Skip to main content

Immunotherapy for Renal Cell Carcinoma

  • Chapter
  • First Online:
  • 1962 Accesses

Part of the book series: Current Clinical Urology ((CCU))

Abstract

Renal cell carcinoma (RCC) is a highly immunogenic tumor as evidenced by the occasional dramatic spontaneous remission seen even in advanced disease. Since the earliest days, immunotherapeutic approaches have been utilized in an attempt to replicate this.

Based on early single agent trials that demonstrated a modest survival benefit, IFN-α became the reference standard in phase III trials including the initial trials involving molecular targeted agents. Although HD IL-2 results in durable complete remissions in a small subset of treated patients, the treatment-related morbidity, administration costs, and low response rate limit wider use. Early phase studies of alternative immunotherapeutic strategies including vaccines, carbonic-anhydrase IX (CAIX) antibody therapy, and attempts at non-myeloablative allo-transplantation have demonstrated interesting responses but these have not been pursued in the phase III setting.

Following the advent of the therapies targeting vascular endothelial growth factor (VEGF), tyrosine kinase (TK) and mammalian target of rapamycin (mTOR) pathways, immunotherapeutic approaches have become increasingly limited except for the upfront combination of IFN-α with bevacizumab and high-dose IL-2 in selected patients. However, improved understanding of immunoregulatory pathways in RCC suggests that targeted immunotherapy using immune checkpoint inhibitors may be promising, and clinical trials are underway. This chapter discusses various immunotherapeutic options that have been evaluated in the management of advanced RCC.

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

Buying options

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  1. Rohdenburg GL. Fluctuations in the growth energy of malignant tumours in man, with special reference to spontaneous regression. J Cancer Res. 1918;3:193.

    Google Scholar 

  2. Vogelzang NJ, Priest ER, Borden L. Spontaneous regression of histologically proved pulmonary metastases from renal cell carcinoma: a case with 5-year followup. J Urol. 1992;148(4):1247–8.

    PubMed  CAS  Google Scholar 

  3. 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  PubMed  CAS  Google Scholar 

  4. Middleton RG. Surgery for metastatic renal cell carcinoma. J Urol. 1967;97(6):973–7.

    PubMed  CAS  Google Scholar 

  5. Bloom HJ. Hormone-induced and spontaneous regression of metastatic renal cancer. Cancer. 1973;32(5):1066–71.

    Article  PubMed  CAS  Google Scholar 

  6. Elhilali MM, Gleave M, Fradet Y, et al. Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma. The Canadian Urologic Oncology Group. BJU Int. 2000;86(6):613–8.

    Article  PubMed  CAS  Google Scholar 

  7. Gleave ME, Elhilali M, Fradet Y, et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med. 1998;338(18):1265–71.

    Article  PubMed  CAS  Google Scholar 

  8. Parada SA, Franklin JM, Uribe PS, Manoso MW. Renal cell carcinoma metastases to bone after a 33-year remission. Orthopedics. 2009;32(6):446.

    Article  PubMed  Google Scholar 

  9. Young RC. Metastatic renal-cell carcinoma: what causes occasional dramatic regressions? N Engl J Med. 1998;338(18):1305–6.

    Article  PubMed  CAS  Google Scholar 

  10. Morgan DA, Ruscetti FW, Gallo R. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science. 1976;193(4257):1007–8.

    Article  PubMed  CAS  Google Scholar 

  11. Lotze MT, Robb RJ, Sharrow SO, Frana LW, Rosenberg SA. Systemic administration of interleukin-2 in humans. J Biol Response Mod. 1984;3(5):475–82.

    PubMed  CAS  Google Scholar 

  12. Rosenberg SA, Grimm EA, McGrogan M, et al. Biological activity of recombinant human interleukin-2 produced in Escherichia coli. Science. 1984;223(4643):1412–4.

    Article  PubMed  CAS  Google Scholar 

  13. Taniguchi T, Matsui H, Fujita T, et al. Structure and expression of a cloned cDNA for human interleukin-2. Nature. 1983;302(5906):305–10.

    Article  PubMed  CAS  Google Scholar 

  14. Rosenberg SA, Mule JJ, Spiess PJ, Reichert CM, Schwarz SL. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985;161(5):1169–88.

