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1 Pharmacotherapeutics Immunotherapy for Renal Cell Carcinoma Dong Soo Park, MD Department of Urology, Pochon Cha University College of Medicine E mail : dsparkmd@cha.ac.kr J Korean Med Assoc 2008; 51(6): Abstract Since spontaneous regression of metastatic renal cell carcinoma (mrcc) has been reported, immunotherapy for mrcc has been the therapeutic option. The goal of modulating an immune response to the tumor cell with passive and/or active immunotherapy can be achieved through the increasing technological sophistication and the understanding of the immune system. Currently, among the several available cytokines to treat mrcc, high dose interleukin 2 (IL 2) administration is the only way to obtain complete remission. However, due to the lack of prominent benefit and toxicity of high dose IL 2 therapy, cytokine based immunotherapy for the treatment of mrcc is threatened by the intriguing molecularly targeted agents, which are still under the trials. Different types of cellular (autologous tumor cell, gene modified tumor cell, dendritic cell) and non cellular therapeutic vaccines of mrcc have been applied in the clinical setting, and the success of clinical effectiveness in selected population has been reported. Future treatment approaches for mrcc or locally advanced RCC would be directed with combined therapy with immunotherapy and targeted agent. Additionally, molecularly targeted agents and vaccines modulating tumor immunology cascade will be another immunotherapeutic approach for RCC. Keywords : Carcinoma; Renal cell; Immunotherapy 569

2 Park DS Remaining tumor glands Surrounding parenchyme Fibrosis RCC A B Figure 1. Evidence of host immune response in 73 year old male renal cell carcinoma patient. (A) low power, (B) high power. 570

Immunotherapy for Renal Cell Carcinoma Ex vivo IL 4 IFN PGE 2 GM CSF mature Dendritic Cells TAA Tumor cells Tumor cell killing Immature Dendritic Cells B2 microglobulin Class I MHC TCR Tumor Antigen

3 Immunotherapy for Renal Cell Carcinoma Ex vivo IL 4 IFN PGE 2 GM CSF mature Dendritic Cells TAA Tumor cells Tumor cell killing Immature Dendritic Cells B2 microglobulin Class I MHC TCR Tumor Antigen CD3 In vivo CD8 Activated CD8+ T Cells Stem Cell Factor fit 3 ligand IL 3 TGF TNF PGE 2 GM CSF Direct interaction and stimulation of CD8+ T cell B7 CD28 Class MHC CTLA4 TCR T helper cell activation CD40 CD40 ligand CD4+ T helper cells GM CSF Cytokines IL 2 IFN IL 12 Activated CD4+ T helper cells TNF IL 10 (inhibition) CD8+ T Cells Figure 2. Tumor immunologic response scheme. Cytotoxic T lymphocytic activation 571

4 Park DS A Lymphocytic infiltration Tumor necrosis B Figure 3. Evidence of immunity related tumor of renal cell carcinoma after exposure to IL 2 therapy in 46 year old male patient. (A) low power, (B) high power. Table 1. Two major randomized trials of IL 2 therapy in advanced renal cell carcinoma Investigator Treatment comparison Response rate (%) Yang (10) High dose i.v. IL 2 21 vs. Low dose i.v. IL 2 13 vs. Low dose s.c. IL 2 10 McDermott (9) High dose i.v. IL vs. IL 2, IFN s.c

5 Immunotherapy for Renal Cell Carcinoma Table 2. Therapeutic tumor vaccines trials Vaccine type Vaccines Adjuvant Stage Investigator TC Autologous irradiated BCG I III Galligioni (21) TC Autologous cryo killed None II III Jocham (16) Modified TC Autologous irradiated B7.1 IL 2 mrcc Antonia (22) DC Allogeneic irradiated DC with None mrcc Marten (23) Autologous or Allogeneic TC DC Autologous DC with CA 9 KLH mrcc Bleumer (24) DC Allogeneic DC with autologous TC None mrcc Avigan (25) DC Autologous or Allogeneic DC with None III, mrcc Park (26) Autologous TC Peptide CAIX derived peptide Freund s adjuvant mrcc Uemura (27) TC: tumor cell, DC: Dendritic cell, CAIX: carbonic anhydrase IX, mrcc: metastatic renal cell carcinoma, BCG: bacillus Calmette Guerin, KLH: keyhole limpet hemocyanin 573

6 Park DS 11. Jenkins GD. Regression of pulmonary metastasis following nephrectomy for hypernephroma: eight year followup. J Urol 1959; 82: Yang JC, Hughes M, Kammula U, Royal R, Sherry RM, Topalian SL, Suri KB, Levy C, Allen T, Mavroukakis S, Lowy I, White DE, Rosenberg SA. Ipilimumab (anti CTL4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 2007; 30: Parmar S, Plantanias LC. Interferons: mechanisms of action and clinical applications. Curr Opin Oncol 2005; 15: Rini BI. Is sorafenib plus interferon a2b safe and effective in patients with renal cell carcinoma? Nat Clin Pract Urol 2008; 5: Costa LJ, Drabkin HA. Renal cell carcinoma: new developments in molecular biology and potential for targeted therapies. Oncologist 2007; 12: 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: Fisher RI, Rosenberg SA, Fyfe G. Long term survival update for high dose recombinant interleukin 2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6(S): S Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C, Ravaud A, Mercatello A, Peny J, Mousseau M, Philip T, Tursz T. Recombinant human interleukin 2, recombinant human interferon alpha 2a, or both in metastatic renal cell carcinoma. Groupe Francais d Immunotherapie. N Engl J Med 1998; 338: McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, Kirkwood JM, Gordon MS, Sosman JA, Ernstoff MS, Tretter CP, Urba WJ, Smith JW, Margolin KA, Mier JW, Gollob JA, Dutcher JP, Atkins MB. Randomized phase III trial of high dose interleukin 2 versus subcutaneous interleukin 2 574

