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Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab
Open accessPublished version of a preprint
Abstract
Purpose: To identify baseline peripheral blood biomarkers associated with clinical outcome following ipilimumab treatment in advanced melanoma patients. Experimental Design: Frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg), serum lactate dehydrogenase (LDH), routine blood counts, and clinical characteristics were assessed in 209 patients. Endpoints were overall survival (OS) and best overall response. Statistical calculations were done by Kaplan–Meier and Cox regression analysis, including calibration and discrimination by C-statistics. Results: Low baseline LDH, absolute monocyte counts (AMC), Lin−CD14+HLA-DR−/low-MDSC frequencies, and high absolute eosinophil counts (AEC), relative lymphocyte counts (RLC), and CD4+CD25+FoxP3+-Treg frequencies were significantly associated with better survival, and were considered in a combination model. Patients (43.5%) presenting with the best biomarker signature had a 30% response rate and median survival of 16 months. In contrast, patients with the worst biomarkers (27.5%) had only a 3% response rate and median survival of 4 months. The occurrence of adverse events correlated with neither baseline biomarker signatures nor the clinical benefit of ipilimumab. In another model, limited to the routine parameters LDH, AMC, AEC, and RLC, the number of favorable factors (4 vs. 3 vs. 2–0) was also associated with OS (P < 0.001 for all pairwise comparisons) in the main study and additionally in an independent validation cohort. Conclusions: A baseline signature of low LDH, AMC, and MDSCs as well as high AEC, Tregs, and RLC is associated with favorable outcome following ipilimumab. Prospective investigation of the predictive impact of these markers following ipilimumab and other treatments, e.g., PD-1 antibodies, is warranted. Clin Cancer Res; 22(12); 2908–18. ©2016 AACR.
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“Furthermore, an elevated eosinophil count prior to treatment was associated with longer overall survival in several studies.8–12”
In the citing paper
“increased lymphocyte counts in the blood are associated not only with favorable treatment outcome but also with increased overall survival in patients with melanoma treated with ICIs (132-135).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [134]
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“numerous studies of patients with cancer have indeed found that these myeloid cell subsets, whether in the tumor or in peripheral tissues, were negatively correlated with effective ICI therapy (134, 161, 168-171).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [134]
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“both a low baseline frequency of MDSCs and a low frequency of MDSCs in the blood of patients with melanoma following ipilimumab treatment were associated with favorable therapy outcome (134, 169-171).”
From Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance (2021) · cites this paper as [134]
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Citations
Cites
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
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Self-citationSafety, activity, and immune correlates of anti–PD-1 antibody in cancer
Topalian, S. L., Hodi, F. S., Brahmer, J. R., Gettinger, S. N., Smith, D. C., McDermott, D. F., Powderly, J. D., Carvajal, R. D., Sosman, J. A., Atkins, M. B., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200690 · Cited by 12,628 · cited 1×
“Moreover, recent breakthroughs in immunotherapy, especially anti-PD-1 (5, 21) and anti-programmed cell death ligand-1 (PD-L1) antibodies (22), impressively demonstrate the capacity of a modulated immune system to reject cancer.”
BackgroundSafety and activity of anti-PD-L1 antibody in patients with advanced cancer
Brahmer, J. R., Tykodi, S. S., Chow, L. Q. M., Hwu, W.-J., Topalian, S. L., Hwu, P., Drake, C. G., Camacho, L. H., Kauh, J., Odunsi, K., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1200694 · Cited by 7,945 · cited 1×
“Moreover, recent breakthroughs in immunotherapy, especially anti-PD-1 (5, 21) and anti-programmed cell death ligand-1 (PD-L1) antibodies (22), impressively demonstrate the capacity of a modulated immune system to reject cancer.”
BackgroundMyeloid-derived-suppressor cells as regulators of the immune system
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“MDSCs and Tregs have been shown to exert suppressive function on T cells, thereby possibly counteracting the beneficial effect of ipilimumab (28, 45).”
BackgroundFinal Version of 2009 AJCC Melanoma Staging and Classification
Balch, C. M., Gershenwald, J. E., Soong, S.-J., Thompson, J. F., Atkins, M. B., Byrd, D. R., Buzaid, A. C., Cochran, A. J., Coit, D. G., Ding, S., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2009.23.4799 · Cited by 4,653 · cited 1×
“The aim of the present studywas to identify baseline peripheral blood biomarkers associated with overall survival (OS) and tumor response of melanoma patients treated with ipilimumab, by a comprehensive analysis of routine blood counts, frequencies of immune cell subsets analyzed by flow cytometry, and established pro…”
BackgroundIpilimumab plus Dacarbazine for Previously Untreated Metastatic Melanoma
Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Weber, J., Garbe, C., Lebbe, C., Baurain, J.-F., Testori, A., Grob, J.-J., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1104621 · Cited by 4,496 · cited 1×
“Ipilimumab was the first agent to prolong survival of melanoma patients in randomized phase III studies (1, 2).”
BackgroundSelf-citationGenetic Basis for Clinical Response to CTLA-4 Blockade in Melanoma
Snyder, A., Makarov, V., Merghoub, T., Yuan, J., Zaretsky, J. M., Desrichard, A., Walsh, L. A., Postow, M. A., Wong, P., Ho, T. S., et al. (2014) · New England Journal of Medicine · doi:10.1056/nejmoa1406498 · Cited by 4,286 · cited 3×
“CD4þ T helper cells (15), CD8þ cytotoxic T cells (16, 17), and those targeting melanoma-associated- (18) or neoantigens (19, 20) are in principle able to attack cancer cells and are most likely responsible for the beneficial effects of ipilimumab.”