    Article  PubMed  CAS  Google Scholar 

  15. Lafreniere R, Rosenberg SA. Successful immunotherapy of murine experimental hepatic metastases with lymphokine-activated killer cells and recombinant interleukin 2. Cancer Res. 1985;45(8):3735–41.

    PubMed  CAS  Google Scholar 

  16. Lotze MT, Chang AE, Seipp CA, Simpson C, Vetto JT, Rosenberg SA. High-dose recombinant interleukin 2 in the treatment of patients with disseminated cancer. Responses, treatment-related morbidity, and histologic findings. JAMA. 1986;256(22):3117–24.

    Article  PubMed  CAS  Google Scholar 

  17. Rosenberg SA, Lotze MT, Muul LM, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313(23):1485–92.

    Article  PubMed  CAS  Google Scholar 

  18. 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.

    PubMed  CAS  Google Scholar 

  19. Rosenberg SA, Lotze MT, Yang JC, et al. Prospective randomized trial of high dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst. 1993;85(8):622–32.

    Article  PubMed  CAS  Google Scholar 

  20. Yang JC, Topalian SL, Parkinson D, et al. Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol. 1994;12(8):1572–6.

    PubMed  CAS  Google Scholar 

  21. Yang JC, Topalian SL, Schwartzentruber DJ, et al. The use of polyethylene glycolmodified interleukin-2 (PEG-IL-2) in the treatment of patients with metastatic renal cell carcinoma and melanoma. A phase I study and a randomized prospective study comparing IL-2 alone versus IL-2 combined with PEG-IL-2. Cancer. 1995;76(4):687–94.

    Article  PubMed  CAS  Google Scholar 

  22. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med. 1998;338(18):1272–8.

    Article  PubMed  CAS  Google Scholar 

  23. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. 2003;21(16):3127–32.

    Article  PubMed  CAS  Google Scholar 

  24. McDermott DF, Regan MM, Clark JI, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23(1):133–41.

    Article  PubMed  CAS  Google Scholar 

  25. Negrier S, Perol D, Ravaud A, et al. Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer. 2007;110(11):2468–77.

    Article  PubMed  CAS  Google Scholar 

  26. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2010;28(Suppl):15s [Abstr 4514].

    Google Scholar 

  27. Lotze MT, Matory YL, Rayner AA, et al. Clinical effects and toxicity of interleukin-2 in patients with cancer. Cancer. 1986;58(12):2764–72.

    Article  PubMed  CAS  Google Scholar 

  28. Majhail NS, Wood L, Elson P, Finke J, Olencki T, Bukowski RM. Adjuvant subcutaneous interleukin-2 in patients with resected renal cell carcinoma: a pilot study. Clin Genitourin Cancer. 2006;5(1):50–6.

    Article  PubMed  CAS  Google Scholar 

  29. Clark JI, Atkins MB, Urba WJ, et al. Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. J Clin Oncol. 2003;21(16):3133–40.

    Article  PubMed  CAS  Google Scholar 

  30. Dandamudi UB, Ghebremichael MS, Sosman JA, et al. A phase II study of bevacizumab (B) and high-dose aldesleukin (IL-2) in patients (p) with metastatic renal cell carcinoma (mRCC): a Cytokine Working Group Study (CWGS). J Clin Oncol. 2010;28(Suppl 15S) [Abstr 4530].

    Google Scholar 

  31. Procopio G, Verzoni E, Bracarda S, et al. Sorafenib with interleukin-2 vs sorafenib alone in metastatic renal cell carcinoma: the ROSORC trial. Br J Cancer. 2011;104(8):1256–61.

    Article  PubMed  CAS  Google Scholar 

  32. Leibovich BC, Han K-R, Bui MHT, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma. Cancer. 2003;98(12):2566–75.

    Article  PubMed  Google Scholar 

  33. Motzer RJ, Bacik J, Mariani T, Russo P, Mazumdar M, Reuter V. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol. 2002;20(9):2376–81.

    Article  PubMed  Google Scholar 

  34. Upton MP, Parker RA, Youmans A, McDermott DF, Atkins MB. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother. 2005;28(5):488–95.

    Article  PubMed  CAS  Google Scholar 

  35. Pantuck AJ, Fang Z, Liu X, et al. Gene expression and tissue microarray analysis of interleukin-2 complete responders in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23(16S) [Abstr 4535].

