Skip to main content
SpringerLink
Log in

The Immunotherapy Landscape in Renal Cell Carcinoma

  • Review Article
  • Published:
BioDrugs Aims and scope Submit manuscript

Abstract

The past 30 years have borne witness to a gradual evolution in the treatment landscape of advanced renal cell carcinoma (aRCC). Early immunotherapy approaches such as interferon-α and high-dose interleukin-2 (IL-2) therapy in this immunogenic tumor provided durable responses in only a minority of patients and came with toxic side effects. A growing understanding of the tumor biology elucidated pathways of tumorigenesis, which in turn revealed novel targets amenable to targeted therapies. Inhibition of angiogenesis and cell signaling emerged as cornerstones of treatment with the approval of bevacizumab and several pan-kinase and tyrosine kinase inhibitors. Though effective, their use has been limited by low rates of durable response, resistance, and side effects. The immunotherapy revolution of the past decade has led to immunotherapy-based combination regimens such as ipilimumab plus nivolumab, pembrolizumab plus axitinib, and avelumab plus axitinib, displacing single agent anti-angiogenic therapy in the first-line setting by demonstrating durable responses and improved survival over sunitinib. These immunotherapy-based combinations define first-line standard of care for aRCC today. The pipeline of second-line agents for consideration in patients who have disease progression despite immunotherapy regimens is robust but still in early stages of development.

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

Similar content being viewed by others

References

  1. Saad AM, Gad MM, Al-Husseini MJ, Ruhban IA, Sonbol MB, Ho TH. Trends in renal-cell carcinoma incidence and mortality in the United States in the last 2 decades: A SEER-based study. Clin Genitourin Cancer. 2019;17(1):46–57 (e45).

    Article  PubMed  Google Scholar 

  2. Hakimi AA, Pham CG, Hsieh JJ. A clear picture of renal cell carcinoma. Nat Genet. 2013;45(8):849–50.

    Article  CAS  PubMed  Google Scholar 

  3. Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;7(5):277–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356(2):115–24.

    Article  CAS  PubMed  Google Scholar 

  5. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(22):3584–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang JC, Haworth L, Sherry RM, Hwu P, Schwartzentruber DJ, Topalian SL, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med. 2003;349(5):427–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol. 2008;26(33):5422–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370(9605):2103–11.

    Article  PubMed  Google Scholar 

  9. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28(6):1061–8.

    Article  CAS  PubMed  Google Scholar 

  10. Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369(8):722–31.

    Article  CAS  PubMed  Google Scholar 

  11. Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356(22):2271–81.

    Article  CAS  PubMed  Google Scholar 

  12. Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372(9637):449–56.

    Article  CAS  PubMed  Google Scholar 

  13. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1814–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Choueiri TK, Escudier B, Powles T, Tannir NM, Mainwaring PN, Rini BI, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2016;17(7):917–27.

    Article  CAS  PubMed  Google Scholar 

  15. Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16(15):1473–82.

    Article  CAS  PubMed  Google Scholar 

  16. Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol. 2016;17(1):e4–5.

    Article  PubMed  Google Scholar 

  17. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol. 2009;10(10):992–1000.

    Article  CAS  PubMed  Google Scholar 

  18. Gotink KJ, Broxterman HJ, Labots M, de Haas RR, Dekker H, Honeywell RJ, et al. Lysosomal sequestration of sunitinib: a novel mechanism of drug resistance. Clin Cancer Res. 2011;17(23):7337–466.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gotink KJ, Rovithi M, de Haas RR, Honeywell RJ, Dekker H, Poel D, et al. Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib. Cell Oncol (Dordr). 2015;38(2):119–29.

    Article  CAS  Google Scholar 

  20. Carew JS, Kelly KR, Nawrocki ST. Mechanisms of mTOR inhibitor resistance in cancer therapy. Target Oncol. 2011;6(1):17–27.

    Article  PubMed  Google Scholar 

  21. Buczek M, Escudier B, Bartnik E, Szczylik C, Czarnecka A. Resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma: from the patient's bed to molecular mechanisms. Biochim Biophys Acta. 2014;1845(1):31–41.

