Christopher Alvarez-Breckenridge, MD, PhD, CRI-Chordoma Foundation CLIP Investigator The University of Texas MD Anderson Cancer Center Chordomas are rare, locally aggressive neoplasms of the axial skeleton. Their anatomic location makes surgical resection challenging and even patients undergoing an en-bloc resection with negative margins are at risk of recurrence. Recurrent chordomas are nearly impossible to eradicate due to limited effective surgical and chemotherapeutic options—highlighting an unmet clinical need. With the broadening use of immune checkpoint inhibitors (ICI) across solid tumor types, there is emerging interest exploring these agents for chordomas. Dr. Alvarez-Breckenridge recently reviewed the MD Anderson institutional experience of recurrent chordomas treated with ICI, including seventeen patients with chordoma involving the skull base, spine, and sacrum who were treated at the time of disease recurrence between 2016 and 2020. Treatment was well tolerated with a 1-year overall survival of 87%, median progression free survival of 14 months, and 88% of patients received clinical benefit as measured by RECIST criteria. Taken together, Dr. Alvarez-Breckenridge hypothesize that chordoma harbors unique intrinsic tumor and microenvironmental features that are amenable to immunotherapeutic modulation. To explore this concept, Dr. Alvarez-Breckenridge will analyze available tissue from our cohort of patients previously treated with ICI while also prospectively analyzing future tissue from surgically resected skull base, spinal, and sacral chordomas. Using these two cohorts, Dr. Alvarez-Breckenridge will investigate detailed genomic structural rearrangements, transcriptional and epigenetic modifications, and immune cell spatial heterogeneity in the chordoma tumor microenvironment within the context of ICI treatment and across distinct anatomic locations. This will provide a framework for future clinical trial implementation exploring ICI mechanism of action for patients with chordoma.