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Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge

PURPOSE: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunothera...

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Autores principales: van der Westhuizen, Andre, Lyle, Megan, Graves, Moira C., Zhu, Xiaoqiang, Wong, Jason W. H., Cornall, Kerrie, Ren, Shu, Pugliese, Leanna, Levy, Richard, Majid, Adeeb, Vilain, Ricardo E., Bowden, Nikola A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010343/
https://www.ncbi.nlm.nih.gov/pubmed/36923309
http://dx.doi.org/10.1158/2767-9764.CRC-22-0128
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author van der Westhuizen, Andre
Lyle, Megan
Graves, Moira C.
Zhu, Xiaoqiang
Wong, Jason W. H.
Cornall, Kerrie
Ren, Shu
Pugliese, Leanna
Levy, Richard
Majid, Adeeb
Vilain, Ricardo E.
Bowden, Nikola A.
author_facet van der Westhuizen, Andre
Lyle, Megan
Graves, Moira C.
Zhu, Xiaoqiang
Wong, Jason W. H.
Cornall, Kerrie
Ren, Shu
Pugliese, Leanna
Levy, Richard
Majid, Adeeb
Vilain, Ricardo E.
Bowden, Nikola A.
author_sort van der Westhuizen, Andre
collection PubMed
description PURPOSE: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma. EXPERIMENTAL DESIGN: A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed. RESULTS: The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87–21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67–86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8(+), showed the greatest increase in infiltration. CONCLUSIONS: Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma. SIGNIFICANCE: There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma.
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spelling pubmed-100103432023-03-14 Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge van der Westhuizen, Andre Lyle, Megan Graves, Moira C. Zhu, Xiaoqiang Wong, Jason W. H. Cornall, Kerrie Ren, Shu Pugliese, Leanna Levy, Richard Majid, Adeeb Vilain, Ricardo E. Bowden, Nikola A. Cancer Res Commun Research Article PURPOSE: Drug repurposing offers the opportunity for chemotherapy to be used to reestablish sensitivity to immune checkpoint blockade (ICB) therapy. Here we investigated the clinical and translational aspects of an early phase II study of azacitidine and carboplatin priming for anti-PDL1 immunotherapy (avelumab) in patients with advanced ICB-resistant melanoma. EXPERIMENTAL DESIGN: A total of 20 participants with ICB-resistant metastatic melanoma received 2 × 4-week cycles of azacitidine and carboplatin followed by ICB rechallenge with anti-PD-L1 avelumab. The primary objective was overall response rate after priming and ICB rechallenge. Secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Translational correlation analysis of HLA-A and PD-L1 expression, RNA sequencing, and reduced representation bisulfite sequencing of biopsies at baseline, after priming and after six cycles of avelmuab was performed. RESULTS: The overall response rate (ORR) determined after azacitidine and carboplatin priming was 10% (2/20) with two partial responses (PR). The ORR determined after priming followed by six cycles of avelumab (week 22) was 10%, with 2 of 20 participants achieving immune partial response (iPR). The CBR for azacitidine and carboplatin priming was 65% (13/20) and after priming followed by six cycles of avelumab CBR was 35% (n = 7/20). The median PFS was 18.0 weeks [95% confidence interval (CI): 14.87–21.13 weeks] and the median OS was 47.86 weeks (95% CI: 9.67–86.06 weeks). Translational correlation analysis confirmed HLA-A generally increased after priming with azacitidine and carboplatin, particularly if it was absent at the start of treatment. Average methylation of CpGs across the HLA-A locus was decreased after priming and T cells, in particular CD8(+), showed the greatest increase in infiltration. CONCLUSIONS: Priming with azacitidine and carboplatin can induce disease stabilization and resensitization to ICB for metastatic melanoma. SIGNIFICANCE: There are limited treatments for melanoma once resistance to ICB occurs. Chemotherapy induces immune-related responses and may be repurposed to reinstate the response to ICB. This study provides the first evidence that chemotherapy can provide clinical benefit and increase OS for ICB-resistant melanoma. American Association for Cancer Research 2022-08-17 /pmc/articles/PMC10010343/ /pubmed/36923309 http://dx.doi.org/10.1158/2767-9764.CRC-22-0128 Text en © 2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
van der Westhuizen, Andre
Lyle, Megan
Graves, Moira C.
Zhu, Xiaoqiang
Wong, Jason W. H.
Cornall, Kerrie
Ren, Shu
Pugliese, Leanna
Levy, Richard
Majid, Adeeb
Vilain, Ricardo E.
Bowden, Nikola A.
Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
title Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
title_full Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
title_fullStr Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
title_full_unstemmed Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
title_short Repurposing Azacitidine and Carboplatin to Prime Immune Checkpoint Blockade–resistant Melanoma for Anti-PD-L1 Rechallenge
title_sort repurposing azacitidine and carboplatin to prime immune checkpoint blockade–resistant melanoma for anti-pd-l1 rechallenge
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10010343/
https://www.ncbi.nlm.nih.gov/pubmed/36923309
http://dx.doi.org/10.1158/2767-9764.CRC-22-0128
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