    Google Scholar 

  36. Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res. 2003;9(2):802–11.

    PubMed  CAS  Google Scholar 

  37. Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res. 2005;11(10):3714–21.

    Article  PubMed  CAS  Google Scholar 

  38. Jaeger E, Waldman F, Roydasgupta R, et al. Array-based comparative genomic hybridization (CGH) identifies chromosomal imbalances between Interleukin-2 complete and non-responders. J Clin Oncol. 2008;26(Suppl) [Aabstr 5043].

    Google Scholar 

  39. McDermott DF, Ghebremichael MS, Signoretti S, et al. The high-dose aldesleukin (HD IL-2) “SELECT” trial in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2010;28(15S) [Abstr 4514].

    Google Scholar 

  40. Clement JM, McDermott DF. The high-dose aldesleukin (IL-2) “select” trial: a trial designed to prospectively validate predictive models of response to high-dose IL-2 treatment in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2009;7(2):E7–9.

    Article  PubMed  CAS  Google Scholar 

  41. Lee DS, White DE, Hurst R, Rosenberg SA, Yang JC. Patterns of relapse and response to retreatment in patients with metastatic melanoma or renal cell carcinoma who responded to interleukin-2-based immunotherapy. Cancer J Sci Am. 1998;4(2):86–93.

    PubMed  CAS  Google Scholar 

  42. 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.

    PubMed  Google Scholar 

  43. Atzpodien J, Kirchner H, Jonas U, et al. Interleukin-2- and interferon alfa-2a-based immunochemotherapy in advanced renal cell carcinoma: a Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). J Clin Oncol. 2004;22(7):1188–94.

    Article  PubMed  CAS  Google Scholar 

  44. Atzpodien J, Lopez Hanninen E, Kirchner H, et al. Multiinstitutional home-therapy trial of recombinant human interleukin-2 and interferon alfa-2 in progressive metastatic renal cell carcinoma. J Clin Oncol. 1995;13(2):497–501.

    PubMed  CAS  Google Scholar 

  45. Dutcher JP, Fisher RI, Weiss G, et al. Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer: five-year follow-up of the Cytokine Working Group Study. Cancer J Sci Am. 1997;3(3):157–62.

    PubMed  CAS  Google Scholar 

  46. Vogelzang NJ, Lipton A, Figlin RA. Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: an outpatient multicenter trial. J Clin Oncol. 1993;11(9):1809–16.

    PubMed  CAS  Google Scholar 

  47. van Herpen CM, Jansen RL, Kruit WH, et al. Immunochemotherapy with interleukin-2, interferon-alpha and 5-fluorouracil for progressive metastatic renal cell carcinoma: a multicenter phase II study. Dutch Immunotherapy Working Party. Br J Cancer. 2000;82(4):772–6.

    Article  PubMed  Google Scholar 

  48. Atkins MB, Dutcher J, Weiss G, et al. Kidney cancer: the Cytokine Working Group experience (1986–2001): part I. IL-2-based clinical trials. Med Oncol. 2001;18(3):197–207.

    Article  PubMed  CAS  Google Scholar 

  49. Rathmell WK, Malkowicz SB, Holroyde C, Luginbuhl W, Vaughn DJ. Phase II trial of 5-fluorouracil and leucovorin in combination with interferon-alpha and interleukin-2 for advanced renal cell cancer. Am J Clin Oncol. 2004;27(2):109–12.

    Article  PubMed  CAS  Google Scholar 

  50. Rosenberg SA, Lotze MT, Yang JC, et al. Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. J Clin Oncol. 1989;7(12):1863–74.

    PubMed  CAS  Google Scholar 

  51. Atkins MB, Sparano J, Fisher RI, et al. Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol. 1993;11(4):661–70.

    PubMed  CAS  Google Scholar 

  52. Sznol M, Mier JW, Sparano J, et al. A phase I study of high-dose interleukin-2 in combination with interferon-alpha 2b. J Biol Response Mod. 1990;9(6):529–37.

    PubMed  CAS  Google Scholar 

  53. Bergmann L, Fenchel K, Weidmann E, et al. Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. A phase II study. Cancer. 1993;72(5):1733–42.

