Immunologic Therapy of Renal Cell Carcinoma

Oncology & Hematology Review, 2014;10(1):54–60

Abstract:

Interleukin-2 (IL-2) has been the mainstay of immunotherapy of metastatic renal cell carcinoma (mRCC) therapy for over 20 years. Although IL-2 treatment is limited to fit patients, a select group of these patients have derived substantial, durable benefit from it, for some translating into cures with no ongoing therapy or chronic toxicity. While targeted therapies are applicable to most patients, improvements of median survival have been measured in months. Immunotherapy, encompassing not only IL-2 but also newer checkpoint and vaccine approaches, therefore still has an important role for many as a main choice in RCC treatment. Enhanced patient selection techniques have evolved over time, and the overall response rate to high-dose (HD) IL-2 has improved among those selected patients. An increased understanding of immunotherapy has led to other novel approaches. These include checkpoint inhibitors mediating changes of T-cell behavior acting at the lymphocyte protein receptor programmed death-1 (PD-1), such as nivolumab, and vaccine immunotherapies, including peptide and dendritic cell vaccines in pivotal trials, and coordinated use of radiation therapy with IL-2, encouraging in early phase testing. Such approaches have the potential to expand the immune approach to achieve outcomes with better overall survival for many patients with mRCC.

Keywords: Interleukin-2, immunotherapy, programmed death-1, renal cell carcinoma, vaccines
Disclosure: Neeraj Agarwal, MD, has no conflicts of interests to declare. Mayer Fishman, MD, PhD, has participated in clinical trials related to immunotherapy of kidney cancer for BMS (nivolumab), Prometheus (IL-2), and Argos (ADAPT study), holds Data and Safety Monitoring Board (DSMB) membership: Immatics (IMA=901 study), and is on the speakers bureau for Prometheus (IL-2).
Acknowledgments: Editorial assistance was provided by Katrina Mountfort, PhD, at Touch Medical Media.
Received: April 09, 2014 Accepted April 22, 2014 Citation Oncology & Hematology Review, 2014;10(1):54–60
Correspondence: Mayer Fishman, MD, PhD, Department of Genitourinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, US. E: Mayer.Fishman@moffitt.org
Support: The publication of this article was supported by Prometheus. The views and opinions expressed are those of the authors and not necessarily those of Prometheus.

Renal cell carcinoma (RCC) represents 2–3 % of all cancers, and is responsible for 13,570 annual US deaths.1 Surgical resection of localized RCC can be curative, but disease recurrence eventually occurs in many patients, at rates that can be directly related to features including tumor size or grade. In addition, many patients are diagnosed with either locally advanced and unresectable or metastatic disease at the time of initial presentation. Subtypes of tumors arising in the kidney are classified according to the World Health Organization (WHO) classification system.2 The most common subtype is clear cell RCC, which accounts for over 80 % of malignant, nonurothelial kidney tumors.3 The molecular profile of this clear cell RCC is heterogeneous.4 Recent studies suggest the presence of two major molecular subtypes, which may explain the variable clinical course and response to therapy among patients with clear cell RCC.5 However, even within a single patient, substantial differences of gene expression have been observed within the primary tumor, or between the metastases and the primary.6,7 Heterogeneity of patient clinical features is acknowledged to be a dominant factor of the incident RCC population, with impacts on overall survival (OS) from the disease features greater than many treatment choices. Ultimately, however, around 70 % of RCC patients develop metastases, and until the introduction of targeted therapies, the 5-year OS of metastatic RCC (mRCC) was around 5–10 %.8

Over the last decade, an increased understanding of tumor biology helped drive development of targeted therapies for mRCC.9 These easily administered oral and intravenous therapies, targeted against intracellular signaling pathways such as those activated by vascular endothelial growth factor (VEGF) and the mammalian target of rapamycin (mTOR) pathway, have revolutionized the way mRCC is treated. However, despite the advent of these newer agents, and a significant improvement of the median OS from 13 months in 200210 to about 28 months in 2012 to 2013,11,12 almost all patients eventually experience disease progression, and die of their disease. The management of mRCC therefore remains a therapeutic challenge.

