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The renal adverse effects of cancer immunotherapy

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Abstract

Over the past decade, the development and clinical use of immunotherapy agents has increased exponentially. As clinical experience builds with these agents so too does our understanding of the associated adverse effects. In particular, the effects of immunotherapy on the kidneys, individual nephrons, and kidney function remain less well described than the adverse effects on barrier organ systems such as the gastrointestinal tract and skin. However, phase IV post-marketing surveillance and clinical case studies together with basic research has begun to reveal mechanisms by which immunotherapy mediates renal adverse effects. This work may lead to improvements in treatment guidelines and therapy. These advances are particularly important as post-cancer survival increases leaving patients to cope with the consequences of not only the cancer, but the short- and long-term adverse effects of treatment. Here we discuss the major renal adverse effects encountered with individual immunotherapeutic agents, putative mechanisms, their current management, and how cancer survivorship programs can help patients who have been treated with immunotherapy.

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References

  1. Khan IS et al (2014) Enhancement of an anti-tumor immune response by transient blockade of central T cell tolerance. J Exp Med 211(5):761–768

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Trager U et al (2012) The immune response to melanoma is limited by thymic selection of self-antigens. PLoS ONE 7(4):e35005

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Garg AD et al (2015) Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol 6:588

    PubMed  PubMed Central  Google Scholar 

  4. Krysko DV et al (2012) Immunogenic cell death and DAMPs in cancer therapy. Nat Rev Cancer 12(12):860–875

    CAS  PubMed  Google Scholar 

  5. Takeuchi Y, Nishikawa H (2016) Roles of regulatory T cells in cancer immunity. Int Immunol 28(8):401–409

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Jiang X et al (2019) Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer 18(1):10

    PubMed  PubMed Central  Google Scholar 

  7. Marin-Acevedo JA et al (2018) Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol 11(1):8

    PubMed  PubMed Central  Google Scholar 

  8. Woo SR, Corrales L, Gajewski TF (2015) Innate immune recognition of cancer. Annu Rev Immunol 33:445–474

    CAS  PubMed  Google Scholar 

  9. Stolk D et al (2018) Positive and negative roles of innate effector cells in controlling cancer progression. Front Immunol 9:1990

    PubMed  PubMed Central  Google Scholar 

  10. Tsou P et al (2016) The emerging role of B cells in tumor immunity. Cancer Res 76(19):5597–5601

    CAS  PubMed  Google Scholar 

  11. Largeot A et al (2019) The B-side of cancer immunity: the underrated tune. Cells 8(5):449. https://doi.org/10.3390/cells8050449

    Article  CAS  PubMed Central  Google Scholar 

  12. Farhood B, Najafi M, Mortezaee K (2019) CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol 234(6):8509–8521

    CAS  PubMed  Google Scholar 

  13. Capece D et al (2012) Targeting costimulatory molecules to improve antitumor immunity. J Biomed Biotechnol 2012:926321

    PubMed  PubMed Central  Google Scholar 

  14. Martinez-Lostao L, Anel A, Pardo J (2015) How do cytotoxic lymphocytes kill cancer cells? Clin Cancer Res 21(22):5047–5056

    CAS  PubMed  Google Scholar 

  15. Topalian SL, Drake CG, Pardoll DM (2015) Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27(4):450–461

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Valk E, Rudd CE, Schneider H (2008) CTLA-4 trafficking and surface expression. Trends Immunol 29(6):272–279

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Sharma A et al (2019) Anti-CTLA-4 immunotherapy does not deplete FOXP3(+) regulatory T cells (Tregs) in human cancers-response. Clin Cancer Res 25(11):3469–3470

    PubMed  PubMed Central  Google Scholar 

  18. Honda T et al (2014) Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40(2):235–247

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Powles T et al (2014) MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 515(7528):558–562

    CAS  PubMed  Google Scholar 

  20. Postow MA, Callahan MK, Wolchok JD (2015) Immune checkpoint blockade in cancer therapy. J Clin Oncol 33(17):1974–1982

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Xu C et al (2018) Comparative safety of immune checkpoint inhibitors in cancer: systematic review and network meta-analysis. BMJ 363:k4226

    PubMed  PubMed Central  Google Scholar 

  22. Capasso A et al (2019) Summary of the international conference on onco-nephrology: an emerging field in medicine. Kidney Int 96(3):555–567

    PubMed  Google Scholar 

  23. Sury K, Perazella MA, Shirali AC (2018) Cardiorenal complications of immune checkpoint inhibitors. Nat Rev Nephrol 14(9):571–588

    CAS  PubMed  Google Scholar 

  24. Centanni M et al (2019) Clinical pharmacokinetics and pharmacodynamics of immune checkpoint inhibitors. Clin Pharmacokinet 58(7):835–857

