Use of broad-spectrum antibiotics impacts outcome in patients treated with immune checkpoint inhibitors

被引：136

作者：

Ahmed, Jibran ^{[1
]}

Kumar, Arun ^{[1
]}

Parikh, Kaushal ^{[1
]}

Anwar, Asad ^{[1
]}

Knoll, Bettina M. ^{[2
]}

Puccio, Carmelo ^{[1
]}

Chun, Hoo ^{[1
]}

Fanucchi, Michael ^{[1
]}

Lim, Seah H. ^{[1
]}

机构：

[1] Westchester Med Ctr, Div Hematol & Oncol, Hawthorne, NY USA

[2] Westchester Med Ctr, Div Infect Dis, Hawthorne, NY USA

来源：

ONCOIMMUNOLOGY | 2018年 / 7卷 / 11期

关键词：

Immune checkpoint inhibitors; broad-spectrum antibiotics; narrow-spectrum antibiotics; progression-free survival; response rate; HUMAN GUT MICROBIOME; MONOCYTES IN-VITRO; T-CELLS; CANCER;

D O I：

10.1080/2162402X.2018.1507670

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

We carried out a retrospective cohort study on patients with advanced cancer treated with immune checkpoint inhibitors (ICIs) to determine whether antibiotics affect treatment outcome. Sixty consecutive patients were identified, and 17 received systemic antibiotics within 2 weeks before and/or after first dose of ICI. Antibiotic-treated patients were significantly younger (p = 0.0008) and less likely to receive nivolumab (p = 0.08) or had neutrophil:lymphocyte ratio < 5 (p = 0.08). They had a lower response rate (RR) (29.4% vs 62.8%) (p = 0.024) and more inferior progression-free survival (PFS) (p = 0.048). Narrow-spectrum antibiotics did not affect the RR. However, broad-spectrum antibiotics were associated with a lower RR (25% vs 61%) (p = 0.02) and a trend towards longer time to response (median: 14 weeks vs 12 weeks) (p = 0.1). They also had shorter PFS (p = 0.012). Multivariate analysis identified antibiotics as the only factor affecting RR (p = 0.0038) and PFS (p = 0.01). We next examined the 21 patients whose PFS lasted for 12 weeks or more. Five of the 21 patients received broad-spectrum antibiotics within 10 weeks before disease progression. There was a trend towards shorter PFS in these patients (p = 0.1). Finally, antibiotic-treated patients experienced shorter overall survival (OS) (median: 24 months vs 89 months) (p = 0.003). Multivariate analysis found age (p = 0.035) and antibiotics (p = 0.038) to be the only factors affecting OS. Our results point to a detrimental effect of broad-spectrum antibiotics on treatment outcome to ICI therapy.

引用

页数：6

共 30 条

[1] Human Gut Microbiome and Risk for Colorectal Cancer [J].

Ahn, Jiyoung ;

Sinha, Rashmi ;

Pei, Zhiheng ;

Dominianni, Christine ;

Wu, Jing ;

Shi, Jianxin ;

Goedert, James J. ;

Hayes, Richard B. ;

Yang, Liying .

JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, 2013, 105 (24) :1907-1911

[2] The gut microbiota as an environmental factor that regulates fat storage [J].

Bäckhed, F ;

Ding, H ;

Wang, T ;

Hooper, LV ;

Koh, GY ;

Nagy, A ;

Semenkovich, CF ;

Gordon, JI .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (44) :15718-15723

[3] Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab [J].

Chaput, N. ;

Lepage, P. ;

Coutzac, C. ;

Soularue, E. ;

Le Roux, K. ;

Monot, C. ;

Boselli, L. ;

Routier, E. ;

Cassard, L. ;

Collins, M. ;

Vaysse, T. ;

Marthey, L. ;

Eggermont, A. ;

Asvatourian, V. ;

Lanoy, E. ;

Mateus, C. ;

Robert, C. ;

Carbonnel, F. .

ANNALS OF ONCOLOGY, 2017, 28 (06) :1368-1379

[4] Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer [J].

Derosa, L. ;

Hellmann, M. D. ;

Spaziano, M. ;

Halpenny, D. ;

Fidelle, M. ;

Rizvi, H. ;

Long, N. ;

Plodkowski, A. J. ;

Arbour, K. C. ;

Chaft, J. E. ;

Rouche, J. A. ;

Zitvogel, L. ;

Zalcman, G. ;

Albiges, L. ;

Escudier, B. ;

Routy, B. .