Durability versus Chronic Treatment
Long before the clinical use of targeted therapies, immunotherapy was extensively studied as a therapeutic approach to mRCC. In nonrandomized clinical trials, high-dose interleukin-2 (HD IL-2) demonstrated durable complete responses, achieving recurrence-free, treatment-free survival exceeding 10 years in around 8 % of patients with advanced or mRCC who were treated. Despite the established benefit of HD IL-2, and that patients progressing through IL-2 generally remain eligible for subsequent targeted therapies, the population treated with immune therapy with IL-2 remains limited. The bases for the limited utilization of HD IL-2 include toxicity, cost, hospital time, and the lack of benefit in the majority of patients. Regarding toxicity, short-term side effects with IL-2 can be contrasted with more chronic but less severe side effects associated with open-ended treatments on targeted therapies. Regarding drug costs, the overall cumulative cost with targeted therapy can be similar or more than treatment with HD IL-2, particularly for the patient with disease features that predict for multiyear survival. Of course, the duration of treatment used, the patient selection, and the fact that IL-2 is followed by targeted therapy in most cases makes comparisons difficult.

Almost all mRCC patients on targeted therapies eventually experience disease progression, with long-term remissions represented only in isolated cases, and not in the larger phase III studies. Increased understanding of the limitations of the targeted therapies over the last few years and recent advances in the cancer immunotherapies in general has led to a resurgence of interest in the investigation of immunotherapy as a major treatment strategy, with HD IL-2 and other approaches such as checkpoint inhibition and vaccination being investigated in the treatment of mRCC.13,14 This article will review current research investigating immunologic therapy in mRCC with emphasis on the approved therapy with IL-2.

Immunotherapy as a Therapeutic Approach to Metastatic Renal Cell Carcinoma
For the most part, RCC has not shown a significant response to traditional cytotoxic therapy, and this helped to drive interest in other approaches; immunotherapy is known to result in rare but dramatic responses in some RCC. The observation of mRCC apparently showing spontaneous regression in placebo groups of clinical trials is presumably a result of the isolated events of the host immune response waxing stronger over time.15

The antigenic features of certain cancers that make them responsive to immunotherapy are poorly understood and are the subject of considerable research. Melanoma is a particularly immunogenic cancer, for which many tumor antigens are well characterized. An enhanced understanding of the differences in antigenic features between mRCC and melanoma would accelerate the development of immunotherapies for mRCC. One potential difference lies in tumor-associated antigens (TAAs) that trigger the cell-mediated immune response. Tumor-infiltrating lymphocytes (TILs) are found in high numbers in RCC tumors; however, they are not directed at TAAs and have not demonstrated clinical efficacy in mRCC, a contrast with the melanoma experiences. Treatment with CD8+ TILs did not improve response rate or survival in RCC patients treated with lowdose IL-2 after nephrectomy.16 Reasons for lower frequency of clinically useful immune response of the treatment may include a lack of TAA or of more tumor-induced local or systemic immunosuppression. Although preclinical evaluations suggested that adoptive cell transfer (ACT) could be a promising approach in mRCC patients,17 a recent meta-analysis identified five hindrances to the lack of success of such approaches, including high degree of personalization, unsuitable response assessment criteria, inadequate identification of TAAs, lack of effective combination treatments, and insufficient attention paid to the quality of ACT products.18

Removal of the primary tumor by surgical resection may cause a change to the immunologic environment. Since the primary tumor bulk is immunosuppressive, removal of the tumor has a theoretically favorable immunotherapeutic effect.19 Clinical studies have demonstrated that early nephrectomy in patients with good performance status confers a survival advantage.20,21 However, it is important to consider individual risk assessments in any decisions around nephrectomy.22–24 There are also opportunities in the context of clinical trials to integrate nephrectomy with subsequent immunotherapy, including IL-2, but also with others such as dendritic cell (DC)-based vaccines based on primary tumor tissue.25

Cytokine Therapy
Interferon Alpha
The greatest body of clinical experience with immunotherapy in mRCC is in the use of cytokine therapy with interferon alpha (IFN-a) or HD IL-2 (Proleukin®), which are the only immunotherapies recommended in treatment guidelines (see Figure 1)26 and have been a standard of care for over 20 years. However, IFN-a has only a modest impact on survival in selected patients (nonbulky pulmonary and/or soft tissue metastases with performance status ratings of 0–1, according to the Eastern Cooperative Oncology Group [ECOG] rating scale, and no weight loss). In clinical trials, IFN-a proved inferior to HD IL-2,27 to sunitinib,28 and to the combination of bevacizumab + interferon.29,30