    CAS  PubMed  Google Scholar 

  22. Huang D, Ding Y, Zhou M, Rini BI, Petillo D, Qian CN, et al. Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma. Cancer Res. 2010;70(3):1063–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Harmon CS, DePrimo SE, Figlin RA, Hudes GR, Hutson TE, Michaelson MD, et al. Circulating proteins as potential biomarkers of sunitinib and interferon-alpha efficacy in treatment-naive patients with metastatic renal cell carcinoma. Cancer Chemother Pharmacol. 2014;73(1):151–61.

    Article  CAS  PubMed  Google Scholar 

  24. Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, et al. Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol. 2012;13(8):827–37.

    Article  CAS  PubMed  Google Scholar 

  25. Welti JC, Gourlaouen M, Powles T, Kudahetti SC, Wilson P, Berney DM, et al. Fibroblast growth factor 2 regulates endothelial cell sensitivity to sunitinib. Oncogene. 2011;30(10):1183–93.

    Article  CAS  PubMed  Google Scholar 

  26. Rankin EB, Fuh KC, Castellini L, Viswanathan K, Finger EC, Diep AN, et al. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET. Proc Natl Acad Sci USA. 2014;111(37):13373–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ko JS, Rayman P, Ireland J, Swaidani S, Li G, Bunting KD, et al. Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained. Cancer Res. 2010;70(9):3526–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Crawford Y, Kasman I, Yu L, Zhong C, Wu X, Modrusan Z, et al. PDGF-C mediates the angiogenic and tumorigenic properties of fibroblasts associated with tumors refractory to anti-VEGF treatment. Cancer Cell. 2009;15(1):21–34.

    Article  CAS  PubMed  Google Scholar 

  29. Shojaei F, Wu X, Qu X, Kowanetz M, Yu L, Tan M, et al. G-CSF-initiated myeloid cell mobilization and angiogenesis mediate tumor refractoriness to anti-VEGF therapy in mouse models. Proc Natl Acad Sci USA. 2009;106(16):6742–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pal S, Gong J, Mhatre SK, Lin SW, Surinach A, Ogale S, et al. Real-world treatment patterns and adverse events in metastatic renal cell carcinoma from a large US claims database. BMC Cancer. 2019;19(1):548.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. J Clin Oncol. 2010;28(13):2137–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005;1:CD001425.

    Google Scholar 

  33. Wirth MP. Immunotherapy for metastatic renal cell carcinoma. Urol Clin N Am. 1993;20(2):283–95.

    Article  CAS  Google Scholar 

  34. Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma : a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113(2):293–301.

    Article  CAS  PubMed  Google Scholar 

  35. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA. 1994;271(12):907–13.

    Article  CAS  PubMed  Google Scholar 

  36. Fisher RI, Coltman CA Jr, Doroshow JH, Rayner AA, Hawkins MJ, Mier JW, et al. Metastatic renal cancer treated with interleukin-2 and lymphokine-activated killer cells. A phase II clinical trial. Ann Intern Med. 1988;108(4):518–23.

    Article  CAS  PubMed  Google Scholar 

  37. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6(Suppl 1):S55–57.

    PubMed  Google Scholar 

  38. Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13(3):688–96.

    Article  CAS  PubMed  Google Scholar 

  39. McDermott DF, Cheng SC, Signoretti S, Margolin KA, Clark JI, Sosman JA, et al. The high-dose aldesleukin "select" trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res. 2015;21(3):561–8.

    Article  CAS  PubMed  Google Scholar 

  40. Schwartz RN, Stover L, Dutcher JP. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park). 2002;16(11 Suppl 13):11–20.

    Google Scholar 

  41. Oliver RT, Nethersell AB, Bottomley JM. Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma. Br J Urol. 1989;63(2):128–31.

    Article  CAS  PubMed  Google Scholar 

  42. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23(6):703–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 2017;18(8):1009–211.

