Metabolic disease and adverse events from immune checkpoint inhibitors

in European Journal of Endocrinology
View More View Less
  • 1 Division of Endocrinology, Diabetes, and Bone Diseases
  • 2 Division of Rheumatology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, USA
  • 3 Division of Endocrinology, Department of Medicine, New York University Langone Medical Center, New York, USA
  • 4 Department of Rheumatology, Edith Wolfson Medical Center, Holon, Israel
  • 5 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  • 6 Division of Pulmonology, Department of Medicine
  • 7 Division of General Internal Medicine, Department of Medicine
  • 8 Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, USA

Correspondence should be addressed to A Leiter; Email: amanda.leiter@mssm.edu

Objective

Obese and overweight body mass index (BMI) categories have been associated with increased immune-related adverse events (irAEs) in patients with cancer receiving immune checkpoint inhibitors (ICIs); however, the impact of being overweight in conjunction with related metabolic syndrome-associated factors on irAEs have not been investigated. We aimed to evaluate the impact of overweight and obese BMI according to metabolic disease burden on the development of irAEs.

Design and methods

We conducted a retrospective observational study of patients receiving ICIs at a cancer center. Our main study outcome was development of ≥grade 2 (moderate) irAEs. Our main predictor was weight/metabolic disease risk category: (1) normal weight (BMI 18.5–24.9 kg/m2)/low metabolic risk (<2 metabolic diseases (diabetes, dyslipidemia, hypertension)), (2) normal weight/high metabolic risk (≥2 metabolic diseases), (3) overweight (BMI ≥ 25 kg/m2)/low metabolic risk, and (4) overweight/high metabolic risk.

Results

Of 411 patients in our cohort, 374 were eligible for analysis. Overall, 111 (30%) patients developed ≥grade 2 irAEs. In Cox analysis, overweight/low metabolic risk was significantly associated with ≥grade 2 irAEs (hazard ratio (HR): 2.0, 95% confidence interval (95% CI): 1.2–3.4) when compared to normal weight/low metabolic risk, while overweight/high metabolic risk (HR: 1.3, 95% CI: 0.7–2.2) and normal weight/high metabolic risk (HR: 1.5, 95% CI: 0.7–3.0) were not.

Conclusions

Overweight patients with fewer metabolic comorbidities were at increased risk for irAEs. This study provides an important insight that BMI should be evaluated in the context of associated metabolic comorbidities in assessing risk of irAE development and ICI immune response.

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 23 23 23
Full Text Views 1 1 1
PDF Downloads 0 0 0
  • 1

    Pardoll DM The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews: Cancer 2012 12 252264. (https://doi.org/10.1038/nrc3239)

    • Search Google Scholar
    • Export Citation
  • 2

    Khoja L, Day D, Wei-Wu Chen T, Siu LL & Hansen AR Tumour- and class-specific patterns of immune-related adverse events of immune checkpoint inhibitors: a systematic review. Annals of Oncology 2017 28 23772385. (https://doi.org/10.1093/annonc/mdx286)

    • Search Google Scholar
    • Export Citation
  • 3

    Fujii T, Colen RR, Bilen MA, Hess KR, Hajjar J, Suarez-Almazor ME, Alshawa A, Hong DS, Tsimberidou A & Janku F Incidence of immune-related adverse events and its association with treatment outcomes: the MD Anderson Cancer Center experience. Investigational New Drugs 2018 36 638646. (https://doi.org/10.1007/s10637-017-0534-0)

    • Search Google Scholar
    • Export Citation
  • 4

    Cortellini A, Bersanelli M, Buti S, Cannita K, Santini D, Perrone F, Giusti R, Tiseo M, Michiara M & Di Marino P A multicenter study of body mass index in cancer patients treated with anti-PD-1/PD-L1 immune checkpoint inhibitors: when overweight becomes favorable. Journal for ImmunoTherapy of Cancer 2019 7 57. (https://doi.org/10.1186/s40425-019-0527-y)

    • Search Google Scholar
    • Export Citation
  • 5

    Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, Shabafrouz K, Ribi C, Cairoli A & Guex-Crosier Y Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nature Reviews. Clinical Oncology 2019 16 563580. (https://doi.org/10.1038/s41571-019-0218-0)

    • Search Google Scholar
    • Export Citation
  • 6

    Das S & Johnson DB Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. Journal for ImmunoTherapy of Cancer 2019 7 306. (https://doi.org/10.1186/s40425-019-0805-8)

