Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma
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 therap...
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| Format: | Article |
| Language: | English |
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BioMed Central
2020
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| Online Access: | https://hdl.handle.net/1721.1/126359 |
| _version_ | 1826192852861845504 |
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| author | Trujillo, Jonathan A Luke, Jason J Zha, Yuanyuan Segal, Jeremy P Ritterhouse, Lauren L Spranger-Zimmermann, Stefani Matijevich, Karen Gajewski, Thomas F |
| author2 | Koch Institute for Integrative Cancer Research at MIT |
| author_facet | Koch Institute for Integrative Cancer Research at MIT Trujillo, Jonathan A Luke, Jason J Zha, Yuanyuan Segal, Jeremy P Ritterhouse, Lauren L Spranger-Zimmermann, Stefani Matijevich, Karen Gajewski, Thomas F |
| author_sort | Trujillo, Jonathan A |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T09:30:12Z |
| format | Article |
| id | mit-1721.1/126359 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T09:30:12Z |
| publishDate | 2020 |
| publisher | BioMed Central |
| record_format | dspace |
| spelling | mit-1721.1/1263592022-09-30T14:52:14Z Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma Trujillo, Jonathan A Luke, Jason J Zha, Yuanyuan Segal, Jeremy P Ritterhouse, Lauren L Spranger-Zimmermann, Stefani Matijevich, Karen Gajewski, Thomas F Koch Institute for Integrative Cancer Research at MIT 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. NCI (Award R00CA204595) 2020-07-23T18:51:32Z 2020-07-23T18:51:32Z 2019-11-08 2019-06 2020-06-26T11:12:24Z Article http://purl.org/eprint/type/JournalArticle 2051-1426 https://hdl.handle.net/1721.1/126359 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) en 10.1186/s40425-019-0780-0 Journal of ImmunoTherapy for Cancer Creative Commons Attribution https://creativecommons.org/licenses/by/4.0/ The Author(s). application/pdf BioMed Central BioMed Central |
| spellingShingle | Trujillo, Jonathan A Luke, Jason J Zha, Yuanyuan Segal, Jeremy P Ritterhouse, Lauren L Spranger-Zimmermann, Stefani Matijevich, Karen Gajewski, Thomas F Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma |
| title | Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma |
| title_full | Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma |
| title_fullStr | Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma |
| title_full_unstemmed | Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma |
| title_short | Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma |
| title_sort | secondary resistance to immunotherapy associated with β catenin pathway activation or pten loss in metastatic melanoma |
| url | https://hdl.handle.net/1721.1/126359 |
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