Skip to main content

Advertisement

SpringerLink
Log in

Current Status and Future Directions of Immunotherapy in Renal Cell Carcinoma

  • Genitourinary Cancers (DP Petrylak and JW Kim, Section Editors)
  • Published:
Current Oncology Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

Renal cell carcinoma (RCC) was recognized as an immunologically sensitive cancer over 30 years ago. The first therapies to affect the course of RCC were cytokines (interferon alfa-2B and interleukin-2). Subsequently, drugs that inhibit HIF (hypoxia-inducible factor)/VEGF (vascular endothelial growth factor) signaling demonstrated overall survival advantages (tyrosine kinase inhibitors and mTor inhibitors).

Recent Findings

In the last 3 years, the immune checkpoint inhibitors (ICIs) have become the standard of care treatments in the first and second lines for RCC. Emerging data show that combinations of ICI, HIF signaling inhibitors, and cytokines are potentially powerful regimens.

Summary

How to combine and sequence these types of therapies and how to integrate new approaches into the management of RCC are now the key questions for the field. Treatment of RCC is likely to change dramatically in the next few years.

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

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. CA Cancer J Clin. 3rd ed. 2018;68:7–30.

    PubMed  Google Scholar 

  2. Devesa SS, Silverman DT, McLaughlin JK, Brown CC, Connelly RR, Fraumeni JF. Comparison of the descriptive epidemiology of urinary tract cancers. Cancer Causes Control. 1990;1:133–41.

    CAS  PubMed  Google Scholar 

  3. 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;148:1247–8.

    CAS  PubMed  Google Scholar 

  4. Summers J, Cohen MH, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab plus interferon for advanced renal cell carcinoma. The Oncologist. 2010;15:104–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Posadas EM, Limvorasak S, Sharma S, Figlin RA. Targeting angiogenesis in renal cell carcinoma. Expert Opin Pharmacother. Taylor & Francis. 2013;14:2221–36.

    CAS  PubMed  Google Scholar 

  6. Hudes GR, Carducci MA, Choueiri TK, Esper P, Jonasch E, Kumar R, et al. NCCN Task Force report: optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy. J Natl Compr Canc Netw. NIH Public. Access. 2011;9(Suppl 1):S1–29.

    CAS  Google Scholar 

  7. Haase VH. The VHL tumor suppressor: master regulator of HIF. Curr Pharm Des NIH Public Access. 2009;15:3895–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Baldewijns MM, van Vlodrop IJH, Vermeulen PB, Soetekouw PMMB, van Engeland M, de Bruïne AP. VHL and HIF signalling in renal cell carcinogenesis. J Pathol. 2010;221:125–38.

    CAS  PubMed  Google Scholar 

  9. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune responses by mTOR. Annu Rev Immunol Annual Reviews. 2012;30:39–68.

    CAS  PubMed  Google Scholar 

  10. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Molecular and Cellular Biology. Am Soc Microbiol (ASM). 2002;22:7004–14.

    CAS  Google Scholar 

  11. Kondo K, Yao M, Kobayashi K, Ota S, Yoshida M, Kaneko S, et al. PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines. Int J Cancer. 2001;91:219–24.

    CAS  PubMed  Google Scholar 

  12. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature. Nature Publishing Group. 2013;502:333–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Santoni M, Berardi R, Amantini C, Burattini L, Santini D, Santoni G, et al. Role of natural and adaptive immunity in renal cell carcinoma response to VEGFR-TKIs and mTOR inhibitor. Int. J. Cancer. Wiley-Blackwell. 2014;134:2772–7.

    CAS  PubMed  Google Scholar 

  14. • Chevrier S, Levine JH, VRT Z, Silina K, Schulz D, Bacac M, et al. An immune atlas of clear cell renal cell carcinoma. Cell. 2017;169:736–749.e18. This paper is the first detailed description of the immune infiltrate of clear cell renal cell carcinoma.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Finn OJ. Cancer immunology. N Engl J Med. Massachusetts Medical. Society. 2008;358:2704–15.

    CAS  Google Scholar 

  16. Murphy KA, James BR, Guan Y, Torry DS, Wilber A, Griffith TS. Exploiting natural anti-tumor immunity for metastatic renal cell carcinoma. Hum Vaccin Immunother. Taylor & Francis. 2015;11:1612–20.