ANNALS OF ONCOLOGY, 2018, 29 (06) :1437-1444

[5] New response evaluation criteria in solid tumours: Revised RECIST guideline (version 1.1) [J].

Eisenhauer, E. A. ;

Therasse, P. ;

Bogaerts, J. ;

Schwartz, L. H. ;

Sargent, D. ;

Ford, R. ;

Dancey, J. ;

Arbuck, S. ;

Gwyther, S. ;

Mooney, M. ;

Rubinstein, L. ;

Shankar, L. ;

Dodd, L. ;

Kaplan, R. ;

Lacombe, D. ;

Verweij, J. .

EUROPEAN JOURNAL OF CANCER, 2009, 45 (02) :228-247

[6] IN-VIVO EFFECTS OF RUFLOXACIN AND CIPROFLOXACIN ON T-CELL SUBSETS AND TUMOR-NECROSIS-FACTOR PRODUCTION IN MICE INFECTED WITH BACTEROIDES-FRAGILIS [J].

GOLLAPUDI, SV ;

CHUAH, SK ;

HARVEY, T ;

THADEPALLI, HD ;

THADEPALLI, H .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 1993, 37 (08) :1711-1712

[7] Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients [J].

Gopalakrishnan, V. ;

Spencer, C. N. ;

Nezi, L. ;

Reuben, A. ;

Andrews, M. C. ;

Karpinets, T. V. ;

Prieto, P. A. ;

Vicente, D. ;

Hoffman, K. ;

Wei, S. C. ;

Cogdill, A. P. ;

Zhao, L. ;

Hudgens, C. W. ;

Hutchinson, D. S. ;

Manzo, T. ;

de Macedo, M. Petaccia ;

Cotechini, T. ;

Kumar, T. ;

Chen, W. S. ;

Reddy, S. M. ;

Sloane, R. Szczepaniak ;

Galloway-Pena, J. ;

Jiang, H. ;

Chen, P. L. ;

Shpall, E. J. ;

Rezvani, K. ;

Alousi, A. M. ;

Chemaly, R. F. ;

Shelburne, S. ;

Vence, L. M. ;

Okhuysen, P. C. ;

Jensen, V. B. ;

Swennes, A. G. ;

McAllister, F. ;

Sanchez, E. Marcelo Riquelme ;

Zhang, Y. ;

Le Chatelier, E. ;

Zitvogel, L. ;

Pons, N. ;

Austin-Breneman, J. L. ;

Haydu, L. E. ;

Burton, E. M. ;

Gardner, J. M. ;

Sirmans, E. ;

Hu, J. ;

Lazar, A. J. ;

Tsujikawa, T. ;

Diab, A. ;

Tawbi, H. ;

Glitza, I. C. .

SCIENCE, 2018, 359 (6371) :97-103

[8] ERYTHROMYCIN INHIBITION OF LIPOPOLYSACCHARIDE-STIMULATED TUMOR-NECROSIS-FACTOR-ALPHA PRODUCTION BY HUMAN MONOCYTES INVITRO [J].

IINO, Y ;

TORIYAMA, M ;

NATORI, Y ;

KUDO, K ;

YUO, A .

ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY, 1992, 101 (10) :16-20

[9] Alterations of the human gut microbiome in multiple sclerosis [J].

Jangi, Sushrut ;

Gandhi, Roopali ;

Cox, Laura M. ;

Li, Ning ;

von Glehn, Felipe ;

Yan, Raymond ;

Patel, Bonny ;

Mazzola, Maria Antonietta ;

Liu, Shirong ;

Glanz, Bonnie L. ;

Cook, Sandra ;

Tankou, Stephanie ;

Stuart, Fiona ;

Melo, Kirsy ;

Nejad, Parham ;

Smith, Kathleen ;

Topcuolu, Begum D. ;

Holden, James ;

Kivisakk, Pia ;

Chitnis, Tanuja ;

De Jager, Philip L. ;

Quintana, Francisco J. ;

Gerber, Georg K. ;

Bry, Lynn ;

Weiner, Howard L. .

NATURE COMMUNICATIONS, 2016, 7

[10] Direct recognition of LPS by human but not murine CD8+ T cells via TLR4 complex [J].

Komai-Koma, Mousa ;

Gilchrist, Derek S. ;

Xu, Damo .

EUROPEAN JOURNAL OF IMMUNOLOGY, 2009, 39 (06) :1564-1572

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