    Article  CAS  PubMed  Google Scholar 

  44. Senbabaoglu Y, Gejman RS, Winer AG, Liu M, Van Allen EM, de Velasco G, et al. Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures. Genome Biol. 2016;17(1):231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58–67.

    Article  CAS  PubMed  Google Scholar 

  47. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Front Oncol. 2018;8:86.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Lewis LD, et al. Safety and efficacy of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma: the CheckMate 016 study. J Clin Oncol. 2017;35(34):3851–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Motzer RJ, Rini BI, McDermott DF, Aren Frontera O, Hammers HJ, Carducci MA, et al. Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial. Lancet Oncol. 2019;20(10):1370–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tannir NM, McDermott DF, Escudier B, Hammers HJ, Aren OR, Plimack ER, et al. Overall survival and independent review of response in CheckMate 214 with 42-month follow-up: first-line nivolumab + ipilimumab (N+I) versus sunitinib (S) in patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2020;38(6_suppl):609–609.

    Article  Google Scholar 

  52. George DJ, Kaelin WG Jr. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med. 2003;349(5):419–21.

    Article  PubMed  Google Scholar 

  53. Hegde PS, Wallin JJ, Mancao C. Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics. Semin Cancer Biol. 2018;52(Pt 2):117–24.

    Article  CAS  PubMed  Google Scholar 

  54. Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019;176(6):1248–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, et al. Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res. 2009;15(6):2148–57.

    Article  CAS  PubMed  Google Scholar 

  56. Kusmartsev S, Eruslanov E, Kubler H, Tseng T, Sakai Y, Su Z, et al. Oxidative stress regulates expression of VEGFR1 in myeloid cells: link to tumor-induced immune suppression in renal cell carcinoma. J Immunol. 2008;181(1):346–53.

    Article  CAS  PubMed  Google Scholar 

  57. Khan KA, Kerbel RS. Improving immunotherapy outcomes with anti-angiogenic treatments and vice versa. Nat Rev Clin Oncol. 2018;15(5):310–24.

    Article  CAS  PubMed  Google Scholar 

  58. Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Schmittnaegel M, Rigamonti N, Kadioglu E, Cassara A, Wyser Rmili C, Kiialainen A, et al. Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade. Sci Transl Med. 2017;9:385.

    Article  CAS  Google Scholar 

  60. Ghosh S, Paul A, Sen E. Tumor necrosis factor alpha-induced hypoxia-inducible factor 1alpha-beta-catenin axis regulates major histocompatibility complex class I gene activation through chromatin remodeling. Mol Cell Biol. 2013;33(14):2718–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307(5706):58–62.

    Article  CAS  PubMed  Google Scholar 

  62. Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017;9:385.

    Article  CAS  Google Scholar 

  63. Atkins MB, Plimack ER, Puzanov I, Fishman MN, McDermott DF, Cho DC, et al. Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial. Lancet Oncol. 2018;19(3):405–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116–27.

    Article  CAS  PubMed  Google Scholar 

  65. Plimack ER, Rini BI, Stus V, Gafanov R, Waddell T, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC): updated analysis of KEYNOTE-426. J Clin Oncol. 2020;38(15_suppl):5001–5001.

    Article  Google Scholar 

  66. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393(10189):2404–15.

    Article  PubMed  Google Scholar 

  68. Buonerba C, Dolce P, Iaccarino S, Scafuri L, Verde A, Costabile F, et al. Outcomes associated with first-line anti-PD-1/PD-L1 agents vs. sunitinib in patients with sarcomatoid renal cell carcinoma: a systematic review and meta-analysis. Cancers (Basel). 2020;12(2):408.

    Article  CAS  Google Scholar 

  69. McKay RR, Bossé D, Xie W, Wankowicz SAM, Flaifel A, Brandao R, et al. The clinical activity of PD-1/PD-L1 inhibitors in metastatic non-clear cell renal cell carcinoma. Cancer Immunol Res. 2018;6(7):758–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab (pembro) plus axitinib (axi) versus sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC): outcomes in the combined IMDC intermediate/poor risk and sarcomatoid subgroups of the phase 3 KEYNOTE-426 study. J Clin Oncol. 2019;37(15_suppl):4500–4500.