    PubMed  PubMed Central  Google Scholar 

  17. Teft WA, Kirchhof MG, Madrenas J. A molecular perspective of CTLA-4 function. Annu Rev Immunol. 2006;24:65–97.

    CAS  PubMed  Google Scholar 

  18. Chen L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol. Nature Publishing Group. 2004;4:336–47.

    CAS  PubMed  Google Scholar 

  19. Kobayashi M, Suzuki K, Yashi M, Yuzawa M, Takayashiki N, Morita T. Tumor infiltrating dendritic cells predict treatment response to immmunotherapy in patients with metastatic renal cell carcinoma. Anticancer Res. 2007;27:1137–41.

    CAS  PubMed  Google Scholar 

  20. Webster WS, Lohse CM, Thompson RH, Dong H, Frigola X, Dicks DL, et al. Mononuclear cell infiltration in clear-cell renal cell carcinoma independently predicts patient survival. Cancer. 2006;107:46–53.

    PubMed  Google Scholar 

  21. Geissler K, Fornara P, Lautenschläger C, Holzhausen H-J, Seliger B, Riemann D. Immune signature of tumor infiltrating immune cells in renal cancer. Oncoimmunology. Taylor & Francis. 2015;4:e985082.

    PubMed  PubMed Central  Google Scholar 

  22. Donskov F, Maase von der H. Impact of immune parameters on long-term survival in metastatic renal cell carcinoma. J Clin Oncol. 2006;24:1997–2005.

    PubMed  Google Scholar 

  23. Noessner E, Brech D, Mendler AN, Masouris I, Schlenker R, Prinz PU. Intratumoral alterations of dendritic-cell differentiation and CD8(+) T-cell anergy are immune escape mechanisms of clear cell renal cell carcinoma. Oncoimmunology. Taylor & Francis. 2012;1:1451–3.

    PubMed  PubMed Central  Google Scholar 

  24. Finke JH, Rayman PA, Ko JS, Bradley JM, Gendler SJ, Cohen PA. Modification of the tumor microenvironment as a novel target of renal cell carcinoma therapeutics. Cancer J. 2013;19:353–64.

    CAS  PubMed  Google Scholar 

  25. Ning H, Shao Q-Q, Ding K-J, Gao D-X, Lu Q-L, Cao Q-W, et al. Tumor-infiltrating regulatory T cells are positively correlated with angiogenic status in renal cell carcinoma. Chin. Med. J. 2012;125:2120–5.

    CAS  PubMed  Google Scholar 

  26. Clark JI, MKK W, Kaufman HL, Daniels GA, Morse MA, McDermott DF, et al. Impact of sequencing targeted therapies with high-dose interleukin-2 immunotherapy: an analysis of outcome and survival of patients with metastatic renal cell carcinoma from an on-going observational IL-2 clinical trial: PROCLAIM(SM). Clin Genitourin Cancer. 2017;15:31–4.

    PubMed  Google Scholar 

  27. Krown SE. Interferons and interferon inducers in cancer treatment. Seminars in Oncology. 1986;13:207–17.

    CAS  PubMed  Google Scholar 

  28. Quesada JR, Rios A, Swanson D, Trown P, Gutterman JU. Antitumor activity of recombinant-derived interferon alpha in metastatic renal cell carcinoma. J Clin Oncol. 1985;3:1522–8.

    CAS  PubMed  Google Scholar 

  29. Otto U, Conrad S, Schneider AW, Klosterhalfen H. Recombinant interferon gamma in the treatment of metastatic renal cell carcinoma. Results of a phase II trial. Arzneimittelforschung. 1988;38:1658–60.

    CAS  PubMed  Google Scholar 

  30. Quesada JR, Kurzrock R, Sherwin SA, Gutterman JU. Phase II studies of recombinant human interferon gamma in metastatic renal cell carcinoma. J Biol Response Mod. 1987;6:20–7.

    CAS  PubMed  Google Scholar 

  31. Wagstaff J, Smith D, Nelmes P, Loynds P, Crowther D. A phase I study of recombinant interferon gamma administered by s.c. injection three times per week in patients with solid tumours. Cancer Immunol Immunother. 1987;25:54–8.

    CAS  PubMed  Google Scholar 

  32. Aulitzky W, Gastl G, Aulitzky WE, Herold M, Kemmler J, Mull B, et al. Successful treatment of metastatic renal cell carcinoma with a biologically active dose of recombinant interferon-gamma. J Clin Oncol. 1989;7:1875–84.

