2021 SITC: Exome-scale liquid biopsy characterization of emerging immune resistance mechanisms in treatment-resistant GIST

Background

Metastatic gastrointestinal stromal tumors (GIST) are lethal tumors of the GI tract characterized by gain of function mutations in KIT or PDGFRɑ. Transient first-line control is achieved through the inhibition of tyrosine kinase signaling using the KIT inhibitor imatinib, though most patients progress after 2-3 years. Progression through successive lines of therapy results in a molecularly heterogeneous disease with diverse subtypes, driven by distinct collections of exon-specific KIT mutations which directly inform therapy decisions. To address the unmet need of comprehensive understanding of GIST, we used tumor-informed whole exome liquid biopsy to identify and track the evolution of multiple concurrent heterogeneous resistance mechanisms in individual patients receiving tyrosine kinase inhibitors (TKIs).

Methods

Cohort: Baseline matched tumor, normal and longitudinal plasma samples were obtained from 15 metastatic, heavily pretreated GIST patients. Following baseline sample collection, all patients received systemic TKI therapy, and were monitored until disease progression.

Solid Tumor: The ImmunoID NeXT Platform®, an augmented exome/transcriptome platform and analysis pipeline was used to profile paired tumor and normal samples. Gene expression profiling, comprehensive tumor mutation information, neoantigen characterization including our composite neoantigen burden score NEOPS™, HLA typing and allele-specific LOH, TCR repertoire profiling, and tumor microenvironment profiling were generated as outlined in the plot below.

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