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): 569-576 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
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 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
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 2 23.2 vs. IL 2, IFN s.c. 9.9 572
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
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Park DS Peer Reviewers Commentary 576