    CAS  PubMed  Google Scholar 

  33. Ellerhorst JA, Kilbourn RG, Amato RJ, Zukiwski AA, Jones E, Logothetis CJ. Phase II trial of low dose gamma-interferon in metastatic renal cell carcinoma. J Urol. 1994;152:841–5.

    CAS  PubMed  Google Scholar 

  34. Gleave ME, Elhilali M, Fradet Y, Davis I, Venner P, Saad F, et al. Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med. 1998;338:1265–71.

    CAS  PubMed  Google Scholar 

  35. Muss HB, Costanzi JJ, Leavitt R, Williams RD, Kempf RA, Pollard R, et al. Recombinant alfa interferon in renal cell carcinoma: a randomized trial of two routes of administration. J Clin Oncol. 1987;5:286–91.

    CAS  PubMed  Google Scholar 

  36. Collaborators MRCRC. Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. Lancet. 1999;353:14–7.

    Google Scholar 

  37. 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;370:2103–11.

    PubMed  Google Scholar 

  38. 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;28:2137–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Escudier B, Bellmunt J, Negrier S, Bajetta E, Melichar B, Bracarda 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;28:2144–50.

    CAS  PubMed  Google Scholar 

  40. Arenas-Ramirez N, Woytschak J, Boyman O. Interleukin-2: biology, design and application. Trends Immunol. 2015;36:763–77.

    CAS  PubMed  Google Scholar 

  41. 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;13:688–96.

    CAS  PubMed  Google Scholar 

  42. Yang JC, Topalian SL, Parkinson D, Schwartzentruber DJ, Weber JS, Ettinghausen SE, 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;12:1572–6.

    CAS  PubMed  Google Scholar 

  43. Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol. American Society of Clinical Oncology. 2003;21:3127–32.

    CAS  PubMed  Google Scholar 

  44. McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, 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. American Society of Clinical Oncology. 2005;23:133–41.

    CAS  PubMed  Google Scholar 

  45. Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. N Engl J Med. 1998;338:1272–8.

    CAS  PubMed  Google Scholar 

  46. Negrier S, Perol D, Ravaud A, Chevreau C, Bay J-O, Delva R, 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. Wiley Subscription Services, Inc., A Wiley Company. 2007;110:2468–77.

    CAS  PubMed  Google Scholar 

  47. Amin A, White RL. Interleukin-2 in renal cell carcinoma: a has-been or a still-viable option? J Kidney Cancer VHL. 2014;1:74–83.

    PubMed  PubMed Central  Google Scholar 

  48. Dorff TB, Wong MKK, Clark J, Daniels GA, Curti BD, Morse M, et al. High dose interleukin-2 and response in 944 patients with metastatic renal cell cancer (RCC): Data from the PROCLAIM registry. J Clin Oncol. 2018;36:6_suppl, 624.

  49. •• Clark JI, McDermott DF, Dutcher JP, MKK W, Kaufman H, Daniels GA. Extension of overall survival in patients with metastatic renal cell carcinoma who received HD IL-2 followed by targeted therapy and/or immune checkpoint blockade from the PROCLAIM registry. In: ASCO Annual Meeting; 2016. p. 1–2. This PROCLAIM HD IL-2 registry describes outcomes in the largest number of HD IL-2 patients treated with modern supportive care and in combination with current therapies. It demonstrates that in properly selected patients treated at experienced centers, HD IL-2 is an effective therapy and can result in durable responses with possible cures.

    Google Scholar 

  50. • Motzer RJ, Russo P. Cytoreductive nephrectomy - patient selection is key. N Engl J Med. 2018;379:481–2. This opinion essay provides important insight into the Mejean et al. [53] study of sunitinib with or without cytoreductive nephrectomy.

    PubMed  Google Scholar 

  51. Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655–9.

    CAS  PubMed  Google Scholar 

  52. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. European Organisation for Research and Treatment of Cancer EORTC Genitourinary Group. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358:966–70.

    CAS  PubMed  Google Scholar 

  53. Pantuck AJ, Belldegrun AS, Figlin RA. Nephrectomy and interleukin-2 for metastatic renal-cell carcinoma. N Engl J Med. 2001;345:1711–2.