    Article  Google Scholar 

  71. Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348(6230):124–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Luksza M, Riaz N, Makarov V, Balachandran VP, Hellmann MD, Solovyov A, et al. A neoantigen fitness model predicts tumour response to checkpoint blockade immunotherapy. Nature. 2017;551(7681):517–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Conroy JM, Pabla S, Glenn ST, Burgher B, Nesline M, Papanicolau-Sengos A, et al. Analytical validation of a next-generation sequencing assay to monitor immune responses in solid tumors. J Mol Diagn. 2018;20(1):95–109.

    Article  CAS  PubMed  Google Scholar 

  74. Morrison C, Pabla S, Conroy JM, Nesline MK, Glenn ST, Dressman D, et al. Predicting response to checkpoint inhibitors in melanoma beyond PD-L1 and mutational burden. J Immunother Cancer. 2018;6(1):32.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Kotecha RR, Motzer RJ, Voss MH. Towards individualized therapy for metastatic renal cell carcinoma. Nat Rev Clin Oncol. 2019;16(10):621–33.

    Article  CAS  PubMed  Google Scholar 

  76. Badalamenti G, Fanale D, Incorvaia L, Barraco N, Listi A, Maragliano R, et al. Role of tumor-infiltrating lymphocytes in patients with solid tumors: can a drop dig a stone? Cell Immunol. 2019;343:103753.

    Article  CAS  PubMed  Google Scholar 

  77. Shang B, Liu Y, Jiang SJ, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Sci Rep. 2015;5:15179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Berntsson J, Nodin B, Eberhard J, Micke P, Jirstrom K. Prognostic impact of tumour-infiltrating B cells and plasma cells in colorectal cancer. Int J Cancer. 2016;139(5):1129–39.

    Article  CAS  PubMed  Google Scholar 

  79. Jackute J, Zemaitis M, Pranys D, Sitkauskiene B, Miliauskas S, Vaitkiene S, et al. Distribution of M1 and M2 macrophages in tumor islets and stroma in relation to prognosis of non-small cell lung cancer. BMC Immunol. 2018;19(1):3.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Levi I, Amsalem H, Nissan A, Darash-Yahana M, Peretz T, Mandelboim O, et al. Characterization of tumor infiltrating natural killer cell subset. Oncotarget. 2015;6(15):13835–433.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.

    Article  CAS  PubMed  Google Scholar 

  82. Tykodi SS, Donskov F, Lee J-L, Szczylik C, Malik J, Alekseev BY, et al. First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): updated results for KEYNOTE-427 cohort A. J Clin Oncol. 2019;37(15_suppl):4570–4570.

    Article  Google Scholar 

  83. Payne R, Glenn L, Hoen H, Richards B, Smith JW 2nd, Lufkin R, et al. Durable responses and reversible toxicity of high-dose interleukin-2 treatment of melanoma and renal cancer in a Community Hospital Biotherapy Program. J Immunother Cancer. 2014;2(13):1426–2051.

    Google Scholar 

  84. Chow S, Galvis V, Pillai M, Leach R, Keene E, Spencer-Shaw A, et al. High-dose interleukin2 - a 10-year single-site experience in the treatment of metastatic renal cell carcinoma: careful selection of patients gives an excellent outcome. J Immunother Cancer. 2016;4:67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Curti B, Daniels GA, McDermott DF, Clark JI, Kaufman HL, Logan TF, et al. Improved survival and tumor control with Interleukin-2 is associated with the development of immune-related adverse events: data from the PROCLAIMSM registry. J Immunother Cancer. 2017;5(1):102.

    Article  PubMed  PubMed Central  Google Scholar 

  86. Chatzkel JA, Swank J, Ludlow S, Lombardi K, Croft C, Artigas Y, et al. Overall responses with coordinated pembrolizumab and high dose IL-2 (5-in-a-row schedule) for therapy of metastatic clear cell renal cancer: a single center, single arm trial. J Clin Oncol. 2019;37(7_suppl):657–657.

