Skip to main content

Advertisement

SpringerLink
Log in

Recurrent grade 4 panuveitis with serous retinal detachment related to nivolumab treatment in a patient with metastatic renal cell carcinoma

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Blockade of programmed cell death-1 (PD-1) has become one of the most promising immunotherapies for many human cancers. However, immune-related adverse events can be produced by anti-PD-1 therapy. Uveitis is a rare but potentially devastating side effect of anti-PD-1 therapy. Delay in diagnosis or improper treatment may eventually lead to irreversible blindness. Therefore, it is important for the oncologist and the ophthalmologist to recognize and manage this adverse event properly in patients receiving anti-PD-1 therapy in a timely manner. Here we present a grade 4 panuveitis with bilateral serous retinal detachment following treatment with nivolumab for metastatic renal cell carcinoma. Oral prednisone, topical steroid eye drops, periorbital injection of steroid and finally intravitreal injection of steroid implant were administered in our patient. We observed that intravitreal injection of dexamethasone implant, but not the periorbital injection of steroid or the steroid eye drops, was effective to control the posterior uveitis and serous retinal detachment. Oral prednisone was also effective, but it might affect the efficacy of anti-PD-1 therapy and promote tumor growth. We also summarize 15 cases of uveitis reported to date related to nivolumab or pembrolizumab therapy in the present study. The symptoms, signs, potential underlying mechanisms and treatment options regarding this adverse event are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AC:

Anterior chamber

BCVA:

Best-corrected visual acuity

CTCAE:

Common terminology criteria for adverse events

CTLA-4:

Cytotoxic T-lymphocyte antigen-4

EAU:

Experimental autoimmune uveitis

FDA:

Food and Drug Administration

FFA:

Fluorescent fundus angiography

irAEs:

Immune-related adverse events

NSCLC:

Non-small cell lung cancer

OCT:

Optical coherence tomography

PD-1:

Programmed cell death-1

PD-L1/L2:

Programmed cell death ligand 1/ligand 2

VA:

Visual acuity

References

  1. Nishimura H, Nose M, Hiai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11(2):141–151

    Article  CAS  PubMed  Google Scholar 

  2. Okazaki T, Honjo T (2007) PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 19(7):813–824. https://doi.org/10.1093/intimm/dxm057

    Article  CAS  PubMed  Google Scholar 

  3. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800. https://doi.org/10.1038/nm730

    Article  CAS  PubMed  Google Scholar 

  4. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED (2004) Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 101(49):17174–17179. https://doi.org/10.1073/pnas.0406351101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104(9):3360–3365. https://doi.org/10.1073/pnas.0611533104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, Rietz C, Flies DB, Lau JS, Zhu G, Tamada K, Chen L (2005) Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 65(3):1089–1096

    CAS  PubMed  Google Scholar 

  7. Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA (2015) Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med 372(4):320–330. https://doi.org/10.1056/NEJMoa1412082

    Article  CAS  PubMed  Google Scholar 

  8. Garon EB, Rizvi NA, Hui R, Leighl N, Balmanoukian AS, Eder JP, Patnaik A, Aggarwal C, Gubens M, Horn L, Carcereny E, Ahn MJ, Felip E, Lee JS, Hellmann MD, Hamid O, Goldman JW, Soria JC, Dolled-Filhart M, Rutledge RZ, Zhang J, Lunceford JK, Rangwala R, Lubiniecki GM, Roach C, Emancipator K, Gandhi L, KEYNOTE-001 Investigators (2015) Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 372(21):2018–2028. https://doi.org/10.1056/NEJMoa1501824

    Article  PubMed  Google Scholar 

  9. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, Rodriguez-Abreu D, Moro-Sibilot D, Thomas CA, Barlesi F, Finley G, Kelsch C, Lee A, Coleman S, Deng Y, Shen Y, Kowanetz M, Lopez-Chavez A, Sandler A, Reck M, IMpower150 Study Group (2018) Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 378(24):2288–2301. https://doi.org/10.1056/NEJMoa1716948

    Article  CAS  PubMed  Google Scholar 

  10. Michot JM, Bigenwald C, Champiat S, Collins M, Carbonnel F, Postel-Vinay S, Berdelou A, Varga A, Bahleda R, Hollebecque A, Massard C, Fuerea A, Ribrag V, Gazzah A, Armand JP, Amellal N, Angevin E, Noel N, Boutros C, Mateus C, Robert C, Soria JC, Marabelle A, Lambotte O (2016) Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 54:139–148. https://doi.org/10.1016/j.ejca.2015.11.016

    Article  CAS  PubMed  Google Scholar 

  11. Abdel-Rahman O, Oweira H, Petrausch U, Helbling D, Schmidt J, Mannhart M, Mehrabi A, Schob O, Giryes A (2017) Immune-related ocular toxicities in solid tumor patients treated with immune checkpoint inhibitors: a systematic review. Expert Rev Anticancer Ther 17(4):387–394. https://doi.org/10.1080/14737140.2017.1296765