    PubMed  PubMed Central  Google Scholar 

  25. Rofi E et al (2019) Clinical pharmacology of monoclonal antibodies targeting anti-PD-1 axis in urothelial cancers. Crit Rev Oncol Hematol 144:102812

    PubMed  Google Scholar 

  26. Perazella MA, Shirali AC (2020) Immune checkpoint inhibitor nephrotoxicity: what do we know and what should we do? Kidney Int 97:62–74. https://doi.org/10.1016/j.kint.2019.07.022

    Article  CAS  PubMed  Google Scholar 

  27. Izzedine H et al (2014) Kidney injuries related to ipilimumab. Invest New Drugs 32(4):769–773

    CAS  PubMed  Google Scholar 

  28. Lute KD et al (2005) Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood 106(9):3127–3133

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Cortazar FB et al (2016) Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int 90(3):638–647

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Marshall HT, Djamgoz MBA (2018) Immuno-oncology: emerging targets and combination therapies. Front Oncol 8:315

    PubMed  PubMed Central  Google Scholar 

  31. McDermott DF, Atkins MB (2013) PD-1 as a potential target in cancer therapy. Cancer Med 2(5):662–673

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Hamid O et al (2013) Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med 369(2):134–144

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Izzedine H et al (2019) Renal toxicities associated with pembrolizumab. Clin Kidney J 12(1):81–88

    CAS  PubMed  Google Scholar 

  34. Spanou Z et al (2006) Involvement of drug-specific T cells in acute drug-induced interstitial nephritis. J Am Soc Nephrol 17(10):2919–2927

    CAS  PubMed  Google Scholar 

  35. Yan Y et al (2018) Combining immune checkpoint inhibitors with conventional cancer therapy. Front Immunol 9:1739

    PubMed  PubMed Central  Google Scholar 

  36. Wang C et al (2014) In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human primates. Cancer Immunol Res 2(9):846–856

    CAS  PubMed  Google Scholar 

  37. Georgianos PI et al (2019) Acute interstitial nephritis in a patient with non-small cell lung cancer under immunotherapy with nivolumab. Case Rep Nephrol 2019:3614980

    PubMed  PubMed Central  Google Scholar 

  38. Rizvi NA et al (2016) Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer. J Clin Oncol 34(25):2969–2979

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Burova E et al (2017) Characterization of the Anti-PD-1 antibody REGN2810 and its antitumor activity in human PD-1 knock-in mice. Mol Cancer Ther 16(5):861–870

    CAS  PubMed  Google Scholar 

  40. Markham A, Duggan S (2018) Cemiplimab: first global approval. Drugs 78(17):1841–1846

    CAS  PubMed  Google Scholar 

  41. Papadopoulos KP et al (2019) First-in-human study of cemiplimab alone or in combination with radiotherapy and/or low dose cyclophosphamide in patients with advanced malignancies. Clin Cancer Res. https://doi.org/10.1158/1078-0432.CCR-19-2609

    Article  PubMed  Google Scholar 

  42. Herbst RS et al (2014) Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515(7528):563–567

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Mamlouk O et al (2019) Nephrotoxicity of immune checkpoint inhibitors beyond tubulointerstitial nephritis: single-center experience. J Immunother Cancer 7(1):2

    PubMed  PubMed Central  Google Scholar 

  44. Kaufman HL et al (2016) Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial. Lancet Oncol 17(10):1374–1385

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Choueiri TK et al (2018) Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. Lancet Oncol 19(4):451–460

    CAS  PubMed  Google Scholar 

  46. Antonia S et al (2016) Safety and antitumour activity of durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. Lancet Oncol 17(3):299–308

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Wang PF et al (2017) Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol 8:730

    PubMed  PubMed Central  Google Scholar 

  48. Izzedine H et al (2017) Renal effects of immune checkpoint inhibitors. Nephrol Dial Transplant 32(6):936–942

    CAS  PubMed  Google Scholar 

  49. Shirali AC, Perazella MA, Gettinger S (2016) Association of acute interstitial nephritis with programmed cell death 1 inhibitor therapy in lung cancer patients. Am J Kidney Dis 68(2):287–291

    CAS  PubMed  Google Scholar 

  50. Clarkson MR et al (2004) Acute interstitial nephritis: clinical features and response to corticosteroid therapy. Nephrol Dial Transplant 19(11):2778–2783

    CAS  PubMed  Google Scholar 

  51. Perazella MA (2016) Checkmate: kidney injury associated with targeted cancer immunotherapy. Kidney Int 90(3):474–476

    PubMed  Google Scholar 

  52. Reiser J et al (2004) Induction of B7-1 in podocytes is associated with nephrotic syndrome. J Clin Invest 113(10):1390–1397

