of these TILs could mediate a 35% objective response rate in metastatic UM, but many critical challenges remain in TIL therapy for immune-resistant cancers.

In this talk, Dr. Leonardi-Murali will discuss the discovery of a transcriptomic biomarker of TIL anti-tumor reactivity and TIL therapy response, which involved extensive multiomic profiling of the largest known cohort of surgically resected UM metastases. This will be followed by mechanistic studies involving TCR repertoire analysis and single-cell RNA sequencing of metastatic UM tumors. Finally, he will discuss conversion of the UM biomarker to a pan-cancer biomarker (TILscore) with semi-supervised machine learning. HIs group is now prospectively evaluating TILscore in the context of multiple ongoing TIL therapy trials at UPMC.