Soluble PD-L1 as an early marker of progressive disease on nivolumab
Background Soluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear cell renal cell carcinoma (RCC) and melanoma patients, and investigated its re...
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BMJ Publishing Group
2022-02-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/2/e003527.full |
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| author | David F McDermott Gordon J Freeman Toni K Choueiri Petra Ross-MacDonald F Stephen Hodi Megan Wind-Rotolo Long Yuan Kathleen M Mahoney Linan Song Eliseo Veras |
| author_facet | David F McDermott Gordon J Freeman Toni K Choueiri Petra Ross-MacDonald F Stephen Hodi Megan Wind-Rotolo Long Yuan Kathleen M Mahoney Linan Song Eliseo Veras |
| author_sort | David F McDermott |
| collection | DOAJ |
| description | Background Soluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear cell renal cell carcinoma (RCC) and melanoma patients, and investigated its relationship to clinical factors, biomarkers, and outcome.Methods Using a new Single Molecule Array assay, serum sPD-L1 level were determined in RCC (CheckMate 009, n=91) and melanoma (CheckMate 038-Part 1, n=78) prior to, and at two time points on treatment. Gene expression data was obtained from biopsies taken prior to, and at day 28 on treatment. Results were integrated with clinical variables, tumor PD-L1 status from immuno-histochemistry, and genomic mutation status.Results In RCC patients, sPD-L1 levels were higher in patients with progressive disease as their best response. For both RCC and melanoma patients, progressive or stable disease was associated with an increase in sPD-L1 on nivolumab therapy, whereas mean sPD-L1 levels did not change or declined in patients with objective responses. By categorizing RCC patients into transcriptomic molecular subtypes, we identified a subgroup where the associations between sPD-L1 and progressive disease were particularly evident. In baseline biopsies, we identified six biological processes that were associated with sPD-L1 level in both RCC and melanoma: higher sPD-L1 is associated with lower tumor expression of the Hallmark gene sets ‘hypoxia’, ‘fatty acid metabolism’, ‘glycolysis’, ‘MTORC1 signaling’ and ‘androgen response’, and with higher expression of ‘KRAS signaling_Down’.Conclusion Baseline and on-therapy sPD-L1 levels in RCC have the potential to predict progressive disease on PD-1 inhibitor nivolumab. In a hypothesis-generating analysis of tumor gene expression, high baseline sPD-L1 is associated with a tumor metabolic state reflecting potentially targetable processes in both melanoma and RCC. In both trials, we observed associations between change in sPD-L1 on treatment and outcome metrics. sPD-L1 levels may further refine a nivolumab-refractory subtype of RCC within transcriptionally based subtypes of RCC. |
| format | Article |
| id | doaj-art-7c93c3e786c84292b00ec79f0d4a49f9 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-02-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-7c93c3e786c84292b00ec79f0d4a49f92025-08-20T02:12:46ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-02-0110210.1136/jitc-2021-003527Soluble PD-L1 as an early marker of progressive disease on nivolumabDavid F McDermott0Gordon J Freeman1Toni K Choueiri2Petra Ross-MacDonald3F Stephen Hodi4Megan Wind-Rotolo5Long Yuan6Kathleen M Mahoney7Linan Song8Eliseo Veras915 Division of Medical Oncology, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USATranslational Medicine, Bristol Myers Squibb Co, Princeton, New Jersey, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USATranslational Medicine, Bristol Myers Squibb Co, Princeton, New Jersey, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USABeth Israel Deaconess Medical Center, Boston, Massachusetts, USAQuanterix Corporation, Billerica, Massachusetts, USAQuanterix Corporation, Billerica, Massachusetts, USABackground Soluble PD-L1 (sPD-L1) has been associated with worse prognosis in numerous solid tumors. We determined sPD-L1 levels before and during nivolumab treatment in two prospective clinical trials of metastatic clear cell renal cell carcinoma (RCC) and melanoma patients, and investigated its relationship to clinical factors, biomarkers, and outcome.Methods Using a new Single Molecule Array assay, serum sPD-L1 level were determined in RCC (CheckMate 009, n=91) and melanoma (CheckMate 038-Part 1, n=78) prior to, and at two time points on treatment. Gene expression data was obtained from biopsies taken prior to, and at day 28 on treatment. Results were integrated with clinical variables, tumor PD-L1 status from immuno-histochemistry, and genomic mutation status.Results In RCC patients, sPD-L1 levels were higher in patients with progressive disease as their best response. For both RCC and melanoma patients, progressive or stable disease was associated with an increase in sPD-L1 on nivolumab therapy, whereas mean sPD-L1 levels did not change or declined in patients with objective responses. By categorizing RCC patients into transcriptomic molecular subtypes, we identified a subgroup where the associations between sPD-L1 and progressive disease were particularly evident. In baseline biopsies, we identified six biological processes that were associated with sPD-L1 level in both RCC and melanoma: higher sPD-L1 is associated with lower tumor expression of the Hallmark gene sets ‘hypoxia’, ‘fatty acid metabolism’, ‘glycolysis’, ‘MTORC1 signaling’ and ‘androgen response’, and with higher expression of ‘KRAS signaling_Down’.Conclusion Baseline and on-therapy sPD-L1 levels in RCC have the potential to predict progressive disease on PD-1 inhibitor nivolumab. In a hypothesis-generating analysis of tumor gene expression, high baseline sPD-L1 is associated with a tumor metabolic state reflecting potentially targetable processes in both melanoma and RCC. In both trials, we observed associations between change in sPD-L1 on treatment and outcome metrics. sPD-L1 levels may further refine a nivolumab-refractory subtype of RCC within transcriptionally based subtypes of RCC.https://jitc.bmj.com/content/10/2/e003527.full |
| spellingShingle | David F McDermott Gordon J Freeman Toni K Choueiri Petra Ross-MacDonald F Stephen Hodi Megan Wind-Rotolo Long Yuan Kathleen M Mahoney Linan Song Eliseo Veras Soluble PD-L1 as an early marker of progressive disease on nivolumab Journal for ImmunoTherapy of Cancer |
| title | Soluble PD-L1 as an early marker of progressive disease on nivolumab |
| title_full | Soluble PD-L1 as an early marker of progressive disease on nivolumab |
| title_fullStr | Soluble PD-L1 as an early marker of progressive disease on nivolumab |
| title_full_unstemmed | Soluble PD-L1 as an early marker of progressive disease on nivolumab |
| title_short | Soluble PD-L1 as an early marker of progressive disease on nivolumab |
| title_sort | soluble pd l1 as an early marker of progressive disease on nivolumab |
| url | https://jitc.bmj.com/content/10/2/e003527.full |
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