Interleukin-2
IL-2 (aldesleukin) is a recombinant protein that has numerous antitumor actions including enhancing cytotoxic immune cell functions; limiting tumor escape mechanisms such as defective tumor cell expression of class I or II molecules or expansion of regulatory T cells (Tregs); and indirect effects on the tumor microenvironment.31 IL-2 received US Food and Drug Administration (FDA) approval in 1992 for the treatment of mRCC, based on the results of seven phase II clinical trials.32 A subsequent randomized clinical trial (n=156) demonstrated that outcomes could be improved with the higher dosage (HD IL-2).33 A phase III clinical trial (n=192) found superior survival with intravenous HD IL-2 compared with subcutaneous IL-2 plus IFN-a (IL-2/IFN-a). The response rate was 23.2 % for HD IL-2 versus 9.9 % for IL-2/IFN-a (p=0.018). The median response durations were 24 and 15 months, respectively. The median survivals were 17.5 and 13 months (p=0.24).27 A 20-year analysis of patients treated at the National Cancer Institute from 1986 to 2006 (n=259) showed an overall response rate of 20 % with complete response in 9 % of patients with mRCC after treatment with HD IL-2. Median survivals of the partial responders and nonresponders were 39.1 and 15.1 months, respectively. The median survival of the complete responders had not yet been reached after several years, at the time of last follow-up.34