    Article  PubMed  CAS  Google Scholar 

  54. Spencer WF, Linehan WM, Walther MM, et al. Immunotherapy with interleukin-2 and alpha-interferon in patients with metastatic renal cell cancer with in situ primary cancers: a pilot study. J Urol. 1992;147(1):24–30.

    PubMed  CAS  Google Scholar 

  55. Budd GT, Murthy S, Finke J, et al. Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy. J Clin Oncol. 1992;10(5):804–9.

    PubMed  CAS  Google Scholar 

  56. Gore ME, Griffin CL, Hancock B, et al. Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): an open-label randomised trial. Lancet. 2010;375(9715):641–8.

    Article  PubMed  CAS  Google Scholar 

  57. Falcone A, Cianci C, Ricci S, Brunetti I, Bertuccelli M, Conte PF. Alpha-2B-interferon plus floxuridine in metastatic renal cell carcinoma. A phase I-II study. Cancer. 1993;72(2):564–8.

    Article  PubMed  CAS  Google Scholar 

  58. Igarashi T, Marumo K, Onishi T, et al. Interferon-alpha and 5-fluorouracil therapy in patients with metastatic renal cell cancer: an open multicenter trial. The Japanese Study Group Against Renal Cancer. Urology. 1999;53(1):53–9.

    Article  PubMed  CAS  Google Scholar 

  59. Elias L, Blumenstein BA, Kish J, et al. A phase II trial of interferon-alpha and 5-fluorouracil in patients with advanced renal cell carcinoma. A Southwest Oncology Group study. Cancer. 1996;78(5):1085–8.

    Article  PubMed  CAS  Google Scholar 

  60. Neidhart JA, Anderson SA, Harris JE, et al. Vinblastine fails to improve response of renal cancer to interferon alfa-n1: high response rate in patients with pulmonary metastases. J Clin Oncol. 1991;9(5):832–6.

    PubMed  CAS  Google Scholar 

  61. Fossa SD, Martinelli G, Otto U, et al. Recombinant interferon alfa-2a with or without vinblastine in metastatic renal cell carcinoma: results of a European multi-center phase III study. Ann Oncol. 1992;3(4):301–5.

    PubMed  CAS  Google Scholar 

  62. Motzer RJ, Murphy BA, Bacik J, et al. Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol. 2000;18(16):2972–80.

    PubMed  CAS  Google Scholar 

  63. Aass N, De Mulder PH, Mickisch GH, et al. Randomized phase II/III trial of interferon Alfa-2a with and without 13-cis-retinoic acid in patients with progressive metastatic renal cell Carcinoma: the European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951). J Clin Oncol. 2005;23(18):4172–8.

    Article  PubMed  CAS  Google Scholar 

  64. Gollob JA, Rathmell WK, Richmond TM, et al. Phase II trial of sorafenib plus interferon alfa-2b as first- or second-line therapy in patients with metastatic renal cell cancer. J Clin Oncol. 2007;25(22):3288–95.

    Article  PubMed  CAS  Google Scholar 

  65. Ryan CW, Goldman BH, Lara Jr PN, et al. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol. 2007;25(22):3296–301.

    Article  PubMed  CAS  Google Scholar 

  66. Motzer RJ, Hudes G, Wilding G, et al. Phase I trial of sunitinib malate plus interferon-alpha for patients with metastatic renal cell carcinoma. Clin Genitourin Cancer. 2009;7(1):28–33.

    Article  PubMed  CAS  Google Scholar 

  67. Escudier B, Pluzanska A, Koralewski P, 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 

  68. Rini BI, Halabi S, Rosenberg JE, 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  PubMed  CAS  Google Scholar 

  69. Melichar B, Koralewski P, Ravaud A, et al. First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Ann Oncol. 2008;19(8):1470–6.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  71. Bracarda S, Ludovini V, Porta C, et al. Serum thrombospondin-1 (TSP-1), vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and basic-fibroblast growth factor (b-FGF) as predictive factors for sorafenib plus interferon-alfa-2a (IFN) in metastatic renal cell carcinoma (MRCC): Biologic results from the randomized phase II RAPSODY trial. J Clin Oncol. 2010;28(15s) [Abstr 4628].

    Google Scholar 

  72. Buti S, Lazzarelli S, Chiesa MD, et al. Dose-finding trial of a combined regimen with bevacizumab, immunotherapy, and chemotherapy in patients with metastatic renal cell cancer: An Italian Oncology Group for Clinical Research (GOIRC) study. J Immunother. 2010;33(7):735–41.