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Khullar B et al (2018) Interaction of CD80 with Neph1: a potential mechanism of podocyte injury. Clin Exp Nephrol 22(3):508–516

    CAS  PubMed  Google Scholar 

  54. Jayne D (2010) Role of rituximab therapy in glomerulonephritis. J Am Soc Nephrol 21(1):14–17

    CAS  PubMed  Google Scholar 

  55. Chen P et al (2016) HIV infection-induced transcriptional program in renal tubular epithelial cells activates a CXCR2-driven CD4+ T cell chemotactic response. AIDS 30(12):1877–1888

    CAS  PubMed  Google Scholar 

  56. Eshhar Z et al (1993) Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T cell receptors. Proc Natl Acad Sci U S A 90(2):720–724

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kochenderfer JN et al (2010) Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116(20):4099–4102

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Fitzgerald JC et al (2017) Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med 45(2):e124–e131

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Rosenbaum L (2017) Tragedy, perseverance, and chance—the story of CAR-T therapy. N Engl J Med 377(14):1313–1315

    PubMed  Google Scholar 

  60. Neelapu SS et al (2018) Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit 'ALL'. Nat Rev Clin Oncol 15(4):218

    PubMed  PubMed Central  Google Scholar 

  61. Jhaveri KD, Rosner MH (2018) Chimeric antigen receptor T cell therapy and the kidney: what the nephrologist needs to know. Clin J Am Soc Nephrol 13(5):796–798

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Grosser R et al (2019) Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell 36(5):471–482

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Rousseau RF et al (2001) Cancer vaccines. Hematol Oncol Clin N Am 15(4):741–773

    CAS  Google Scholar 

  64. Redelman-Sidi G, Glickman MS, Bochner BH (2014) The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat Rev Urol 11(3):153–162

    CAS  PubMed  Google Scholar 

  65. Mohammed A, Arastu Z (2017) Emerging concepts and spectrum of renal injury following Intravesical BCG for non-muscle invasive bladder cancer. BMC Urol 17(1):114

    PubMed  PubMed Central  Google Scholar 

  66. Raman SS, Hecht JR, Chan E (2019) Talimogene laherparepvec: review of its mechanism of action and clinical efficacy and safety. Immunotherapy 11(8):705–723

    CAS  PubMed  Google Scholar 

  67. Dores GM, Bryant-Genevier M, Perez-Vilar S (2019) Adverse events associated with the use of sipuleucel-T reported to the US Food and Drug Administration's adverse event reporting system, 2010–2017. JAMA Netw Open 2(8):e199249

    PubMed  PubMed Central  Google Scholar 

  68. Puzanov I et al (2017) Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. J Immunother Cancer 5(1):95

    CAS  PubMed  PubMed Central  Google Scholar 

  69. O’Reilly A, Hughes P, Mann J et al (2019) An immunotherapy survivor population: health-related quality of life and toxicity in patients with metastatic melanoma treated with immune checkpoint inhibitors. Support Care Cancer. https://doi.org/10.1007/s00520-019-04818-w

    Article  PubMed  PubMed Central  Google Scholar 

  70. Rubinstein EB et al (2017) Cancer survivorship care in advanced primary care practices: a qualitative study of challenges and opportunities. JAMA Intern Med 177(12):1726–1732

    PubMed  PubMed Central  Google Scholar 

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Author notes

  1. Anna Capasso and Michael W. Lee contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA

    Natalie C. Steinel

  2. Department of Population Health, Division of Family Medicine, Dell Medical School, University of Texas At Austin, Austin, TX, USA

    Ernestine M. Lee

  3. Department of Translational Medical Sciences, University Luigi Vanvitelli, Naples, Italy

    Davide Viggiano

  4. Biogem Institute, Ariano Irpino, Italy

    Davide Viggiano

  5. Department of Oncology, Dell Medical School, The University of Texas at Austin, Health Learning Building, 1501 Red River Street, MC: Z0100, Austin, TX, 78712, USA

    Anna Capasso & Michael W. Lee

  6. Live Strong Cancer Institutes, Dell Medical School, University of Texas at Austin, Austin, TX, USA

    Anna Capasso & Michael W. Lee

  7. Department of Medical Education, Dell Medical School, University of Texas at Austin, Austin, TX, USA

    Michael W. Lee

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  1. Natalie C. Steinel
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  2. Ernestine M. Lee
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  3. Davide Viggiano
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  4. Anna Capasso
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Correspondence to Michael W. Lee.

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Steinel, N.C., Lee, E.M., Viggiano, D. et al. The renal adverse effects of cancer immunotherapy. J Nephrol 33, 467–481 (2020). https://doi.org/10.1007/s40620-019-00691-2

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  • DOI: https://doi.org/10.1007/s40620-019-00691-2

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