References:
  1. Siegel R, Naishadham D, Jemal A, Cancer statistics, 2012, CA Cancer J Clin, 2012;62:10–29.
  2. Eble J, Sauter G, Epstein J, Sesterhenn I (eds), World Health Organization Classification of Tumours: Pathology and Genetics of Tumors of the Urinary System and Male Genital Organs. IARC Press. Lyon, 2004. Available at: http://www.iarc.fr/en/publications/ pdfs-online/pat-gen/bb7/bb7-cover.pdf (accessed 22 April 2014).
  3. Cheville JC, Lohse CM, Zincke H, et al., Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma, Am J Surg Pathol, 2003;27:612–24.
  4. Takahashi M, Teh BT, Kanayama HO, Elucidation of the molecular signatures of renal cell carcinoma by gene expression profiling, J Med Invest, 2006;53:9–19.
  5. Haake S, Brannon A, Hacker K, et al., Use of meta-analysis of clear cell renal cell carcinoma gene expression to define a variant subgroup and identify gender influences on tumor biology, J Clin Oncol, 2013;30(Suppl. 5):abstract 412.
  6. Gerlinger M, Horswell S, Larkin J, et al., Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing, Nat Genet, 2014;46:225–33.
  7. Gerlinger M, Rowan AJ, Horswell S, et al., Intratumor heterogeneity and branched evolution revealed by multiregion sequencing, N Engl J Med, 2012;366:883–92.
  8. Drucker BJ, Renal cell carcinoma: current status and future prospects, Cancer Treat Rev, 2005;31:536–45.
  9. Sun M, Lughezzani G, Perrotte P, et al., Treatment of metastatic renal cell carcinoma, Nat Rev Urol, 2010;7:327–38.
  10. Motzer R, Bono P, Hudes GR, et al., A phase III comparative study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) versus everolimus in patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) previously treated with antiangiogenic therapy, J Clin Oncol, 2013;(Suppl. 31):abstract TPS4592.
  11. Motzer RJ, Hutson TE, Cella D, et al., Pazopanib versus sunitinib in metastatic renal-cell carcinoma, N Engl J Med, 2013;369:722–31.
  12. Harshman LC, Xie W, Bjarnason GA, et al., Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a population-based study, Lancet Oncol, 2012;13:927–35.
  13. Biswas S, Eisen T, Immunotherapeutic strategies in kidney cancer—when TKIs are not enough, Nat Rev Clin Oncol, 2009;6:478–87.
  14. Escudier B, Emerging immunotherapies for renal cell carcinoma, Ann Oncol, 2012;23(Suppl. 8):viii35–40.
  15. 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;86:613–8.
  16. Figlin RA, Thompson JA, Bukowski RM, 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.
  17. Markel G, Cohen-Sinai T, Besser MJ, et al., Preclinical evaluation of adoptive cell therapy for patients with metastatic renal cell carcinoma, Anticancer Res, 2009;29:145–54.
  18. Tang X, Liu T, Zang X, et al., Adoptive cellular immunotherapy in metastatic renal cell carcinoma: a systematic review and meta-analysis, PLoS One, 2013;8:e62847.
  19. Fishman M, Seigne J, Immunotherapy of metastatic renal cell cancer, Cancer Control, 2002;9:293–304.
  20. Flanigan RC, Salmon SE, Blumenstein BA, 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.
  21. Mickisch GH, Garin A, van Poppel H, et al., 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.
  22. Spiess PE, Fishman MN, Cytoreductive nephrectomy vs medical therapy as initial treatment: a rational approach to the sequence question in metastatic renal cell carcinoma, Cancer Control, 2010;17:269–78.
  23. Aizer AA, Urun Y, McKay RR, et al., Cytoreductive nephrectomy in patients with metastatic non-clear cell renal cell carcinoma, BJU Int, 2014;113(5b):E67–74.
  24. Choueiri TK, Xie W, Kollmannsberger C, et al., The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy, J Urol, 2011;185:60–6.
  25. Draube A, Klein-Gonzalez N, Mattheus S, et al., Dendritic cell based tumor vaccination in prostate and renal cell cancer: a systematic review and meta-analysis, PLoS One, 2011;6:e18801.
  26. National Comprehensive Cancer Network, NCCN Guidelines Version 2.2014, Kidney Cancer. Available at: http://www.nccn. org/professionals/physician_gls/pdf/kidney.pdf (accessed 19 March 2014).
  27. 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;23:133–41.
  28. Motzer RJ, Hutson TE, Tomczak P, et al., Sunitinib versus interferon alfa in metastatic renal-cell carcinoma, N Engl J Med, 2007;356:115–24.
  29. 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;26:5422–8.
  30. 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;370:2103–11.
  31. Romo de Vivar Chavez A, de Vera ME, Liang X, et al., The biology of interleukin-2 efficacy in the treatment of patients with renal cell carcinoma, Med Oncol, 2009;26(Suppl. 1):3–12.
  32. Fyfe G, Fisher RI, Rosenberg SA, et al., 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.
