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Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade-resistant Melanoma for Anti-PD-L1
Andre van der Westhuizen1,2, Megan Lyle3, Moira C Graves1
1Hunter Medical Research Institute and School of Medicine and Public Health, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia.
Cancer Research Communications
|March 16, 2023
Summary
Chemotherapy priming with azacitidine and carboplatin can re-sensitize patients with advanced melanoma to immune checkpoint blockade (ICB) therapy, showing promising clinical benefits and increased overall survival.
Area of Science:
- Oncology
- Immunotherapy
- Drug Repurposing
Background:
- Advanced melanoma often develops resistance to immune checkpoint blockade (ICB) therapy, necessitating novel treatment strategies.
- Chemotherapy is being explored for its potential to restore sensitivity to ICB by inducing immune-related responses.
Purpose of the Study:
- To investigate the clinical and translational efficacy of azacitidine and carboplatin as a priming regimen for anti-PD-L1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma.
Main Methods:
- A phase II study involving 20 participants with ICB-resistant metastatic melanoma.
- Participants received azacitidine and carboplatin priming followed by avelumab rechallenge.
- Translational analyses included HLA-A and PD-L1 expression, RNA sequencing, and bisulfite sequencing of tumor biopsies.
Main Results:
- The overall response rate (ORR) after priming and avelumab was 10%.
- Clinical benefit rate (CBR) was 65% after priming and 35% after avelumab treatment.
- Median progression-free survival (PFS) was 18.0 weeks and median overall survival (OS) was 47.86 weeks.
- Priming increased HLA-A expression, decreased CpG methylation at the HLA-A locus, and enhanced CD8+ T cell infiltration.
Conclusions:
- Priming with azacitidine and carboplatin can stabilize disease and resensitize patients with metastatic melanoma to ICB.
- This approach offers a potential strategy to improve outcomes for patients with ICB-resistant melanoma.
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