Secondary resistance to immunotherapy associated with β-catenin pathway activation or PTEN loss in metastatic melanoma.

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.

• Authors: Jonathan A Trujillo, Jason J Luke, Yuanyuan Zha, Jeremy P Segal, Lauren L Ritterhouse, Stefani Spranger, Karen Matijevich, Thomas F Gajewski
• Journal: Journal for immunotherapy of cancer (J Immunother Cancer) Vol. 7 Issue 1 Pg. 295 (11 08 2019) ISSN: 2051-1426 [Electronic] England
• PMID: 31703593 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Immunological
• CTLA-4 Antigen
• CTLA4 protein, human
• CTNNB1 protein, human
• Cancer Vaccines
• Ipilimumab
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• beta Catenin
• Interleukin-12
• Nivolumab
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Adult
• Antineoplastic Agents, Immunological (therapeutic use)
• CTLA-4 Antigen (antagonists & inhibitors)
• Cancer Vaccines (therapeutic use)
• Drug Resistance, Neoplasm
• High-Throughput Nucleotide Sequencing
• Humans
• Immunotherapy
• Interleukin-12 (immunology)
• Ipilimumab (therapeutic use)
• Male
• Melanoma (genetics, metabolism, pathology, therapy)
• Middle Aged
• Nivolumab (therapeutic use)
• PTEN Phosphohydrolase (genetics, metabolism)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Signal Transduction
• Transcriptome
• Young Adult
• beta Catenin (genetics)