    Article  CAS  PubMed  Google Scholar 

  12. U.S. Department of Health and Human Services (2010) Common terminology criteria for adverse events (CTCAE) version 4.03. https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf#search=%2711.+U.S.DEPARTMENT+OF+HEALTH+AND+HUMAN+SERVICES.+Common+Terminology+Criteria+for+Adverse+Events+%28CTCAE%29+Version+4.03%3A+June+14%2C+2010%27. Accessed 15 July 2018

  13. Taylor AW (2009) Ocular immune privilege. Eye 23(10):1885–1889. https://doi.org/10.1038/eye.2008.382

    Article  CAS  PubMed  Google Scholar 

  14. Zhou R, Caspi RR (2010) Ocular immune privilege. F1000 Biol Rep 2. https://doi.org/10.3410/B2-3

  15. Chen L, Pai V, Levinson R, Sharpe AH, Freeman GJ, Braun J, Gordon LK (2009) Constitutive neuronal expression of the immune regulator, programmed death 1 (PD-1), identified during experimental autoimmune uveitis. Ocul Immunol Inflamm 17(1):47–55. https://doi.org/10.1080/09273940802491884

    Article  CAS  PubMed  Google Scholar 

  16. Hori J, Wang M, Miyashita M, Tanemoto K, Takahashi H, Takemori T, Okumura K, Yagita H, Azuma M (2006) B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. J Immunol 177(9):5928–5935

    Article  CAS  PubMed  Google Scholar 

  17. Zamani MR, Aslani S, Salmaninejad A, Javan MR, Rezaei N (2016) PD-1/PD-L and autoimmunity: a growing relationship. Cell Immunol 310:27–41. https://doi.org/10.1016/j.cellimm.2016.09.009

    Article  CAS  PubMed  Google Scholar 

  18. Lee DJ, Taylor AW (2015) Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs. J Leukoc Biol 97(6):1101–1109. https://doi.org/10.1189/jlb.3A1014-466RR

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Theillac C, Straub M, Breton AL, Thomas L, Dalle S (2017) Bilateral uveitis and macular edema induced by Nivolumab: a case report. BMC Ophthalmol 17(1):227. https://doi.org/10.1186/s12886-017-0611-3

    Article  PubMed  PubMed Central  Google Scholar 

  20. Baughman DM, Lee CS, Snydsman BE, Jung HC (2017) Bilateral uveitis and keratitis following nivolumab treatment for metastatic melanoma. Med Case Rep (Wilmington). https://doi.org/10.21767/2471-8041.100044

    Article  Google Scholar 

  21. Matsuo T, Yamasaki O (2017) Vogt–Koyanagi–Harada disease-like posterior uveitis in the course of nivolumab (anti-PD-1 antibody), interposed by vemurafenib (BRAF inhibitor), for metastatic cutaneous malignant melanoma. Clin Case Rep 5(5):694–700. https://doi.org/10.1002/ccr3.911

    Article  PubMed  PubMed Central  Google Scholar 

  22. Richardson DR, Ellis B, Mehmi I, Leys M (2017) Bilateral uveitis associated with nivolumab therapy for metastatic melanoma: a case report. Int J Ophthalmol 10(7):1183–1186. https://doi.org/10.18240/ijo.2017.07.28

    Article  PubMed  PubMed Central  Google Scholar 

  23. Kanno H, Ishida K, Yamada W, Nishida T, Takahashi N, Mochizuki K, Mizuno Y, Matsuyama K, Takahashi T, Seishima M (2017) Uveitis induced by programmed cell death protein 1 inhibitor therapy with nivolumab in metastatic melanoma patient. J Infect Chemother 23(11):774–777. https://doi.org/10.1016/j.jiac.2017.04.007

    Article  PubMed  Google Scholar 

  24. Arai T, Harada K, Usui Y, Irisawa R, Tsuboi R (2017) Case of acute anterior uveitis and Vogt–Koyanagi–Harada syndrome-like eruptions induced by nivolumab in a melanoma patient. J Dermatol 44(8):975–976. https://doi.org/10.1111/1346-8138.13612

    Article  PubMed  Google Scholar 

  25. Karlin J, Gentzler R, Golen J (2018) Bilateral anterior uveitis associated with nivolumab therapy. Ocul Immunol Inflamm 26(2):283–285. https://doi.org/10.1080/09273948.2016.1215473

    Article  PubMed  Google Scholar 

  26. de Velasco G, Bermas B, Choueiri TK (2016) Autoimmune arthropathy and uveitis as complications of programmed death 1 inhibitor treatment. Arthritis Rheumatol 68(2):556–557. https://doi.org/10.1002/art.39406

