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Baseline Peripheral Blood Biomarkers Associated with Clinical Outcome of Advanced Melanoma Patients Treated with Ipilimumab
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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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“To date, despite a number of attempts to identify biomarkers predictive of response to ipilimumabmonotherapy, no biomarker has consistently been shown to be associated with response or clinical benefit (15, 16).”
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“Higher pretreatment levels of circulating Treg cells were associated with improved survival in melanoma patients treated with ipilimumab (Martens et al. 2016).”
BackgroundHou, A., Hou, K., Huang, Q., Lei, Y., & Chen, W.-L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00783 · Cited by 148
de Coaña, Y. P., Wolodarski, M., Poschke, I., Yoshimoto, Y., Yang, Y., Nyström, M., Edbäck, U., Brage, S. E., Lundqvist, A., Masucci, G. V., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15368 · Cited by 139
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Chu, X., Zhao, J., Zhou, J., Zhou, F., Jiang, T., Jiang, S., Sun, X., You, X., Wu, F., Ren, S., et al. (2020) · Lung Cancer · doi:10.1016/j.lungcan.2020.08.015 · Cited by 148
Phase I/Ib Study of Pembrolizumab Plus Vorinostat in Advanced/Metastatic Non–Small Cell Lung Cancer
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Kim, S. H., Li, M., Trousil, S., Zhang, Y., di Magliano, M. P., Swanson, K. D., & Zheng, B. (2017) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.03.033 · Cited by 142
“Indeed, MDSCs have been proposed to contribute to resistance to various cancer therapies, including to anti-CTLA4 and anti-PD-1 blockade (Martens et al., 2016; Sade-Feldman et al., 2016; Weber et al., 2016).”
BackgroundPawelec, G. (2017) · Biogerontology · doi:10.1007/s10522-017-9682-z · Cited by 140
“…anecdotal clinical reports with sufficient accumulated experience, at least for the treatment of advanced melanoma with anti-CTLA-4 antibodies, it seems that response rates may be quite similar in elderly and younger patients (Martens et al. 2016; Helissey et al. 2016; Chiarion Sileni et al. 2014).”
BackgroundSelf-citationBiomarkers for Immunotherapy: Current Developments and Challenges
Spencer, K. R., Wang, J., Silk, A. W., Ganesan, S., Kaufman, H. L., & Mehnert, J. M. (2016) · American Society of Clinical Oncology Educational Book · doi:10.1200/edbk_160766 · Cited by 148
Heppt, M. V., Amaral, T. M. S., Kähler, K. C., Heinzerling, L., Hassel, J. C., Meißner, M., Kreuzberg, N., Loquai, C., Reinhardt, L., Utikal, J. S., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0800-0 · Cited by 141
“As potential serum biomarkers, lactate dehydrogenase (LDH), C-reactive protein (CRP), and the relative counts of lymphocytes (RLC), neutrophils (RNC), and eosinophils (REC) were specifically collected from patient charts and analyzed for their prognostic value [13, 14].”
BackgroundSelf-citationPrognostic role of neutrophil‐to‐lymphocyte ratio in head and neck cancer: A meta‐analysis
Takenaka, Y., Oya, R., Kitamiura, T., Ashida, N., Shimizu, K., Takemura, K., Yamamoto, Y., & Uno, A. (2017) · Head & Neck · doi:10.1002/hed.24986 · Cited by 137
Current and future perspectives of PD-1/PDL-1 blockade in cancer immunotherapy
Makuku, R., Khalili, N., Razi, S., Keshavarz-Fathi, M., & Rezaei, N. (2021) · Journal of Immunology Research · doi:10.1155/2021/6661406 · Cited by 136
“lymphocyte count (ALC), absolute neutrophil count (ANC), and absolute eosinophil count (AEC), were related to survival in melanoma patients undergoing treatment with immune checkpoint inhibitor therapy [115, 116].”
BackgroundWang, P.-F., Song, S., Wang, T., Ji, W., Li, S., Liu, N., & Yan, C. (2018) · OncoImmunology · doi:10.1080/2162402x.2018.1494113 · Cited by 131
Systemic Reprogramming of Monocytes in Cancer
Kiss, M., Caro, A. A., Raes, G., & Laoui, D. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01399 · Cited by 133
“Recent studies have revealed that phenotypical alterations in peripheral blood monocytes can serve as diagnostic (113, 117), predictive (108), and prognostic (116) biomarkers.”