    Article  PubMed  CAS  Google Scholar 

  73. Ryan CW, Goldman BH, Lara Jr PN, Mack PC, Beer TM, Tangen CM, Lemmon D, Pan CX, Drabkin HA, Crawford ED. Sorafenib with interferon alfa-2b as first-line treatment of advanced renal carcinoma: a phase II study of the Southwest Oncology Group. J Clin Oncol. 2007;25(22):3296–301.

    Article  PubMed  CAS  Google Scholar 

  74. Escudier B, Bellmunt J, Négrier S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overall survival. J Clin Oncol. 2010;28(13):2144–50.

    Article  PubMed  CAS  Google Scholar 

  75. Rini BI, Halabi S, Rosenberg JE, 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  PubMed  CAS  Google Scholar 

  76. Niwakawa M, Hashine K, Yamaguchi R, Fujii H, Hamamoto Y, Fukino K, Tanigawa T, Sumiyoshi Y. Phase I trial of sorafenib in combination with interferon-alpha in Japanese patients with unresectable or metastatic renal cell carcinoma. Invest New Drugs. 2011;30:1046–54.

    Article  PubMed  CAS  Google Scholar 

  77. Négrier S, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol. 2011;12(7):673–80.

    Article  PubMed  CAS  Google Scholar 

  78. Ravaud A, Bajetta E, Kay AC, et al. Everolimus with bevacizumab versus interferon alfa-2a plus bevacizumab as first-line therapy in patients with metastatic clear cell renal cell carcinoma. J Clin Oncol. 2010;28(Suppl):15s [Abstr TPS238].

    Google Scholar 

  79. NCT00631371. http://clinicaltrials.gov/ct2/show/NCT00631371.

  80. NCT00378703. http://clinicaltrials.gov/ct2/show/NCT00378703.

  81. Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20(1):289–96.

    Article  PubMed  CAS  Google Scholar 

  82. Srivastava P. Interaction of heat shock proteins with peptides and antigen presenting cells: chaperoning of the innate and adaptive immune responses. Annu Rev Immunol. 2002;20:395–425.

    Article  PubMed  CAS  Google Scholar 

  83. Binder RJ, Srivastava PK. Peptides chaperoned by heat-shock proteins are a necessary and sufficient source of antigen in the cross-priming of CD8+ T cells. Nat Immunol. 2005;6(6):593–9.

    Article  PubMed  CAS  Google Scholar 

  84. Tamura Y, Peng P, Liu K, Daou M, Srivastava PK. Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations. Science. 1997;278(5335):117–20.

    Article  PubMed  CAS  Google Scholar 

  85. Jonasch E, Wood C, Tamboli P, et al. Vaccination of metastatic renal cell carcinoma patients with autologous tumour-derived vitespen vaccine: clinical findings. Br J Cancer. 2008;98(8):1336–41.

    Article  PubMed  CAS  Google Scholar 

  86. Southall PJ, Boxer GM, Bagshawe KD, Hole N, Bromley M, Stern PL. Immunohistological distribution of 5 T4 antigen in normal and malignant tissues. Br J Cancer. 1990;61(1):89–95.

    Article  PubMed  CAS  Google Scholar 

  87. Griffiths RW, Gilham DE, Dangoor A, et al. Expression of the 5 T4 oncofoetal antigen in renal cell carcinoma: a potential target for T-cell-based immunotherapy. Br J Cancer. 2005;93(6):670–7.

    Article  PubMed  CAS  Google Scholar 

  88. Amato RJ, Shingler W, Goonewardena M, et al. Vaccination of renal cell cancer patients with modified vaccinia Ankara delivering the tumor antigen 5 T4 (TroVax) alone or administered in combination with interferon-alpha (IFN-alpha): a phase 2 trial. J Immunother. 2009;32(7):765–72.

    Article  PubMed  CAS  Google Scholar 

  89. Amato RJ, Shingler W, Naylor S, et al. Vaccination of renal cell cancer patients with modified vaccinia ankara delivering tumor antigen 5 T4 (TroVax) administered with interleukin 2: a phase II trial. Clin Cancer Res. 2008;14(22):7504–10.