BackgroundSelf-citationCamp, R. L., Dolled-Filhart, M. P., & Rimm, D. L. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-04-0713 · Cited by 3,748 · cited 1×
“Candidates and respective cutoff points for continuous variables were defined by applying an optimization algorithm similar to those published earlier (10, 33).”
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Pourmir, I., Gey, A., Pineau, J., Lebbé, C., & Tartour, É. (2023) · Bulletin de l Académie Nationale de Médecine · doi:10.1016/j.banm.2023.03.019
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“Opposite results have been obtained in other studies, with significantly increased baseline Tregs characterizing CPI-responders [39,90,91].”
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“З іншого боку, у пацієнтів із підвищеним рів - нем LDH у сироватці порівняно з базовим рівнем LDH спостерігалося прогресування захворювання [67, 68].”
Yu, S., Shu, W., Zhang, J., Cheng, S., Shen, X., Chen, G., Zhang, T., Dong, K., Zhang, J., Laudański, P., et al. (2025) · Research Square · doi:10.21203/rs.3.rs-6189084/v1
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Tucker, M. D., Brown, L. C., Chen, Y.-W., Kao, C., Hirshman, N. A., Kinsey, E. N., Ancell, K. K., Beckermann, K. E., Davis, N. B., McAlister, R. K., et al. (2021) · Figshare · doi:10.6084/m9.figshare.16928502
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Xagara, A., Koinis, F., Tsapakidis, K., Samaras, I., Chantzara, E., Vasilieva, K., Lazarou, A., Georgoulias, V., & Kotsakis, A. P. (2026) · Onco · doi:10.3390/onco6010004
“Additionally, melanoma patients bearing high levels of pre-existing Tregs or memory CD8 + T cells in circulation respond better to Ipilimumab [25,26].”
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Ruta, A., Gray-Gaillard, E. F., Garcia, J. A., Huyer, L. D., Mathkour, Y., Cherry, C., Patatanian, M., Mejías, J. C., Maestas, D. R., Krishnan, K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.02.703323
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“…of circulating immune subsets and survival has been studied in several cancer types treated with ICBt, such as bladder cancer (9, 10), melanoma (11 – 13), head and neck squamous cell carcinoma (14), non-small cell lung cancer (NSCLC) (15), as well as in a pan-cancer analysis encompassing…”
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Metadata
- Authors
- Martens, A., Wistuba-Hamprecht, K., Foppen, M. G., Yuan, J., Postow, M. A., Wong, P., Romano, E., Khammari, A., Dreno, B., Capone, M., Ascierto, P. A., Di Giacomo, A. M., Maio, M., Schilling, B., Sucker, A., Schadendorf, D., Hassel, J. C., Eigentler, T. K., Martus, P., Wolchok, J. D., Blank, C., Pawelec, G., Garbe, C., & Weide, B.
- Affiliations
- Universitätsklinikum Tübingen (DE)
- 1Department of Dermatology, University Medical Center, Tübingen, Germany.
- The Netherlands Cancer Institute (NL)
- Memorial Sloan Kettering Cancer Center (US)
- Institut Curie (FR)
- Inserm (FR)
- 7Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France.
- Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale" (IT)
- 9Division of Medical Oncology and Immunotherapy, University Hospital of Siena, Italy.
- University of Siena (IT)
- Essen University Hospital (DE)
- Heidelberg University (DE)
- University of Tübingen (DE)
- Corresponding author
- Weide, Benjamin
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-06-14
- Volume
- 22
- Issue
- 12
- Pages
- 2908-2918
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC5770142
- OpenAlex
- W2282962877
- Semantic Scholar
- 687f623ec6cd13653346165ccad52a8570919d07
- Cited by
- 541
- References
- 55
- Citations by year
- 2026: 10 · 2025: 29 · 2024: 21 · 2023: 42 · 2022: 50 · 2021: 75 · 2020: 85 · 2019: 61 · 2018: 70 · 2017: 63 · 2016: 33
- FWCI
- 40.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Use Siena air (University of Siena) (submittedVersion, other-oa)
- HAL (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Funders
- Bristol-Myers-Squibb (Munich, Germany) and EU Seventh Framework Program "PRIAT" (305309 and DFG PA 361-22/1)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cutaneous Melanoma Detection and Management
- Health Sciences › Medicine › Oncology › Inflammatory Biomarkers in Disease Prognosis
- Keywords
- advanced melanoma, ipilimumab, predictive biomarkers, myeloid-derived suppressor cells, regulatory T cells, lactate dehydrogenase, absolute monocyte count, absolute eosinophil count, overall survival, best overall response, immune checkpoint inhibitors, anti-PD-1
- MeSH terms
- Myeloid-Derived Suppressor Cells, Antineoplastic Agents, Immunological, Ipilimumab, Aged, Erythrocyte Count, Female, Humans, L-Lactate Dehydrogenase, Male, Melanoma, Skin Neoplasms, Biomarkers, Tumor, Treatment Outcome, Lymphocyte Count, T-Lymphocytes, Regulatory
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