    • Search Google Scholar
    • Export Citation
  • 7

    McQuade JL, Daniel CR, Hess KR, Mak C, Wang DY, Rai RR, Park JJ, Haydu LE, Spencer C & Wongchenko M Association of body-mass index and outcomes in patients with metastatic melanoma treated with targeted therapy, immunotherapy, or chemotherapy: a retrospective, multicohort analysis. Lancet: Oncology 2018 19 310322. (https://doi.org/10.1016/S1470-2045(1830078-0)

    • Search Google Scholar
    • Export Citation
  • 8

    Cortellini A, Bersanelli M, Santini D, Buti S, Tiseo M, Cannita K, Perrone F, Giusti R, De Tursi M & Zoratto F Another side of the association between body mass index (BMI) and clinical outcomes of cancer patients receiving programmed cell death protein-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) checkpoint inhibitors: a multicentre analysis of immune-related adverse events. European Journal of Cancer 2020 128 1726. (https://doi.org/10.1016/j.ejca.2019.12.031)

    • Search Google Scholar
    • Export Citation
  • 9

    Heidelberger V, Goldwasser F, Kramkimel N, Jouinot A, Huillard O, Boudou-Rouquette P, Chanal J, Arrondeau J, Franck N & Alexandre J Sarcopenic overweight is associated with early acute limiting toxicity of anti-PD1 checkpoint inhibitors in melanoma patients. Investigational New Drugs 2017 35 436441. (https://doi.org/10.1007/s10637-017-0464-x)

    • Search Google Scholar
    • Export Citation
  • 10

    An Y, Wu Z, Wang N, Yang Z, Li Y, Xu B & Sun M Association between body mass index and survival outcomes for cancer patients treated with immune checkpoint inhibitors: a systematic review and meta-analysis. Journal of Translational Medicine 2020 18 235. (https://doi.org/10.1186/s12967-020-02404-x)

    • Search Google Scholar
    • Export Citation
  • 11

    Harpsoe MC, Basit S, Andersson M, Nielsen NM, Frisch M, Wohlfahrt J, Nohr EA, Linneberg A & Jess T Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort. International Journal of Epidemiology 2014 43 843855. (https://doi.org/10.1093/ije/dyu045)

    • Search Google Scholar
    • Export Citation
  • 12

    Hotamisligil GS Inflammation and metabolic disorders. Nature 2006 444 860867. (https://doi.org/10.1038/nature05485)

  • 13

    Wang Z, Aguilar EG, Luna JI, Dunai C, Khuat LT, Le CT, Mirsoian A, Minnar CM, Stoffel KM & Sturgill IR Paradoxical effects of obesity on T cell function during tumor progression and PD-1 checkpoint blockade. Nature Medicine 2019 25 141151. (https://doi.org/10.1038/s41591-018-0221-5)

    • Search Google Scholar
    • Export Citation
  • 14

    Lysaght J, van der Stok EP, Allott EH, Casey R, Donohoe CL, Howard JM, McGarrigle SA, Ravi N, Reynolds JV & Pidgeon GP Pro-inflammatory and tumour proliferative properties of excess visceral adipose tissue. Cancer Letters 2011 312 6272. (https://doi.org/10.1016/j.canlet.2011.07.034)

    • Search Google Scholar
    • Export Citation
  • 15

    Cao Z, Zheng X, Yang H, Li S, Xu F, Yang X & Wang Y Association of obesity status and metabolic syndrome with site-specific cancers: a population-based cohort study. British Journal of Cancer 2020 123 13361344. (https://doi.org/10.1038/s41416-020-1012-6)

    • Search Google Scholar
    • Export Citation
  • 16

    Richard C, Wadowski M, Goruk S, Cameron L, Sharma AM & Field CJ Individuals with obesity and type 2 diabetes have additional immune dysfunction compared with obese individuals who are metabolically healthy. BMJ Open Diabetes Research and Care 2017 5 e000379. (https://doi.org/10.1136/bmjdrc-2016-000379)

    • Search Google Scholar
    • Export Citation
  • 17

    Lynch LA, O’Connell JM, Kwasnik AK, Cawood TJ, O’Farrelly C & O’Shea DB Are natural killer cells protecting the metabolically healthy obese patient? Obesity 2009 17 601605. (https://doi.org/10.1038/oby.2008.565)

    • Search Google Scholar
    • Export Citation
  • 18

    Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C & Harrison DG Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction. Journal of Experimental Medicine 2007 204 24492460. (https://doi.org/10.1084/jem.20070657)