  33. 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;21:3127–32.
  34. Klapper JA, Downey SG, Smith FO, 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;113:293–301.
  35. Belldegrun AS, Klatte T, Shuch B, et al., Cancer-specific survival outcomes among patients treated during the cytokine era of kidney cancer (1989–2005): a benchmark for emerging targeted cancer therapies, Cancer, 2008;113:2457–63.
  36. Birkhauser FD, Pantuck AJ, Rampersaud EN, et al., Salvagetargeted kidney cancer therapy in patients progressing on high-dose interleukin-2 immunotherapy: the UCLA experience, Cancer J, 2013;19:189–96.
  37. Agarwal N, Clinical benefit (CB) of high-dose interleukin-2 (HD IL-2) in clear cell (cc) metastatic renal cell carcinoma (mRCC), J Clin Oncol, 2014;32(Suppl. 4):abstact 461.
  38. Motzer RJ, Michaelson MD, Redman BG, et al., Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma, J Clin Oncol, 2006;24:16–24.
  39. Sternberg CN, Davis ID, Mardiak J, et al., Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial, J Clin Oncol, 2010;28:1061–8.
  40. Rini BI, Melichar B, Ueda T, et al., Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial, Lancet Oncol, 2013;14:1233–42.
  41. Hutson TE, Lesovoy V, Al-Shukri S, et al., Axitinib versus sorafenib as first-line therapy in patients with metastatic renalcell carcinoma: a randomised open-label phase 3 trial, Lancet Oncol, 2013;14:1287–94.
  42. Rixe O, Bukowski RM, Michaelson MD, et al., Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study, Lancet Oncol, 2007;8:975–84.
  43. Motzer RJ, Escudier B, Tomczak P, et al., Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial, Lancet Oncol, 2013;14:552–62.
  44. Summary of Important Safety Information for Proleukin® (aldesleukin) for injection for intravenous infusion. Available at: http://www.proleukin.com (accessed 18 December 2013).
  45. Dutcher J, Atkins MB, Margolin K, et al., Kidney cancer: the Cytokine Working Group experience (1986-2001): part II. Management of IL-2 toxicity and studies with other cytokines, Med Oncol, 2001;18:209–19.
  46. Kammula US, White DE, Rosenberg SA, Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer, Cancer, 1998;83:797–805.
  47. Shablak A, Sikand K, Shanks JH, et al., High-dose interleukin-2 can produce a high rate of response and durable remissions in appropriately selected patients with metastatic renal cancer, J Immunother, 2011;34:107–12.
  48. Upton MP, Parker RA, Youmans A, et al., Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy, J Immunother, 2005;28:488–95.
  49. Hawkins R, Galvis V, Shablak A, Selecting patients for high-dose interleukin-2 on the basis of tumour histology, Ann Oncol, 2012;23(Suppl. 9):abstract 808P.
  50. Casamassima A, Picciariello M, Quaranta M, et al., C-reactive protein: a biomarker of survival in patients with metastatic renal cell carcinoma treated with subcutaneous interleukin-2 based immunotherapy, J Urol, 2005;173:52–5.
  51. McDermott D, Ghebremichael M, Signoretti S, et al., The high dose aldesleukin (HD-IL2) “Select” trial in patients with metastatic renal cell carcinoma, J Clin Oncol, 2010;28(Suppl. 15):abstract 4514.
  52. 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:E7–9.
  53. Leibovich BC, Han KR, Bui MH, et al., Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials, Cancer, 2003;98:2566–75.
  54. 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;11:3714–21.
  55. Choueiri TK, Figueroa DJ, Liu Y, et al., Correlation of PDL1 tumor expression and treatment outcomes in patients with renal cell carcinoma (RCC) receiving tyrosine kinase inhibitors: COMPARZ study analysis, J Clin Oncol, 2014;32:(Suppl. 4), abstract 416.
  56. Stenehjem DD, Parikh K, Batten JA, et al., Association of clinical parameters and overall survival (OS) in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with high-dose interleukin-2 (HD IL-2), J Clin Oncol, 2014;(Suppl. 4); abstract 476.
  57. Chen ML, Pittet MJ, Gorelik L, et al., Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo, Proc Natl Acad Sci U S A, 2005;102:419–24.
  58. Curiel TJ, Tregs and rethinking cancer immunotherapy, J Clin Invest, 2007;117:1167–74.
  59. Mougiakakos D, Choudhury A, Lladser A, et al., Regulatory T cells in cancer, Adv Cancer Res, 2010;107:57–117.
  60. Sim GC, Martin-Orozco N, Jin L, et al., IL-2 therapy promotes suppressive ICOS+ Treg expansion in melanoma patients, J Clin Invest, 2014;124:99–110.
  61. Acquavella N, Kluger H, Rhee J, et al., Toxicity and activity of a twice daily high-dose bolus interleukin 2 regimen in patients with metastatic melanoma and metastatic renal cell cancer, J Immunother, 2008;31:569–76.