    Article  Google Scholar 

  87. McDermott DF, Lee J-L, Szczylik C, Donskov F, Malik J, Alekseev BY, et al. Pembrolizumab monotherapy as first-line therapy in advanced clear cell renal cell carcinoma (accRCC): results from cohort A of KEYNOTE-427. J Clin Oncol. 2018;36(15_suppl):4500–4500.

    Article  Google Scholar 

  88. Lee J-L, Ziobro M, Gafanov R, Matveev VB, Suarez C, Donskov F, et al. KEYNOTE-427 cohort B: First-line pembrolizumab (pembro) monotherapy for advanced non-clear cell renal cell carcinoma (NCC-RCC). J Clin Oncol. 2019;37(15_suppl):4569–4569.

    Article  Google Scholar 

  89. Diab A, Hurwitz ME, Cho DC, Papadimitrakopoulou V, Curti BD, Tykodi SS, et al. NKTR-214 (CD122-biased agonist) plus nivolumab in patients with advanced solid tumors: preliminary phase 1/2 results of PIVOT. J Clin Oncol. 2018;36(15_suppl):3006–3006.

    Article  Google Scholar 

  90. Tomita Y, Fukasawa S, Shinohara N, Kitamura H, Oya M, Eto M, et al. Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the Phase III CheckMate 025 study. Jpn J Clin Oncol. 2019;49(6):506–14.

    Article  PubMed  Google Scholar 

  91. Tannir NM, Agarwal N, Pal SK, Formiga MN, Guo J, George DJ, et al. A phase III randomized open label study comparing bempegaldesleukin (NKTR-214) plus nivolumab to sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma. J Clin Oncol. 2019;37(15_suppl):TPS4595.

    Article  Google Scholar 

  92. Nadal RM, Mortazavi A, Stein M, Pal SK, Davarpanah NN, Parnes HL, et al. Results of phase I plus expansion cohorts of cabozantinib (Cabo) plus nivolumab (Nivo) and CaboNivo plus ipilimumab (Ipi) in patients (pts) with with metastatic urothelial carcinoma (mUC) and other genitourinary (GU) malignancies. J Clin Oncol. 2018;36(6_suppl):515–515.

    Article  Google Scholar 

  93. Choueiri TK, Apolo AB, Powles T, Escudier B, Aren OR, Shah A, et al. A phase 3, randomized, open-label study of nivolumab combined with cabozantinib vs sunitinib in patients with previously untreated advanced or metastatic renal cell carcinoma (RCC; CheckMate 9ER). J Clin Oncol. 2018;36(15_suppl):TPS4598.

    Article  Google Scholar 

  94. Choueiri TK, Albiges L, Powles T, Scheffold C, Wang F, Motzer RJ. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carcinoma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020;38(6 suppl):TPS767.

    Article  Google Scholar 

  95. Bergerot P, Lamb P, Wang E, Pal SK. Cabozantinib in combination with immunotherapy for advanced renal cell carcinoma and urothelial carcinoma: rationale and clinical evidence. Mol Cancer Ther. 2019;18(12):2185–93.

    Article  CAS  PubMed  Google Scholar 

  96. Agarwal N, Vaishampayan U, Green M, di Nucci F, Chang PY, Scheffold C, et al. Phase Ib study (COSMIC-021) of cabozantinib in combination with atezolizumab: results of the dose escalation stage in patients (pts) with treatment-naïve advanced renal cell carcinoma (RCC). Ann Oncol. 2018;29:viii308.

    Article  Google Scholar 

  97. Zhang T, Ballman KV, Choudhury AD, Chen RC, Watt C, Wen Y, et al. PDIGREE: An adaptive phase 3 trial of PD-inhibitor nivolumab and ipilimumab (IPI-NIVO) with VEGF TKI cabozantinib (CABO) in metastatic untreated renal cell cancer (Alliance A031704). J Clin Oncol. 2019;37(15_suppl):TPS4596.