BackgroundEosinophil–lymphocyte interactions in the tumor microenvironment and cancer immunotherapy
Grisaru‐Tal, S., Rothenberg, M. E., & Munitz, A. (2022) · Nature Immunology · doi:10.1038/s41590-022-01291-2 · Cited by 131
Nosrati, A., Tsai, K. K., Goldinger, S. M., Tumeh, P. C., Grimes, B. A., Loo, K. L., Algazi, A. P., Nguyen‐Kim, T. D. L., Levesque, M. P., Dummer, R., et al. (2017) · British Journal of Cancer · doi:10.1038/bjc.2017.70 · Cited by 126
“…cell populations, such as MDSCs and Treg cells (Pawelec et al, 2010; Goronzy and Weyand, 2013), and MDSCs have been reported as potential predictors of resistance to ipilimumab therapy (Meyer et al, 2014; Martens et al, 2016), which would suggest a similar effect in anti-PD-1-treated patients.”
BackgroundHarnessing the chemokine system to home CAR-T cells into solid tumors
Foeng, J., Comerford, I., & McColl, S. R. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100543 · Cited by 133
“An analysis of 209 advanced melanoma patients identified multiple parameters that correlate with prolonged survival following ipilimumab (a-CTLA-4) treatment, including low baseline serum lactate dehydrogenase levels and monocyte, eosinophil, and lymphocyte abundance.(75) Furthermore, CyTOF analysis of peripheral bloo…”
BackgroundThe Cancer Immunogram as a Framework for Personalized Immunotherapy in Urothelial Cancer
van Dijk, N., Funt, S. A., Blank, C. U., Powles, T. B., Rosenberg, J. E., & van der Heijden, M. S. (2018) · European Urology · doi:10.1016/j.eururo.2018.09.022 · Cited by 121
Self-citationRosner, S., Kwong, E., Shoushtari, A. N., Friedman, C. F., Warner, A. B., Brady, M. S., Coit, D. G., Callahan, M. K., Wolchok, J. D., Chapman, P. B., et al. (2018) · Cancer Medicine · doi:10.1002/cam4.1356 · Cited by 127
“Nonetheless, our finding that monocytes were negatively associated with outcomes is consistent with other studies [12, 25].”
BackgroundResultSelf-citationTengesdal, I. W., Dinarello, A., Powers, N. E., Burchill, M. A., Joosten, L. A. B., Marchetti, C., & Dinarello, C. A. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.661323 · Cited by 126
“Levels of MDSCs have been proposed as a predictive marker for response to immunotherapy (43, 44).”
BackgroundMastio, J., Condamine, T., Dominguez, G., Kossenkov, A. V., Donthireddy, L., Veglia, F., Lin, C., Wang, F., Fu, S., Zhou, J., et al. (2019) · Journal of Experimental Medicine · doi:10.1084/jem.20181952 · Cited by 115
“, 2016; Wang and Yang, 2016), including immunotherapies (Kimura et al., 2013; Martens et al., 2016; Sade-Feldman et al., 2016; Weber et al., 2016; Butterfield et al., 2017; de Coaña et al., 2017).”
Barta, S. K., Zain, J. M., Macfarlane, A. W., Smith, S. M., Ruan, J., Fung, H. C. H., Tan, C. R. C., Yang, Y., Alpaugh, R. K., Dulaimi, E., et al. (2019) · Clinical Lymphoma Myeloma & Leukemia · doi:10.1016/j.clml.2019.03.022 · Cited by 119
Alicea-Torres, K. M., Sanseviero, E., Gui, J., Chen, J., Veglia, F., Yu, Q., Donthireddy, L., Kossenkov, A. V., Lin, C., Fu, S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22033-2 · Cited by 123
The biomarkers of hyperprogressive disease in PD-1/PD-L1 blockage therapy
Wang, X., Wang, F., Zhong, M., Yarden, Y., & Fu, L. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01200-x · Cited by 124
Predictive biomarkers for response to immune checkpoint inhibition
Shum, B., Larkin, J., & Turajlic, S. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.03.036 · Cited by 118
Targeting inflammation as cancer therapy
Wang, M., Chen, S., He, X., Yuan, Y., & Wei, X. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01528-7 · Cited by 126
“For instance, patients with lower fractions of circulating MDSCs are more sensitive to ipili-mumab treatment [89], especially melanoma patients [90, 91].”
BackgroundChesney, J. A., Mitchell, R. A., & Yaddanapudi, K. (2017) · Journal of Leukocyte Biology · doi:10.1189/jlb.5vmr1116-458rrr · Cited by 120
Wistuba-Hamprecht, K., Martens, A., Heubach, F., Romano, E., Geukes Foppen, M., Yuan, J., Postow, M., Wong, P., Mallardo, D., Schilling, B., et al. (2017) · European Journal of Cancer · doi:10.1016/j.ejca.2016.12.011 · Cited by 108
“The prognostic impact of frequencies of other circulating immune cell subsets such as myeloidderived suppressor cells, Tregs and gd T-cells was reported by us before in partially overlapping cohorts [31,43,44].”