7 Immunotherapy for Renal Cell Carcinoma and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005; 23: Yang JC, Sherry RM, Steinberg SM. Topalian SL, Schwartzentruber DJ, Hwu P, Seipp CA, Rogers Freezer L, Morton KE, White DE, Liewehr DJ, Merino MJ, Rosenberg SA. Randomized study of high dose and low dose interleukin 2 in patients with metastatic renal cancer. J Clin Oncol 2003; 21: Atzpodien J, Korfer A, Palmer PA, Franks CR, Poliwoda H, Kirchner H. Treatment of metastatic renal cell cancer patients with recombinant subcutaneous human interleukin 2 and interferon alpha. Ann Oncol 1990; 1: Ravaud A, Negrier S, Cany L, Merrouche Y, Le Guillow M, Blay JY, Clavel M, Gaston R, Oskam R, Philip T. Subcutaneous low dose recombinant interleukin 2 and alpha interferon in patients with metastatic renal cell carcinoma. Br J Cancer 1994; 69: Huland E, Heinzer H, Huland H, and Yung R. Overview of interleukin 2 inhalation therapy. Cancer J Sci Am 2000; 6(S): S Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A, Febbo P, Upton M, Lechpammer M, Signoretti S. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005; 11: Schwaab T, Heaney JA, Schned AR, Harris RD, Cole BF, Noelle RJ, Phillips DM, Stempkowski L, Ernstoff MS. A randomized phase II trial comparing two different sequence combinations of autologous vaccine and human recombinant of autologous vaccine and human recombinant interferon gamma and human recombinant interferon alpha2b therapy in patients with metastatic renal cell carcinoma: clinical outcome and analysis of immunological parameters. J Urol 2000; 163: Jocham D, Richter A, Hoffmann L, Iwig K, Fahlenkamp D, Zakrzewski G, Schmitt E, Dannenberg T, Lehmacher W, von Wietersheim J, Doehn C. Adjuvant autologous renal tumour cell vaccine and risk of tumour progression in patients with renal cell carcinoma after radical nephrectomy: phase III, randomised controlled trial. Lancet 2004; 363: Sallusto F, Lanzavecchia A. Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by granulocyte/macrophage colony stimulating factor plus interleukin 4 and downregulated by tumor necrosis factor alpha. J Exp Med 1994; 179: Brossart P, Wirths S, Brugger W, Kanz L. Dendritic cells in cancer vaccines. Exp Hematol 2001; 29: Schuler G, Schuler Thurner B, Steinman RM. The use of dendritic cells in cancer immunotherapy. Curr Opin Immunol 2003; 15: Holtl L, Zelle Rieser C, Gander H, Papesh C, Ramoner R, Bartsch G, Rogatsch H, Barsoum AL, Coggin JH Jr, Thurnher M. Immunotherapy of metastatic renal cell carcinoma with tumor lysate pulsed autologous dendritic cells. Clin Cancer Res 2002; 8: Galligioni E, Quaia M, Merlo A, Carbone A, Spada A, Favaro D, Santarosa M, Sacco C, Talamini R. Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and bacillus Calmette Guerin: five year results of a prospective randomized study. Cancer 1996: 77; Antonia SJ, Seigne J, Diaz J, Muro Cacho C, Extermann M, Farmelo MJ, Friberg M, Alsarraj M, Mahany JJ, Pow Sang J, Cantor A, Janssen W. Phase I trial of a B7 1 (CD80) gene modified autologous tumor cell vaccine in combination with systemic interleukin 2 in patients with metastatic renal cell carcinoma. J Urol 2002; 167: Marten A, Renoth S, Heinicke T, Albers P, Pauli A, Mey U, Caspari R, Flieger D, Hanfland P, Von Ruecker A, Eis Hubinger AM, Muller S, Schwaner I, Lohmann U, Heylmann G, Sauerbruch T, Schmidt Wolf IG. Allogeneic dendritic cells fused with tumor cells: preclinical results and outcome of a clinical phase I/II trial in patients with metastatic renal cell carcinoma. Hum Gene Ther 2003; 14: Bleumer I, Tiemessen DM, Oosterwijik Wakka JC, Voller MC, De Weijer K, Mulders PF, Oosterwijk E. Preliminary analysis of patients with progressive renal cell carcinoma vaccinated with CA9 peptide pulsed mature dendritic cells. J Immunother 2007; 30: Avigan DE, Vasir B, George DJ, Oh WK, Atikins MB, Mc- Dermott DF, Kantoff PW, Figlin RA, Vasconcelles MJ, Xu Y, Kufe D, Bukowski RM. Phase I/II study of vaccination with electrofused Allogeneic dendritic cells/autologous tumor derived cells in patients with stage IV renal cell carcinoma. J Immunother 2007; 30: Park DS, Cho HJ, Han MY, Lee SJ, Oh DY, Hwang SK. Development and application of mixed vaccines in renal cell carcinoma: combining autologous tumor cells with dendritic cells derived from autologous or allogeneic origin. Korean J Urol 2007; 48: Uemura H, Fujimoto K, Tanaka M, Yoshikawa M, Hirao Y, Uejima S, Yoshikawa K, Itoh K. A phase I trial of vaccination of CA9 derived peptides for HLA A24 positive patients with cytokine refractory metastatic renal cell carcinoma. Clin Cancer Res 2006; 12:

8 Park DS Peer Reviewers Commentary 576

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R