    Article  Google Scholar 

  98. Yoo YG, Christensen J, Huang LE. HIF-1alpha confers aggressive malignant traits on human tumor cells independent of its canonical transcriptional function. Cancer Res. 2011;71(4):1244–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang J, Zhang X, Zhang Y, Zhu D, Zhang L, Li Y, et al. HIF-2alpha promotes epithelial-mesenchymal transition through regulating Twist2 binding to the promoter of E-cadherin in pancreatic cancer. J Exp Clin Cancer Res. 2016;35:26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Lim E, Kuo CC, Tu HF, Yang CC. The prognosis outcome of oral squamous cell carcinoma using HIF-2alpha. J Chin Med Assoc. 2017;80(10):651–6.

    Article  PubMed  Google Scholar 

  101. Gao ZJ, Wang Y, Yuan WD, Yuan JQ, Yuan K. HIF-2alpha not HIF-1alpha overexpression confers poor prognosis in non-small cell lung cancer. Tumour Biol. 2017;39(6):1010428317709637.

    PubMed  Google Scholar 

  102. Fan Y, Li H, Ma X, Gao Y, Chen L, Li X, et al. Prognostic significance of hypoxia-inducible factor expression in renal cell carcinoma: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2015;94(38):e1646.

    Article  CAS  Google Scholar 

  103. Fallah J, Rini BI. HIF inhibitors: status of current clinical development. Curr Oncol Rep. 2019;21(1):6.

    Article  PubMed  Google Scholar 

  104. Wallace EM, Rizzi JP, Han G, Wehn PM, Cao Z, Du X, et al. A small-molecule antagonist of HIF2alpha is efficacious in preclinical models of renal cell carcinoma. Cancer Res. 2016;76(18):5491–500.

    Article  CAS  PubMed  Google Scholar 

  105. Courtney KD, Infante JR, Lam ET, Figlin RA, Rini BI, Brugarolas J, et al. Phase I dose-escalation trial of PT2385, a first-in-class hypoxia-inducible factor-2alpha antagonist in patients with previously treated advanced clear cell renal cell carcinoma. J Clin Oncol. 2018;36(9):867–74.

    Article  CAS  PubMed  Google Scholar 

  106. Rini BI, Appleman LJ, Figlin RA, Plimack ER, Merchan JR, Wang K, et al. Results from a phase I expansion cohort of the first-in-class oral HIF-2α inhibitor PT2385 in combination with nivolumab in patients with previously treated advanced RCC. J Clin Oncol. 2019;37(7_suppl):558–558.

    Article  Google Scholar 

  107. Wong TW, Shrimali R, Contreras C, Cheng T, Czerwinski RM, Dixon DD, et al. Abstract B140: PT2977, a novel HIF-2a antagonist, has potent antitumor activity and remodels the immunosuppressive tumor microenvironment in clear cell renal cell cancer. Mol Cancer Ther. 2018;17(1 Supplement):B140–B140140.

    Article  CAS  Google Scholar 

  108. Abstracts from the Sixteenth International Kidney Cancer Symposium, 2nd-3rd November 2017, Miami, Florida. Kidney Cancer. 2018;2:50.

  109. Papadopoulos KP, Jonasch E, Zojwalla NJ, Wang K, Bauer TM. A first-in-human phase 1 dose-escalation trial of the oral HIF-2a inhibitor PT2977 in patients with advanced solid tumors. J Clin Oncol. 2018;36(15_suppl):2508–2508.

    Article  Google Scholar 

  110. Choueiri TK, Plimack ER, Bauer TM, Merchan JR, Papadopoulos KP, McDermott DF, et al. Phase I/II study of the oral HIF-2 α inhibitor MK-6482 in patients with advanced clear cell renal cell carcinoma (RCC). J Clin Oncol. 2020;38(6_suppl):611–611.