    CAS  PubMed  Google Scholar 

  54. •• Mejean A, Ravaud A, Thezenas S, Colas S, Beauval J-B, Bensalah K, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379:417–27. This is the only randomized study to assess the value of cytoreductive nephrectomy in patients receiving TKI therapy and suggests that nephrectomy is not beneficial in these patients. See [50] for context.

    CAS  PubMed  Google Scholar 

  55. Culp SH, Tannir NM, Abel EJ, Margulis V, Tamboli P, Matin SF, et al. Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy? Cancer. 2010;116:3378–88.

    PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366:2443–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol. American Society of Clinical Oncology. 2015;33:1430–7.

    CAS  PubMed  Google Scholar 

  59. •• 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;373:1803–13. This paper demonstrated that nivolumab (anti-PD-1) is superior to everolimus (mTor inhibitor) in the second-line setting after TKI therapy and was the basis of nivolumab monotherapy becoming a standard of care for second-line therapy of mRCC.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. McDermott DF, Sosman JA, Sznol M, Massard C, Gordon MS, Hamid O, et al. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J Clin Oncol. American Society of Clinical Oncology. 2016;34:833–42.

    CAS  PubMed  Google Scholar 

  61. 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. https://doi.org/10.1200/JCO.2016.72.1985.

  62. •• Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. Massachusetts Medical Society. 2018;378:1277–90. This paper demonstrated that ipilimumab/nivolumab (anti-CTLA4/anti-PD-1) is superior to sunitinib (TKI) in the first-line setting for patients with IMDC intermediate and high-risk disease and is the basis of ipilimumab/nivolumab becoming the standard of care for first-line therapy of intermediate/high-risk mRCC.

    CAS  Google Scholar 

  63. Heng DYC, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol. American Society of Clinical Oncology. 2009;27:5794–9.

    CAS  PubMed  Google Scholar 

  64. Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. American Association for Cancer Research. 2010;70:6171–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Manning EA, Ullman JGM, Leatherman JM, Asquith JM, Hansen TR, Armstrong TD, et al. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin Cancer Res. American Association for Cancer Research. 2007;13:3951–9.

    CAS  PubMed  Google Scholar 

  66. Huang Y, Yuan J, Righi E, Kamoun WS, Ancukiewicz M, Nezivar J, et al. Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy. Proc Natl Acad Sci. National Acad Sciences. 2012;109:17561–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Yasuda S, Sho M, Yamato I, Yoshiji H, Wakatsuki K, Nishiwada S, et al. Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo. Clin. Exp. Immunol. 2013;172:500–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 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. Nature Publishing Group. 2016;7:12624.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. • Atkins MB, McDermott DF, Powles T, Motzer RJ, Rini BI, Fong L. IMmotion150: a phase II trial in untreated metastatic renal cell carcinoma (mRCC) patients (pts) of atezolizumab (atezo) and bevacizumab (bev) vs and following atezo or sunitinib (sun). In: ASCO Annual Meeting; 2017. p. 1–2. This is one of a number of papers that demonstrate high response rates with the combination of TKI and anti-PD-1 or anti-PDL1 therapies. It is the basis of an ongoing phase III randomized clinical trial.

    Google Scholar 

  70. • McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. Nature Publishing Group. 2018;24:749–57. This is one of a number of papers that demonstrate high response rates with the combination of TKI and anti-PD-1 or anti-PDL1 therapies. It is the basis of an ongoing phase III randomized clinical trial.

    CAS  Google Scholar 

  71. • Chowdhury S, Mc Dermott DF, Voss MH, Hawkins RE, Aimone P, Vol M. A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC). In: ASCO Annual Meeting; 2017. p. 1–2. This is one of a number of papers that demonstrate high response rates with the combination of TKI and anti-PD-1 or anti-PDL1 therapies. However, it demonstrated too much toxicity and is not being used as the basis for phase III randomized trials.

    Google Scholar 

  72. • 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;19:405–15. This is one of a number of papers that demonstrate high response rates with the combination of TKI and anti-PD-1 or anti-PDL1 therapies. It is the basis of an ongoing phase III randomized clinical trial.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Lee C-H, Makker V, Rasco DW, Taylor MH, Stepan DE, Shumaker RC, et al. Lenvatinib + pembrolizumab in patients with renal cell carcinoma: Updated results. J Clin Oncol. 2018;36:Suppl 15. https://doi.org/10.1200/JCO.2018.36.15_suppl.4560.