Self-citationMonitoring immune responses in the tumor microenvironment
Wargo, J. A., Reddy, S. M., Reuben, A., & Sharma, P. (2016) · Current Opinion in Immunology · doi:10.1016/j.coi.2016.05.006 · Cited by 116
“Though prognostic signatures to therapy have been described [11,26,27], phenotypic analysis of conventional markers in peripheral blood alone does not provide sufficient information about the tumor immune microenvironment and should be discouraged.”
MethodZhang, W., Yan, C., Zhang, T., Chen, X., Dong, J., Zhao, J., Han, D., Wang, J., Zhao, G., Cao, F., et al. (2021) · OncoImmunology · doi:10.1080/2162402x.2021.1971418 · Cited by 111
PD-1 and LAG-3 Dominate Checkpoint Receptor–Mediated T-cell Inhibition in Renal Cell Carcinoma
Zelba, H., Bedke, J., Hennenlotter, J., Mostböck, S., Zettl, M., Zichner, T., Chandran, A., Stenzl, A., Rammensee, H., & Gouttefangeas, C. (2019) · Cancer Immunology Research · doi:10.1158/2326-6066.cir-19-0146 · Cited by 105
“Baseline levels of LDH are associated with survival upon checkpoint blockade therapy (26).”
BackgroundKomura, N., Mabuchi, S., Shimura, K., Yokoi, E., Kozasa, K., Kuroda, H., Takahashi, R., Sasano, T., Kawano, M., Matsumoto, Y., et al. (2020) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-020-02628-2 · Cited by 110
“It was recently reported that higher MDSC numbers are associated with a poorer clinical outcome following treatment with checkpoint inhibitors [36, 37], the reason and solution for which remain unknown.”
BackgroundThe role of cancer stem cells in the modulation of anti-tumor immune responses
Maccalli, C., Rasul, K. I., Elawad, M., & Ferrone, S. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.09.006 · Cited by 105
“Of note, the presence of MDSCs in TME can be associated with patients’ survival [141], and these cells have been shown also to be a predictive marker of clinical activity of immunotherapy in melanoma patients [151,152].”
BackgroundUgurel, S., Schadendorf, D., Horny, K., Sucker, A., Schramm, S., Utikal, J. S., Pföhler, C., Herbst, R. A., Schilling, B., Blank, C. U., et al. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2019.09.005 · Cited by 110
Self-citationPeripheral Blood-Based Biomarkers for Immune Checkpoint Inhibitors
An, H. J., Chon, H. J., & Kim, C. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22179414 · Cited by 107
“However, regarding Tregs, the results are controversial; while some studies revealed a positive correlation, another study reported a negative correlation, and other studies reported no such relationship between Tregs and ICI outcomes [27,30,36,41,43,45].”
BackgroundResultNarita, Y., Arakawa, Y., Yamasaki, F., Nishikawa, R., Aoki, T., Kanamori, M., Nagane, M., Kumabe, T., Hirose, Y., Ichikawa, T., et al. (2018) · Neuro-Oncology · doi:10.1093/neuonc/noy200 · Cited by 101
Metabolic flexibility in melanoma: A potential therapeutic target
Ruocco, M. R., Avagliano, A., Granato, G., Vigliar, E., Masone, S., Montagnani, S., & Arcucci, A. (2019) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.07.016 · Cited by 106
Agrawal, L., Engel, K. B., Greytak, S. R., & Moore, H. M. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.12.008 · Cited by 104
“A higher frequency of myeloid-derived suppressor cells (MDSCs) and CD4+, CD25+, FoxP3+ regulatory T-cells (or Tregs) were associated with an improvement in overall patient survival among melanoma patients receiving Ipilimumab [147].”
Fujisawa, Y., Yoshino, K., Otsuka, A., Funakoshi, T., Fujimura, T., Yamamoto, Y., Hata, H., Gosho, M., Tanaka, R., Yamaguchi, K., et al. (2017) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2017.07.007 · Cited by 101
Liquid biomarkers in melanoma: detection and discovery
Lim, S. Y., Lee, J., Diefenbach, R. J., Kefford, R. F., & Rizos, H. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0757-5 · Cited by 99
“In a study with 209 melanoma patients treated with ipilimumab, low absolute monocyte counts, and high absolute eosinophil count, T regulatory cells and relative lymphocyte counts were associated with a favorable outcome [128].”
BackgroundDoes patient age influence anti-cancer immunity?
Pawelec, G. (2018) · Seminars in Immunopathology · doi:10.1007/s00281-018-0697-6 · Cited by 97
Self-citation
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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