    Article  PubMed  CAS  Google Scholar 

  90. Amato RJ, Hawkins RE, Kaufman HL, et al. Vaccination of metastatic renal cancer patients with MVA-5 T4: a randomized, double-blind, placebo-controlled phase III study. Clin Cancer Res. 2010;16(22):5539–47.

    Article  PubMed  CAS  Google Scholar 

  91. Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, et al. Monoclonal antibody G 250 recognizes a determinant present in renal-cell carcinoma and absent from normal kidney. Int J Cancer. 1986;38(4):489–94.

    Article  PubMed  CAS  Google Scholar 

  92. Oosterwijk E, Bander NH, Divgi CR, et al. Antibody localization in human renal cell carcinoma: a phase I study of monoclonal antibody G250. J Clin Oncol. 1993;11(4):738–50.

    PubMed  CAS  Google Scholar 

  93. Bleumer I, Knuth A, Oosterwijk E, et al. A phase II trial of chimeric monoclonal antibody G250 for advanced renal cell carcinoma patients. Br J Cancer. 2004;90(5):985–90.

    Article  PubMed  CAS  Google Scholar 

  94. Brouwers AH, Buijs WC, Mulders PF, et al. Radioimmunotherapy with [131I]cG250 in patients with metastasized renal cell cancer: dosimetric analysis and immunologic response. Clin Cancer Res. 2005;11(19 Pt 2):7178s–86.

    Article  PubMed  CAS  Google Scholar 

  95. Childs RW, Clave E, Tisdale J, Plante M, Hensel N, Barrett J. Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect. J Clin Oncol. 1999;17(7):2044–9.

    PubMed  CAS  Google Scholar 

  96. Childs R, Chernoff A, Contentin N, et al. Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med. 2000;343(11):750–8.

    Article  PubMed  CAS  Google Scholar 

  97. Tykodi SS, Sandmaier BM, Warren EH, Thompson JA. Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after. Expert Opin Biol Ther. 2011;11(6):763–73.

    Article  PubMed  Google Scholar 

  98. Mellor AL, Chandler P, Baban B, et al. Specific subsets of murine dendritic cells acquire potent T cell regulatory functions following CTLA4-mediated induction of indoleamine 2,3 dioxygenase. Int Immunol. 2004;16(10):1391–401.

    Article  PubMed  CAS  Google Scholar 

  99. Chambers CA, Sullivan TJ, Truong T, Allison JP. Secondary but not primary T cell responses are enhanced in CTLA-4-deficient CD8+ T cells. Eur J Immunol. 1998;28(10):3137–43.

    Article  PubMed  CAS  Google Scholar 

  100. Chambers CA, Kuhns MS, Allison JP. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates primary and secondary peptide-specific CD4(+) T cell responses. Proc Natl Acad Sci USA. 1999;96(15):8603–8.

    Article  PubMed  CAS  Google Scholar 

  101. Sutmuller RP, van Duivenvoorde LM, van Elsas A, et al. Synergism of cytotoxic T lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. J Exp Med. 2001;194(6):823–32.

    Article  PubMed  CAS  Google Scholar 

  102. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH. Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity. 1995;3(5):541–7.

    Article  PubMed  CAS  Google Scholar 

  103. Waterhouse P, Penninger JM, Timms E, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–8.

    Article  PubMed  CAS  Google Scholar 

  104. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734–6.

    Article  PubMed  CAS  Google Scholar 

  105. Yang YF, Zou JP, Mu J, et al. Enhanced induction of antitumor T-cell responses by cytotoxic T lymphocyte-associated molecule-4 blockade: the effect is manifested only at the restricted tumor-bearing stages. Cancer Res. 1997;57(18):4036–41.

    PubMed  CAS  Google Scholar 

  106. van Elsas A, Hurwitz AA, Allison JP. Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J Exp Med. 1999;190(3):355–66.

    Article  PubMed  Google Scholar 

  107. Hurwitz AA, Yu TF, Leach DR, Allison JP. CTLA-4 blockade synergizes with tumor-derived granulocyte-macrophage colony-stimulating factor for treatment of an experimental mammary carcinoma. Proc Natl Acad Sci USA. 1998;95(17):10067–71.