    Article  PubMed  Google Scholar 

  27. Aaberg MT, Aaberg TM Jr (2017) Pembrolizumab administration associated with posterior uveitis. Retin Cases Brief Rep 11(4):348–351. https://doi.org/10.1097/ICB.0000000000000368

    Article  PubMed  Google Scholar 

  28. Basilious A, Lloyd JC (2016) Posterior subcapsular cataracts and hypotony secondary to severe pembrolizumab induced uveitis: case report. Can J Ophthalmol 51(1):e4–e6. https://doi.org/10.1016/j.jcjo.2015.09.008

    Article  PubMed  Google Scholar 

  29. Hanna KS (2016) A rare case of pembrolizumab-induced uveitis in a patient with metastatic melanoma. Pharmacotherapy 36(11):e183–e188. https://doi.org/10.1002/phar.1839

    Article  PubMed  Google Scholar 

  30. Diem S, Keller F, Ruesch R, Maillard SA, Speiser DE, Dummer R, Siano M, Urner-Bloch U, Goldinger SM, Flatz L (2016) Pembrolizumab-triggered uveitis: an additional surrogate marker for responders in melanoma immunotherapy? J Immunother 39(9):379–382. https://doi.org/10.1097/CJI.0000000000000143

    Article  CAS  PubMed  Google Scholar 

  31. Abu Samra K, Valdes-Navarro M, Lee S, Swan R, Foster CS, Anesi SD (2016) A case of bilateral uveitis and papillitis in a patient treated with pembrolizumab. Eur J Ophthalmol 26(3):e46–e48. https://doi.org/10.5301/ejo.5000724

    Article  PubMed  Google Scholar 

  32. Fife BT, Bluestone JA (2008) Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 and PD-1 pathways. Immunol Rev 224:166–182. https://doi.org/10.1111/j.1600-065X.2008.00662.x

    Article  CAS  PubMed  Google Scholar 

  33. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723. https://doi.org/10.1056/NEJMoa1003466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454. https://doi.org/10.1056/NEJMoa1200690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, Drake CG, Camacho LH, Kauh J, Odunsi K, Pitot HC, Hamid O, Bhatia S, Martins R, Eaton K, Chen S, Salay TM, Alaparthy S, Grosso JF, Korman AJ, Parker SM, Agrawal S, Goldberg SM, Pardoll DM, Gupta A, Wigginton JM (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465. https://doi.org/10.1056/NEJMoa1200694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M (2013) Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 369(2):122–133. https://doi.org/10.1056/NEJMoa1302369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kwon ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, Krainer M, Houede N, Santos R, Mahammedi H, Ng S, Maio M, Franke FA, Sundar S, Agarwal N, Bergman AM, Ciuleanu TE, Korbenfeld E, Sengelov L, Hansen S, Logothetis C, Beer TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators (2014) Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol 15(7):700–712. https://doi.org/10.1016/S1470-2045(14)70189-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, Linette GP, Meyer N, Giguere JK, Agarwala SS, Shaheen M, Ernstoff MS, Minor D, Salama AK, Taylor M, Ott PA, Rollin LM, Horak C, Gagnier P, Wolchok JD, Hodi FS (2015) Nivolumab and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 372(21):2006–2017. https://doi.org/10.1056/NEJMoa1414428

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This study was funded by grants from the National Natural Science Foundation of China (No. 81870660), the Shanghai Science and Technology Foundation (18ZR1405900) and the Shanghai Hospital Development Center (SHDC12016116).

Author information

Authors and Affiliations

  1. Department of Ophthalmology and Vision Science, Eye and ENT Hospital, Shanghai Medical College, Fudan University, 83 Fenyang Road, Shanghai, 200031, China

    Wei Wang & Ling Chen

  2. Key Laboratory of Myopia of State Health Ministry (Fudan University) and Laboratory of Myopia, Chinese Academy of Medical Sciences, Shanghai, 200031, China

    Wei Wang & Ling Chen

  3. Department of Ophthalmology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China

    Wei Wang & Wai-Ching Lam

Authors
  1. Wei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Wai-Ching Lam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors, WW, W-CL and LC, take responsibility for the integrity of the data. All authors made substantial contributions to data interpretation, discussion, manuscript preparation, review, revision and final approval.

Corresponding author

Correspondence to Ling Chen.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Informed consent

Written informed consent was obtained from the patient for publication of this case report.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, W., Lam, WC. & Chen, L. Recurrent grade 4 panuveitis with serous retinal detachment related to nivolumab treatment in a patient with metastatic renal cell carcinoma. Cancer Immunol Immunother 68, 85–95 (2019). https://doi.org/10.1007/s00262-018-2260-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-018-2260-7

Keywords

Search

Navigation