  62. Coventry BJ, Ashdown ML, The 20th anniversary of interleukin-2 therapy: bimodal role explaining longstanding random induction of complete clinical responses, Cancer Manag Res, 2012;4:215–21.
  63. Finkelstein SE, Carey T, Fricke I, et al., Changes in dendritic cell phenotype after a new high-dose weekly schedule of interleukin-2 therapy for kidney cancer and melanoma, J Immunother, 2010;33:817–27.
  64. McDermott DF, Atkins MB, Application of IL-2 and other cytokines in renal cancer, Expert Opin Biol Ther, 2004;4:455–68.
  65. Bhatia S, Curti B, Ernstoff MS, et al., Recombinant interleukin-21 plus sorafenib for metastatic renal cell carcinoma: a phase 1/2 study, J Immunother Cancer, 2014;2:2.
  66. A phase I study of intravenous recombinant human il-15 in adults with refractory metastatic malignant melanoma and metastatic renal cell cancer. Available at: http://clinicaltrials. gov/show/NCT01021059 (accessed 20 February 2014).
  67. Dandamudi UB, Ghebremichael M, Sosman JA, et al., A phase II study of bevacizumab and high-dose interleukin-2 in patients with metastatic renal cell carcinoma: a Cytokine Working Group (CWG) study, J Immunother, 2013;36:490–5.
  68. Procopio G, Verzoni E, Bracarda S, et al., Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): final results of the ROSORC trial, Ann Oncol, 2013;24:2967–71.
  69. Maroto JP, del Muro XG, Mellado B, et al., Phase II trial of sequential subcutaneous interleukin-2 plus interferon alpha followed by sorafenib in renal cell carcinoma (RCC), Clin Transl Oncol, 2013;15:698–704.
  70. Aitchison M, Bray CA, Van Poppel H, et al., Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: Results of a Phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/ National Cancer Research Institute trial, Eur J Cancer, 2014;50:70–7.
  71. Study of Hydroxychloroquine and Aldesleukin in Renal Cell Carcinoma Patients (RCC). Available at: http://clinicaltrials.gov/ show/NCT01550367 (accessed 16 December 2013).
  72. Genistein and interleukin-2 in treating patients with metastatic melanoma or kidney cancer. http://clinicaltrials.gov/ct2/show/ NCT00276835?term=interleukin+renal+cell+carcinoma&rank=8 (accessed 16 December 2013).
  73. Seung SK, Curti BD, Crittenden M, et al., Phase 1 study of stereotactic body radiotherapy and interleukin-2--tumor and immunological responses, Sci Transl Med, 2012;4:137ra74.
  74. Brignone C, Escudier B, Grygar C, et al., A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma, Clin Cancer Res, 2009;15:6225–31.
  75. Bedke J, Stenzl A, IMA901: a peptide vaccine in renal cell carcinoma, Expert Opin Investig Drugs, 2013;22:1329–36.
  76. Rini B, Eisen T, Stenzl A, et al., IMA901 Multipeptide Vaccine Randomized International Phase III Trial (IMPRINT): A randomized, controlled study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/ metastatic RCC, J Clin Oncol, 2011;29(Suppl.):abstr TPS183.
  77. Amin A, Dudek A, Logan T, et al., Prolonged survival with personalized immunotherapy (AGS-003) in combination with sunitinib in unfavorable risk metastatic RCC (mRCC), J Clin Oncol, 2013;31(Suppl. 6; abstr 357).
  78. Phase 3 Trial of Autologous Dendritic Cell Immunotherapy (AGS-003) Plus Standard Treatment of Advanced Renal Cell Carcinoma (RCC) (ADAPT). Available at: http://clinicaltrials.gov/ show/NCT01582672 (accessed 24 February 2014).
  79. Aitchison M, Bray CA, Van Poppel H, et al., Adjuvant 5-flurouracil, alpha-interferon and interleukin-2 versus observation in patients at high risk of recurrence after nephrectomy for renal cell carcinoma: results of a phase III randomised European Organisation for Research and Treatment of Cancer (Genito-Urinary Cancers Group)/ National Cancer Research Institute trial, Eur J Cancer, 2014;50:70–7.
  80. Amaravadi RK, Lippincott-Schwartz J, Yin XM, et al., Principles and current strategies for targeting autophagy for cancer treatment, Clin Cancer Res, 2011;17:654–66.
  81. Majid S, Dar AA, Ahmad AE, et al., BTG3 tumor suppressor gene promoter demethylation, histone modification and cell cycle arrest by genistein in renal cancer, Carcinogenesis, 2009;30:662–70.
  82. Keir ME, Butte MJ, Freeman GJ, et al., PD-1 and its ligands in tolerance and immunity, Annu Rev Immunol, 2008;26:677–704.
  83. Drake CG, Lipson EJ, Brahmer JR, Breathing new life into immunotherapy: review of melanoma, lung and kidney cancer, Nat Rev Clin Oncol, 2014;11:24–37.
  84. 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;13:1757–61.
  85. 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;366:2443–54.
  86. 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;366:2455–65.