    • Search Google Scholar
    • Export Citation
  • 19

    Singh MV, Chapleau MW, Harwani SC & Abboud FM The immune system and hypertension. Immunologic Research 2014 59 243253. (https://doi.org/10.1007/s12026-014-8548-6)

    • Search Google Scholar
    • Export Citation
  • 20

    Samson S, Mundkur L & Kakkar VV Immune response to lipoproteins in atherosclerosis. Cholesterol 2012 2012 571846. (https://doi.org/10.1155/2012/571846)

    • Search Google Scholar
    • Export Citation
  • 21

    Zhong J, Gong Q & Mima A Inflammatory regulation in diabetes and metabolic dysfunction. Journal of Diabetes Research 2017 2017 5165268. (https://doi.org/10.1155/2017/5165268)

    • Search Google Scholar
    • Export Citation
  • 22

    Oren O, Yang EH, Molina JR, Bailey KR, Blumenthal RS & Kopecky SL Cardiovascular health and outcomes in cancer patients receiving immune checkpoint inhibitors. American Journal of Cardiology 2020 125 19201926. (https://doi.org/10.1016/j.amjcard.2020.02.016)

    • Search Google Scholar
    • Export Citation
  • 23

    BMI. Classification. World Health Organization, 2015.

  • 24

    Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM & Ginex P Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline. Journal of Clinical Oncology 2018 36 17141768. (https://doi.org/10.1200/JCO.2017.77.6385)

    • Search Google Scholar
    • Export Citation
  • 25

    Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0. United States Department of Health and Human Services, 2017.

  • 26

    Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chávez A, Keegan N, Khamashta MA, Lambotte O, Mariette X, Prat A & Suárez-Almazor ME Immune-related adverse events of checkpoint inhibitors. Nature Reviews: Disease Primers 2020 6 38. (https://doi.org/10.1038/s41572-020-0160-6)

    • Search Google Scholar
    • Export Citation
  • 27

    Hsiehchen D, Watters MK, Lu R, Xie Y & Gerber DE Variation in the assessment of immune-related adverse event occurrence, grade, and timing in patients receiving immune checkpoint inhibitors. JAMA Network Open 2019 2 e1911519. (https://doi.org/10.1001/jamanetworkopen.2019.11519)

    • Search Google Scholar
    • Export Citation
  • 28

    Smith GI, Mittendorfer B & Klein S Metabolically healthy obesity: facts and fantasies. Journal of Clinical Investigation 2019 129 39783989. (https://doi.org/10.1172/JCI129186)

    • Search Google Scholar
    • Export Citation
  • 29

    Buscemi S, Chiarello P, Buscemi C, Corleo D, Massenti MF, Barile AM, Rosafio G, Maniaci V, Settipani V & Cosentino L Characterization of metabolically healthy obese people and metabolically unhealthy normal-weight people in a general population cohort of the ABCD study. Journal of Diabetes Research 2017 2017 9294038. (https://doi.org/10.1155/2017/9294038)

    • Search Google Scholar
    • Export Citation
  • 30

    Cortellini A, Buti S, Santini D, Perrone F, Giusti R, Tiseo M, Bersanelli M, Michiara M, Grassadonia A & Brocco D Clinical outcomes of patients with advanced cancer and pre-existing autoimmune diseases treated with anti-programmed death-1 immunotherapy: a real-world transverse study. Oncologist 2019 24 e327e337. (https://doi.org/10.1634/theoncologist.2018-0618)

    • Search Google Scholar
    • Export Citation
  • 31

    Duma N, Abdel-Ghani A, Yadav S, Hoversten KP, Reed CT, Sitek AN, Enninga EAL, Paludo J, Aguilera JV & Leventakos K Sex differences in tolerability to anti-programmed cell death protein 1 therapy in patients with metastatic melanoma and non-small cell lung cancer: are we all equal? Oncologist 2019 24 e1148–e1155. (https://doi.org/10.1634/theoncologist.2019-0094)

    • Search Google Scholar
    • Export Citation
  • 32

    van Holstein Y, Kapiteijn E, Bastiaannet E, van den Bos F, Portielje J & de Glas NA Efficacy and adverse events of immunotherapy with checkpoint inhibitors in older patients with cancer. Drugs and Aging 2019 36 927938. (https://doi.org/10.1007/s40266-019-00697-2)

    • Search Google Scholar
    • Export Citation
  • 33

    Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R & Hollebecque A Immune-related adverse events with immune checkpoint blockade: a comprehensive review. European Journal of Cancer 2016 54 139148. (https://doi.org/10.1016/j.ejca.2015.11.016)