  74. • Choueiri TK, Larkin J, Oya M, Thistlethwaite F, Martignoni M, Nathan P, et al. 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. 2018;19:451–60. This is one of a number of papers that demonstrate high response rates with the combination of TKI and anti-PD-1 or anti-PDL1 therapies. It is the basis of an ongoing phase III randomized clinical trial.

    CAS  PubMed  Google Scholar 

  75. Akalu YT, Rothlin CV, Ghosh S. TAM receptor tyrosine kinases as emerging targets of innate immune checkpoint blockade for cancer therapy. Immunol Rev Wiley/Blackwell (10.1111). 2017;276:165–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Charych DH, Hoch U, Langowski JL, Lee SR, Addepalli MK, Kirk PB, et al. NKTR-214, an engineered cytokine with biased IL2 receptor binding, increased tumor exposure, and marked efficacy in mouse tumor models. Clin Cancer Res. American Association for Cancer Research. 2016;22:680–90.

    CAS  PubMed  Google Scholar 

  77. 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. In: ASCO Annual Meeting; 2018. p. 1–1.

    Google Scholar 

  78. Rosenberg S. Lymphokine-activated killer cells: a new approach to immunotherapy of cancer. J Natl Cancer Inst. 1985;75:595–603.

    CAS  PubMed  Google Scholar 

  79. Topalian SL, Solomon D, Avis FP, Chang AE, Freerksen DL, Linehan WM, et al. Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study. J Clin Oncol. 1988;6:839–53.

    CAS  PubMed  Google Scholar 

  80. Kradin RL, Kurnick JT, Lazarus DS, Preffer FI, Dubinett SM, Pinto CE, et al. Tumour-infiltrating lymphocytes and interleukin-2 in treatment of advanced cancer. Lancet. 1989;1:577–80.

    CAS  PubMed  Google Scholar 

  81. Figlin RA, Thompson JA, Bukowski RM, Vogelzang NJ, Novick AC, Lange P, et al. Multicenter, randomized, phase III trial of CD8(+) tumor-infiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol. 1999;17:2521–9.

    CAS  PubMed  Google Scholar 

  82. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. Rockefeller Univ Press. 2005;202:907–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Wrzesinski C, Paulos CM, Gattinoni L, Palmer DC, Kaiser A, Yu Z, et al. Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8 T cells. J Clin Invest. American Society for. Clin Investig. 2007;117:492–501.

    CAS  Google Scholar 

  84. Wrzesinski C, Paulos CM, Kaiser A, Muranski P, Palmer DC, Gattinoni L, et al. Increased intensity lymphodepletion enhances tumor treatment efficacy of adoptively transferred tumor-specific T cells. J Immunother. 2010;33:1–7.

    PubMed  PubMed Central  Google Scholar 

  85. Baldan V, Griffiths R, Hawkins RE, Gilham DE. Efficient and reproducible generation of tumour-infiltrating lymphocytes for renal cell carcinoma. Br J Cancer. Nature Publishing Group. 2015;112:1510–8.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Yale Comprehensive Cancer Center, 333 Cedar Street, New Haven, CT, 06520, USA

    Bryden Considine & Michael E. Hurwitz

Authors
  1. Bryden Considine
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael E. Hurwitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael E. Hurwitz.

Ethics declarations

Conflict of Interest

Bryden Considine declares that he has no conflict of interest.

Michael E. Hurwitz declares the following disclosures: (1) Advisory Boards/Consulting: Nektar Therapeutics, Janssen Pharmaceuticals, CRISPR Therapeutics; (2) Research: Apexigen, Astellas, AstraZeneca, Bayer, Bristol Myer Squibb, Clovis, Corvus, Eli Lilly, Endocyte, Genentech, Genmab, Innocrin, Iovance, MedImmune, Merck, Nektar Therapeutics, Novartis, Pfizer, Progenics, Roche Laboratories, Sanofi Aventis, Seattle Genetics; and (3) Other: Gamida Cell.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Genitourinary Cancers

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Considine, B., Hurwitz, M.E. Current Status and Future Directions of Immunotherapy in Renal Cell Carcinoma. Curr Oncol Rep 21, 34 (2019). https://doi.org/10.1007/s11912-019-0779-1

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11912-019-0779-1

Keywords

Search

Navigation