Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma
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40425_2019_Article_780.pdf
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Author(s)
Trujillo, Jonathan A
Luke, Jason J
Zha, Yuanyuan
Segal, Jeremy P
Ritterhouse, Lauren L
Spranger-Zimmermann, Stefani
Matijevich, Karen
Gajewski, Thomas F
Date Issued
November 8, 2019
Journal
Journal of ImmunoTherapy for Cancer
Publisher
BioMed Central
Citation
Trujillo, Jonathan A. et al. "Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma." Journal of ImmunoTherapy for Cancer 7, 1 (November 2019): 295 ©2019 Author(s)
Version
Final published version
Abstract
BACKGROUND: While cancer immunotherapies including checkpoint blockade antibodies, adoptive T cell therapy, and even some vaccines have given rise to major clinical responses with durability in many cases, a subset of patients who initially respond subsequently develop secondary resistance to therapy. Tumor-intrinsic mechanisms of acquired immunotherapy resistance are incompletely understood. METHODS: Baseline and treatment-resistant tumors underwent molecular analysis via transcriptional profiling or genomic sequencing for oncogenic alterations and histologic analysis for T cell infiltration to investigate mechanisms contributing to T cell exclusion and acquired resistance to immunotherapy. RESULTS: We describe two patients with metastatic melanoma who initially showed a durable partial response to either a melanoma-peptide/interleukin-12 vaccine or combined anti-CTLA-4 + anti-PD-1 therapy, but subsequently developed new treatment-resistant metastases. In the first case, the recurrent tumor showed new robust tumor expression of β-catenin, whereas in the second case genomic sequencing revealed acquired PTEN loss. Both cases were associated with loss of T cell infiltration, and both pathways have been mechanistically linked to immune resistance preclinically. CONCLUSION: Our results suggest that secondary resistance to immunotherapies can arise upon selection for new oncogenic variants that mediate T cell exclusion. To identify the spectrum of underlying mechanisms of therapeutic resistance, similar evaluation for the emergence of tumor-intrinsic alterations in resistant lesions should be done prospectively at the time of relapse in a range of additional patients developing secondary resistance.
MIT Department
Koch Institute for Integrative Cancer Research at MIT
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DOI of Published Version
https://doi.org/10.1186/s40425-019-0780-0