    • Search Google Scholar
    • Export Citation
  • 34

    Peravali M, Gomes-Lima C, Tefera E, Baker M, Sherchan M, Farid S, Burman KD, Constantinescu F & Veytsman I Racial disparities in immune-related adverse events (irAE) of immune checkpoint inhibitors (ICPi) and association with survival based on clinical and biochemical responses. Journal of Clinical Oncology 2020 38 70257025. (https://doi.org/10.1200/JCO.2020.38.15_suppl.7025)

    • Search Google Scholar
    • Export Citation
  • 35

    Sakata Y, Kawamura K, Ichikado K, Shingu N, Yasuda Y, Eguchi Y, Anan K, Hisanaga J, Nitawaki T & Iio M The association between tumor burden and severe immune-related adverse events in non-small cell lung cancer patients responding to immune-checkpoint inhibitor treatment. Lung Cancer 2019 130 159161. (https://doi.org/10.1016/j.lungcan.2019.02.011)

    • Search Google Scholar
    • Export Citation
  • 36

    Cameron AR, Morrison VL, Levin D, Mohan M, Forteath C, Beall C, McNeilly AD, Balfour DJ, Savinko T & Wong AK Anti-inflammatory effects of metformin irrespective of diabetes status. Circulation Research 2016 119 652665. (https://doi.org/10.1161/CIRCRESAHA.116.308445)

    • Search Google Scholar
    • Export Citation
  • 37

    Zeiser R Immune modulatory effects of statins. Immunology 2018 154 6975. (https://doi.org/10.1111/imm.12902)

  • 38

    Guzman-Prado Y, Ben Shimol J & Samson O Body mass index and immune-related adverse events in patients on immune checkpoint inhibitor therapies: a systematic review and meta-analysis. Cancer Immunology, Immunotherapy 2021 70 89100. (https://doi.org/10.1007/s00262-020-02663-z)

    • Search Google Scholar
    • Export Citation
  • 39

    Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P & Chandra AB Current diagnosis and management of immune related adverse events (irAEs) induced by immune checkpoint inhibitor therapy. Frontiers in Pharmacology 2017 8 49. (https://doi.org/10.3389/fphar.2017.00049)

    • Search Google Scholar
    • Export Citation
  • 40

    Kichenadasse G, Miners JO, Mangoni AA, Rowland A, Hopkins AM & Sorich MJ Association Between body mass index and overall survival with immune checkpoint inhibitor therapy for advanced non-small cell lung cancer. JAMA Oncology 2020 6 512518. (https://doi.org/10.1001/jamaoncol.2019.5241)

    • Search Google Scholar
    • Export Citation
  • 41

    Unkel S, Amiri M, Benda N, Beyersmann J, Knoerzer D, Kupas K, Langer F, Leverkus F, Loos A & Ose C On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies. Pharmaceutical Statistics 2019 18 166183. (https://doi.org/10.1002/pst.1915)

    • Search Google Scholar
    • Export Citation
  • 42

    Yu S, Wu X, Shi Z, Huynh M, Jena PK, Sheng L, Zhou Y, Han D, Wan YY & Hwang ST Diet-induced obesity exacerbates imiquimod-mediated psoriasiform dermatitis in anti-PD-1 antibody-treated mice: implications for patients being treated with checkpoint inhibitors for cancer. Journal of Dermatological Science 2020 97 194200. (https://doi.org/10.1016/j.jdermsci.2020.01.011)

    • Search Google Scholar
    • Export Citation
  • 43

    Versini M, Jeandel PY, Rosenthal E & Shoenfeld Y Obesity in autoimmune diseases: not a passive bystander. Autoimmunity Reviews 2014 13 9811000. (https://doi.org/10.1016/j.autrev.2014.07.001)

    • Search Google Scholar
    • Export Citation
  • 44

    Campello E, Zabeo E, Radu CM, Spiezia L, Gavasso S, Fadin M, Woodhams B, Vettor R & Simioni P Hypercoagulability in overweight and obese subjects who are asymptomatic for thrombotic events. Thrombosis and Haemostasis 2015 113 8596. (https://doi.org/10.1160/TH14-02-0156)

    • Search Google Scholar
    • Export Citation
  • 45

    Sun P, Jin Q, Nie S, Jia S, Li Y, Li X & Guo F Unlike PD-L1, PD-1 is downregulated on partial immune cells in type 2 diabetes. Journal of Diabetes Research 2019 2019 5035261. (https://doi.org/10.1155/2019/5035261)

    • Search Google Scholar
    • Export Citation