  87. McDermott D, Drake C, Sznol M, et al., Clinical activity and safety of anti-programmed death-1 (PD-1) (BMS-936558/MDX- 1106/ONO538) in patients with previously treated metastatic renal cell carcinoma: an updated analysis, J Clin Oncol, 2013;31(Suppl. 6):abstract 351.
  88. Available at: http://clinicaltrials.gov/show/NCT01358721, Phase I Biomarker Study (BMS-936558) (accessed 20 February 2014).
  89. Amin A, Ernstoff MS, Infante JR, et al., A phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC), J Clin Oncol, 2013;31(Suppl; abstr TPS4593).
  90. Brayer J, Fishman M, Regression of metastatic clear cell kidney cancer with interleukin-2 treatment following nivolumab (anti- PD-1) treatment, J Immunother, 2014;37:187–91.
  91. Atchison E, Eklund J, Martone B, et al., A pilot study of denileukin diftitox (DD) in combination with high-dose interleukin-2 (IL-2) for patients with metastatic renal cell carcinoma (RCC), J Immunother, 2010;33:716–22.
  92. 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;30:825–30.
  93. Maker AV, Phan GQ, Attia P, et al., Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyteassociated antigen 4 blockade and interleukin 2: a phase I/II study, Ann Surg Oncol, 2005;12:1005–16.
  94. 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;117:758–67.
  95. Casati C, Camisaschi C, Rini F, et al., Soluble human LAG-3 molecule amplifies the in vitro generation of type 1 tumorspecific immunity, Cancer Res, 2006;66:4450–60.
  96. Hawkins R, Gore ME, Shparyk Y, et al., A randomized phase II/III study of naptumomab estafenatox plus IFN-a versus IFN-a in advanced renal cell carcinoma, J Clin Oncol, 2013;31:(Suppl.); abstr. 3073.
  97. Oudard S, Rixe O, Beuselinck B, et al., A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal clear-cell carcinoma: clinical and immunological findings, Cancer Immunol Immunother, 2011;60:261–71.
  98. Walter S, Weinschenk T, Stenzl A, et al., Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival, Nat Med, 2012;18:1254–61.
  99. Walter S, Weinschenk T, Reinhardt C, et al., Single-dose cyclophosphamide synergizes with immune responses to the renal cell cancer vaccine IMA901, Oncoimmunology, 2013;2:e22246.
  100. Available at: http://clinicaltrials.gov/show/NCT01265901, IMA901 in Patients Receiving Sunitinib for Advanced/ Metastatic Renal Cell Carcinoma (accessed 20 February 2014).
  101. Kantoff PW, Higano CS, Shore ND, et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer, N Engl J Med, 2010;363:411–22.
  102. Wierecky J, Muller MR, Wirths S, et al., Immunologic and clinical responses after vaccinations with peptide-pulsed dendritic cells in metastatic renal cancer patients, Cancer Res, 2006;66:5910–8.
  103. Schwaab T, Schwarzer A, Wolf B, et al., Clinical and immunologic effects of intranodal autologous tumor lysatedendritic cell vaccine with Aldesleukin (Interleukin 2) and IFN-a2a therapy in metastatic renal cell carcinoma patients, Clin Cancer Res, 2009;15:4986–92.
  104. Baek S, Kim CS, Kim SB, et al., Combination therapy of renal cell carcinoma or breast cancer patients with dendritic cell vaccine and IL-2: results from a phase I/II trial, J Transl Med, 2011;9:178.
  105. Fishman M, Hunter TB, Soliman H, et al., Phase II trial of B7-1 (CD-86) transduced, cultured autologous tumor cell vaccine plus subcutaneous interleukin-2 for treatment of stage IV renal cell carcinoma, J Immunother, 2008;31:72–80.
  106. Nivolumab (BMS-936558; MDX-1106) in combination with sunitinib, pazopanib, or ipilimumab in subjects with metastatic renal cell carcinoma (RCC) (CheckMate 016). Available at: http:// clinicaltrials.gov/show/NCT01472081 (accessed 22 April 2014).
  107. Chakraborty M, Abrams SI, Camphausen K, et al., Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy, J Immunol, 2003;170:6338–47.
  108. Chakraborty M, Abrams SI, Coleman CN, et al., External beam radiation of tumors alters phenotype of tumor cells to render them susceptible to vaccine-mediated T-cell killing, Cancer Res, 2004;64:4328–37.
  109. Apetoh L, Ghiringhelli F, Tesniere A, et al., Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy, Nat Med, 2007;13:1050–9.
  110. High Dose IL-2 and stereotactic ablative body radiation therapy for metastatic renal cancer. Available at: http://clinicaltrials. gov/ct2/show/NCT01896271?term=radiation+renal+cell+carcin oma&recr=Open&rank=6 (accessed 12 March 2014).
  111. Radiotherapy as an immunological booster in patients with metastatic melanoma or renal cell carcinoma treated with high-dose interleukin-2 (IL2HD). Available at: http://clinicaltrials. gov/ct2/show/NCT01884961?term=radiation+renal+cell+carcin oma&recr=Open&rank=3 (accessed 12 March 2014).
Keywords: Interleukin-2, immunotherapy, programmed death-1, renal cell carcinoma, vaccines