    Article  Google Scholar 

  111. Auvray M, Auclin E, Barthelemy P, Bono P, Kellokumpu-Lehtinen P, Gross-Goupil M, et al. Second-line targeted therapies after nivolumab-ipilimumab failure in metastatic renal cell carcinoma. Eur J Cancer. 2019;108:33–40.

    Article  CAS  PubMed  Google Scholar 

  112. McKay RR, Xie W, McGregor BA, Braun DA, Wei XX, Kyriakopoulos C, et al. Optimized management of nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma (RCC): a response-based phase II study (OMNIVORE). J Clin Oncol. 2020;38(15_suppl):5005–5005.

    Article  Google Scholar 

  113. Atkins MB, Jegede O, Haas NB, McDermott DF, Bilen MA, Drake CG, et al. Phase II study of nivolumab and salvage nivolumab + ipilimumab in treatment-naïve patients (pts) with advanced renal cell carcinoma (RCC) (HCRN GU16-260). J Clin Oncol. 2020;38(15_suppl):5006–5006.

    Article  Google Scholar 

  114. Lee C-H, Shah AY, Hsieh JJ, Rao A, Pinto A, Bilen MA, et al. Phase II trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) for disease progression after PD-1/PD-L1 immune checkpoint inhibitor (ICI) in metastatic clear cell renal cell carcinoma (mccRCC). J Clin Oncol. 2020;38(15_suppl):5008–5008.

    Article  Google Scholar 

Download references

Author information

Author notes

  1. Landon C. Brown and Kunal Desai: Co-first authors.

Authors and Affiliations

  1. Division of Medical Oncology, Department of Medicine, Duke University, DUMC 103861, Durham, NC, 27710, USA

    Landon C. Brown & Tian Zhang

  2. Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA

    Landon C. Brown & Tian Zhang

  3. Department of Internal Medicine, Cleveland Clinic, 9500 Euclid Avenue, NA10, Cleveland, OH, 44195, USA

    Kunal Desai

  4. Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

    Moshe C. Ornstein

  5. Genitourinary Oncology, Cleveland Clinic Taussig Cancer Institute, 9500 Euclid Ave, CA-60, Cleveland, OH, 44195, USA

    Moshe C. Ornstein

Authors
  1. Landon C. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kunal Desai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tian Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Moshe C. Ornstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Moshe C. Ornstein.

Ethics declarations

Funding

No external funding was used in the preparation of this manuscript.

Conflict of interest

Dr Landon Brown and Dr Kunal Desai declare that they have no conflicts of interest that might be relevant to the contents of this manuscript. Dr Tian Zhang declares that she has research funding from Astra Zeneca, Janssen, OmniSeq, PGDx, Pfizer, Merrimack, Abbvie/Stemcentrx, Novartis, Merck, Mirati, Astellas, and Regeneron; Advisory/consultant role with Genentech Roche, Exelixis, Bayer, AstraZeneca, Pfizer, Sanofi-Aventis, Janssen, Foundation Medicine, Amgen, BMS, Merck, Pharmacyclics, and Seattle Genetics; Speakers’ bureau for Genentech Roche (2018), Exelixis (2019), Sanofi-Aventis, Genomic Health/Exact Sciences; and Stocks/Employment from Capio Biosciences and Archimmune Therapeutics (spouse). Dr Moshe Ornstein declares research funding from Pfizer & Bristol-Myers Squibb; advisory/consulting roles from Pfizer, Bristol-Myers Squibb, Exelixis; Speakers’ bureau for Bristol Myers Squibb (2019) and Exelixis (2019).

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and material

Not applicable.

Code availability

Not applicable.

Author contributions

Drs Landon Brown and Kunal Desai wrote the majority of the content. Drs Tian Zhang and Moshe Ornstein reviewed all content and provided editorial input.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brown, L.C., Desai, K., Zhang, T. et al. The Immunotherapy Landscape in Renal Cell Carcinoma. BioDrugs 34, 733–748 (2020). https://doi.org/10.1007/s40259-020-00449-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40259-020-00449-4

Search

Navigation