    Article  PubMed  CAS  Google Scholar 

  108. Ribas A, Camacho LH, Lopez-Berestein G, et al. Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol. 2005;23(35):8968–77.

    Article  PubMed  CAS  Google Scholar 

  109. Beck KE, Blansfield JA, Tran KQ, et al. Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4. J Clin Oncol. 2006;24(15):2283–9.

    Article  PubMed  CAS  Google Scholar 

  110. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  PubMed  CAS  Google Scholar 

  111. Yang JC, Hughes M, Kammula U, et al. Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother. 2007;30(8):825–30.

    Article  PubMed  CAS  Google Scholar 

  112. Rini BI, Stein M, Shannon P, et al. Phase 1 dose-escalation trial of tremelimumab plus sunitinib in patients with metastatic renal cell carcinoma. Cancer. 2011;117(4):758–67.

    Article  PubMed  CAS  Google Scholar 

  113. Agata Y, Kawasaki A, Nishimura H, et al. Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol. 1996;8(5):765–72.

    Article  PubMed  CAS  Google Scholar 

  114. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J. 1992;11(11):3887–95.

    PubMed  CAS  Google Scholar 

  115. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–8.

    Article  PubMed  CAS  Google Scholar 

  116. Zha Y, Blank C, Gajewski TF. Negative regulation of T-cell function by PD-1. Crit Rev Immunol. 2004;24(4):229–37.

    Article  PubMed  CAS  Google Scholar 

  117. Nishimura H, Nose M, Hiai H, Minato N, Honjo T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity. 1999;11(2):141–51.

    Article  PubMed  CAS  Google Scholar 

  118. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319–22.

    Article  PubMed  CAS  Google Scholar 

  119. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA. 2004;101(49):17174–9.

    Article  PubMed  CAS  Google Scholar 

  120. Thompson RH, Gillett MD, Cheville JC, et al. Costimulatory molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer. 2005;104(10):2084–91.

    Article  PubMed  CAS  Google Scholar 

  121. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res. 2007;13(6):1757–61.

    Article  PubMed  CAS  Google Scholar 

  122. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of single-agent anti–programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol. 2010;28(19):3167–75.

    Article  PubMed  CAS  Google Scholar 

  123. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Google Scholar 

  124. Brahmer JR, Tykodi SS, Chow LQ, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Google Scholar 

  125. Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15(23):7412–20.

    Google Scholar 

  126. Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127–37.

    Google Scholar 

  127. Pardoll DM, Topalian SL. The role of CD4+ T cell responses in antitumor immunity. Curr Opin Immunol. 1998;10(5):588–94.

    Article  PubMed  CAS  Google Scholar 

  128. Onishi T, Ohishi Y, Imagawa K, Ohmoto Y, Murata K. An assessment of the immunological environment based on intratumoral cytokine production in renal cell carcinoma. BJU Int. 1999;83(4):488–92.

    Article  PubMed  CAS  Google Scholar 

  129. Finke JH, Rini B, Ireland J, et al. Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res. 2008;14(20):6674–82.

    Article  PubMed  CAS  Google Scholar 

  130. Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E. Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res. 1999;59(13):3128–33.

    PubMed  CAS  Google Scholar 

  131. Ko JS, Zea AH, Rini BI, 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  PubMed  CAS  Google Scholar 

  132. Kusmartsev S, Gabrilovich DI. Role of immature myeloid cells in mechanisms of immune evasion in cancer. Cancer Immunol Immunother. 2006;55(3):237–45.

    Article  PubMed  Google Scholar 

  133. Hoechst B, Ormandy LA, Ballmaier M, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008;135(1):234–43.

    Article  PubMed  CAS  Google Scholar 

  134. Almand B, Clark JI, Nikitina E, et al. Increased production of immature myeloid cells in cancer patients: a mechanism of immunosuppression in cancer. J Immunol. 2001;166(1):678–89.

    PubMed  CAS  Google Scholar 

  135. Wood et al. Lancet 2008, 372: 145.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Leonard J. Appleman .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Davar, D., Fenton, M., Appleman, L.J. (2013). Immunotherapy for Renal Cell Carcinoma. In: Campbell, S., Rini, B. (eds) Renal Cell Carcinoma. Current Clinical Urology. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-062-5_16

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-062-5_16

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-061-8

  • Online ISBN: 978-1-62703-062-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics