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FRONTIERS IN NEPHROLOGY |
Department of Medicine, Division of Hematology/Oncology, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
Correspondence to Dr. Jeffrey A. Sosman, Department of Medicine, Division of Hematology/Oncology, Vanderbilt University School of Medicine, Vanderbilt-Ingram Cancer Center, 777 Preston Research Building, Nashville, TN 37232. Phone: 615-322-4967; Fax: 615-343-7602;
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Abstract |
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 Top Abstract IntroductionSystemic Therapy of RCCReferences |
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and high-dose IL-2 seemed to have positive effects on patient outcomes. IFN has prolonged the lives of patients by a few months, and high-dose IL-2 is capable of inducing very prolonged remissions (>5 yr) for a small number of patients. Nephrectomy in the presence of metastatic disease has been established as an effective procedure for select patients, providing palliation and prolonging survival. Finally, enthusiasm has focused on the use of nonmyeloablative allogeneic stem cell transplantation and donor leukocyte infusion for the induction of graft versus tumor effects. Early results are both provocative and promising. A number of agents that target the critical gene products downstream from pVHL and hypoxia-inducible factor-1, such as vascular endothelial growth factor, PDGF, EGF receptor, and TGF-, have recently become available. The new agents are capable of inhibiting specific cellular targets, and the biologic characteristics of clear cell carcinoma of the kidney support their application. If the correct targets are carefully selected for inhibition in tumors in which the targets are present (clear cell histologic features and loss of VHL expression), then results should resemble those others have observed with targeted therapy, such as the use of STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech, South San Francisco, CA) for treatment of breast cancer. E-mail: jeff.sosman@vanderbilt.edu |
Introduction |
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TopAbstractIntroductionSystemic Therapy of RCCReferences |
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Systemic Therapy of RCC |
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TopAbstractIntroductionSystemic Therapy of RCCReferences |
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Cytokine-Based Therapy
In part because of the poor results obtained with chemotherapy and the immune phenomena (spontaneous remissions and responses to nonspecific immune-stimulating agents) associated with RCC, investigators have examined cytokine-based therapies for treatment of renal cancer. Initially, in the 1970s and 1980s, IFN was studied for the treatment of advanced RCC (12). In the late 1980s and 1990s, IL-2 therapy played a significant role in the treatment of RCC (13,18). To summarize the effects of IFN on RCC, phase III studies have suggested that IFN- may have modest effects on survival rates among patients with advanced renal cancer (15,16). For example, a phase III trial comparing IFN-2a plus vinblastine and vinblastine alone reported a median survival time of 67.6 wk for patients who received IFN- plus vinblastine, compared with 37.8 wk for patients who received vinblastine alone (P = 0.0049) (15). In another trial, which randomized patients with advanced disease to receive either IFN- or Megace (Bristol-Myers Squibb, New York, NY), there was a 28% reduction in the risk of death for the IFN- group (P = 0.017) and an improvement in the median survival time of 2.5 mo (16). Other IFN, such as IFN-
, have been inactive (17). Combination of IFN- with other agents (cytokines or chemotherapeutic drugs) did not improve the effects of the drug.
Clinical investigations of the use of IL-2 to treat RCC began in the middle 1980s (18). The initial studies were performed with high-dose bolus IL-2 and lymphokine-activated killer cells, on the basis of results from animal studies (18). Dramatic durable responses were reported for a subset of patients. Subsequent clinical studies demonstrated that high-dose bolus IL-2 possesses antitumor activity that is essentially equivalent to that of the combination of IL-2 and lymphokine-activated killer cells. In 1992, high-dose bolus IL-2 received United States Food and Drug Administration approval for use in metastatic RCC, on the basis of data for 255 patients treated in seven clinical trials at 21 institutions. In those studies, recombinant IL-2 (600,000 to 720,000 IU/kg, Proleukin; Chiron Corp., Emeryville, CA) was administered by 15-min intravenous infusion every 8 h on days 1 to 5 and days 15 to 19 (maximum of 28 doses). Treatment was repeated at approximately 12-wk intervals for responding patients, for a maximum of three cycles. Because of considerable toxicity (hypotension, capillary leakage, and central nervous system toxicity) associated with this regimen, treatment needed to be administered in a setting providing intensive care unit-level care and was restricted to carefully selected patients with excellent organ function, who were treated at experienced treatment centers. The Food and Drug Administration was presented with objective responses for 36 of the 255 patients (response rate, 14%). There were 12 complete responses (5%) and 24 partial responses (9%). At that time, the median duration of response was 23.2 mo for all responders (partial responders, 18.8 mo; complete responders, median not reached) (13). The quality and durability of the responses prompted Food and Drug Administration approval, despite the relatively low response rate and the high level of toxicity. Follow-up data for those patients were accumulated through late 1998 (median follow-up period, 8 yr). The clinical results seemed to steadily improve with time. Seventeen patients (7%) were classified as complete responders and 20 (8%) as partial responders. The survival time for the group as a whole was 16.3 mo, with 10 to 15% of patients being estimated to remain alive 5 to 10 yr after treatment with high-dose IL-2. The median response duration for all objective responders was 54 mo (range, 3 to >131 mo). The median response duration for partial responders was 20 mo; that for complete responders had not been reached but was at least 80 mo at the time of that analysis. Eleven patients underwent resection of residual disease either while still responding or after limited-site progression, and nine remained progression-free for a minimum of 65 mo. Therefore, a large percentage of responding patients, particularly those who remained free from progression for >2 yr and those who underwent resection to disease-free status after responding to high-dose IL-2, seemed unlikely to exhibit progression and might actually have been "cured." A large phase III trial comparing high-dose IL-2 with outpatient, subcutaneously administered IL-2 and IFN-2b enrolled 193 patients, of whom 187 were able to be evaluated with respect to responses (19). Tumor responses were observed for 25 of 97 patients (26%) who received high-dose IL-2, compared with 10 of 90 patients (11%) who received low-dose IL-2 and IFN (P = 0.01). High-dose IL-2 produced eight complete responses and nine patients remained progression-free at 3 yr, compared with three complete responses and two patients remaining progression-free at 3 yr with low-dose IL-2 and IFN. These data again support the preferential use of high-dose IL-2 for patients who have access to such treatments and are considered able to tolerate the therapy.
More recently, several interesting observations have been made concerning the histologic features and phenotype of renal cancers that respond to IL-2 and the pVHL-HIF pathway. It seems that major responses have been observed predominantly among patients with clear cell carcinoma and not other histologic types (20). In addition, high rates of expression (>85%) of carbonic anhydrase IX (CAIX), a gene product regulated by HIF, are associated with better outcomes and improved response rates with high-dose IL-2 (21). The IL-2 results correlating clinical responses with CAIX expression are very preliminary.
Nonmyeloablative Allogeneic Transplantation
A more purely immunologic approach to the treatment of advanced RCC, i.e., nonmyeloablative allogeneic stem cell transplantation (with donor leukocyte infusions), has gained favor in the research community (14). Such treatment is of great interest, in part because of the definite role that allogeneic immune cells play in the antitumor effects. However, results with nonmyeloablative allogeneic stem cell transplantation are still quite preliminary and the treatment is complicated. Since its therapeutic introduction, allogeneic bone marrow transplantation has evolved from a means of achieving chemotherapeutic dose escalation to a form of adoptive immunotherapy. There is extensive evidence supporting the presence of a graft versus malignancy effect with hematologic malignancies, and preliminary data demonstrated the presence of a graft versus tumor effect with solid tumors (22,23). Different groups began developing nonmyeloablative allogeneic bone marrow and peripheral blood stem cell transplantation regimens for use for both hematologic and solid tumors (22–26). The goal is to create a conditioning regimen sufficient for proper donor cell engraftment with the least recipient graft ablation possible. Preliminary experiences with nonmyeloablative allogeneic transplantation among patients with RCC have been reported by a number of centers (14,22,24–26). In all studies, the provision existed for posttransplantation donor lymphocyte infusion if complete donor chimerism was not achieved. The largest series, reported by Childs et al. (14), demonstrated responses for 10 of 19 patients, with a conditioning regimen of cyclophosphamide and fludarabine. Complete donor chimerism seemed to be a prerequisite for responses, as was some degree of graft versus host disease.
There is a great deal of interest in understanding what antigens on host renal cancer are recognized by donor leukocytes. Such understanding would facilitate specific, more focused approaches that could potentially avoid the toxicity of graft versus host disease. It is possible that genes induced by HIF because of the VHL mutation represent immune target proteins. CAIX may be an immune target for T lymphocytes (27). There must be other proteins, growth factors, or receptors that could be targeted by donor T lymphocytes, and they might be regulated upstream by pVHL and HIF. Finally, the VHL mutation itself may represent a unique epitope (peptide including the amino acid mutation) that could be targeted by T lymphocytes. The same issues are important for patients responding to high-dose IL-2. Does the pVHL-HIF pathway lead to the expression of important immune targets (antigens)?
Role of Nephrectomy with Systemic Therapy
The primary role for nephrectomy (either standard radical, laparoscopic, or partial) is in the complete resection of primary RCC. Although patients with very large primary tumors (>10 cm), high histologic grade (Fuhrman Grade II to III/III or III to IV/IV), penetration into the perinephric tissues (T3a) or through Gerota’s fascia (T4), extensive inferior vena cava involvement below (T3b) or above (T3c) the diaphragm, or lymph node involvement in one (N1) or more (N2) regional sites are at increased risk for recurrence, no adjuvant systemic therapy has proven effective in preventing recurrences. A number of trials have studied various forms of IFN, and a small trial recently examined high-dose IL-2 therapy. Those trials all failed to demonstrate a definitive benefit with treatment (28,29).
In the setting of advanced disseminated disease, two recent randomized controlled trials demonstrated that nephrectomy followed by IFN- yielded significantly better overall survival rates than did treatment with IFN- alone (30,31). How nephrectomy in the setting of disseminated disease improves survival rates is unclear, but the effects are not attributable to a significant increase in the overall frequency of tumor regressions. The effects may be a result of the reduction in tumor bulk and reduction in the source of both immunosuppressive factors, such as vascular endothelial growth factor (VEGF), and tumor growth-enhancing factors.
Advances in Our Understanding of the VHL-HIF-Hypoxia-Induced Gene Pathway
The above discussion represents a general overview of the treatment of advanced RCC before the introduction of targeted therapy. We are now aware that biallelic VHL inactivation resulting from somatic mutations and/or hypermethylation is observed in 50 to 75% of sporadic clear cell carcinoma cases (32–34). Cells lacking pVHL (such as the majority of sporadic clear cell carcinomas) are unable to suppress the accumulation of hypoxia-inducible genes, including VEGF, under even well oxygenated conditions. In short, whereas normal cells produce hypoxia-inducible mRNA only under hypoxic conditions, cells lacking pVHL produce these mRNA constitutively.
The HIF family of transcription factors plays a central role in maintaining oxygen homeostasis. HIF- and -
regulate an array of many (>20) HIF target genes that have already been identified, including VEGF, PDGF, TGF-, EGF receptor (EGFR), and erythropoietin (Figure 1). These protein products play critical roles in cellular and systemic physiologic responses to hypoxia. TGF- has been demonstrated to be a powerful renal epithelial cell mitogen and may contribute to the development of RCC (35). HIF is a heterodimer composed of and subunits. Whereas the HIF- subunit is constitutively expressed, HIF- is normally degraded in the presence of oxygen and accumulates only under hypoxic conditions. Degradation is regulated by a 200-amino acid, oxygen-dependent, degradation domain that lies within the central region of HIF-1 (36), as well described in the accompanying discussions. In the absence of oxygen, modification does not take place and pVHL does not bind to HIF; therefore, HIF-1 accumulates.
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provides a biologic basis for some of the clinical manifestations of renal cancer (41,42). VEGF production likely plays a role in the vascularity that is pronounced in renal cancer. The tendency of these tumors to bleed and their intense vascular networks have been extensively described. Also, the induction of erythropoietin has been associated with polycythemia among patients with renal cancer. In fact, normalization of hemoglobin levels frequently predates clinical regression of disease among responding renal cancer patients. It is also possible that the induction of GLUT1 and CAIX affects glucose metabolism and acidic changes, respectively, within the tumor environment, resulting in barriers to a number of different types of therapy (21). There is enthusiasm regarding the potential of gene microarray technology to provide molecular profiles of different renal cancers. There is currently minimal information, compared with that for other malignancies (such as breast cancer, lymphoma, and lung cancer) (43). However, there is hope that, by analyzing these microarrays, we will be able to identify specific genes that lead to the expression of targets for immunotherapy (cellular or passive immunotherapy with antibodies) or targets for signal inhibitors. Overexpression of genes associated with either a good or poor prognosis may suggest targets for antibodies/vaccines or small-molecule signal inhibitors (such as tyrosine kinase inhibitors). Finally, attempts have been made and will continue to be made to determine the molecular profiles of cancers that have proven responsive to therapy. To date, no therapy has been effective enough to indicate much potential for this approach. In the future, with small-molecule therapy (described below), expression arrays may provide important information. In addition, in attempts to inhibit the pVHL-HIF pathway, it will be important to identify changes in other genes within tumors that may affect outcomes.
Targeting of the VHL-HIF-Hypoxia-Induced Gene Pathway for RCC Therapy
One of the obvious results of the scientific advances in RCC biologic characterization is the importance of recognizing the differences in the biologic features underlying the pathogenesis of the various histologic subtypes of RCC. This is true for at least clear cell and papillary renal cancers (8). Such findings not only will likely affect how we select patients for future therapy but also should be addressed in assessments of the results of prior therapy with IFN- or IL-2 or nephrectomy (12,20,30).
The ideal therapeutic targets for treatment of patients with advanced clear cell carcinoma would be genes or gene products critical to the development or maintenance of the cancer, with inhibition of the targets by the therapeutic agents not being life-threatening to the normal cells of the host (Figure 1). Ideally, the defect could be corrected and the function of the lost VHL protein replaced (37). This was elegantly demonstrated in a human renal cell line (37). This has been the goal of most gene therapies, without successful results. Recent efforts have been aimed at targeting HIF-1 itself. Previous screenings of small molecules and the novel pharmacologic activity of a potential antiplatelet agent (YC-1) provided a basis for testing of the effects of HIF-1 inhibition on cancer growth and toxicity in normal tissues (38,39). These efforts have been initiated in preclinical animal models, but clinical evaluations should be undertaken with caution, because of the risk of impairing critical physiologic responses to tissue hypoxia (40).
A number of agents that should allow us to target the actual critical gene products induced by HIF, including VEGF, PDGF, EGFR, and TGF-, have become available (Table 1). These molecules, in combination, form the critical links between pVHL, HIF, and RCC. VEGF and PDGF are critical for angiogenesis and metastatic potential, whereas EGFR and TGF- are important in renal cell mitogenesis and antiapoptotic effects. A number of agents used clinically may, alone or in combination, affect these pathways and mediate antitumor effects. The most obvious target has been VEGF, targeted with antibodies such as anti-VEGF (Avastin; Genentech, South San Francisco, CA), kinase inhibitors (SU5416 and PTK787), and cytokine traps (Fc Ig linked to receptors such as VEGF receptors 1 and 2) (44–47). In addition, there are antibodies directed to EGFR, such as C225 (ImClone, New York, NY) and ABX-EGF (Abgenix, Fremont, CA) (48,49). There are compounds inhibiting the EGFR tyrosine kinases, such as Iressa (AstraZeneca, Wilmington, DE) and OSI-774, and PDGF receptor tyrosine kinases, such as SU6668 and STI-571 (Gleevec; Novartis Pharmaceuticals, East Hanover, NJ) (50–52). Finally, there are a number of kinase inhibitors, such as PTK787, ZD6474, and SU11248, that exhibit promiscuous activities and inhibit a number of receptor pathways (46,52–54). These offer some potential for simultaneous blockade of several cooperating signaling pathways. There is even evidence that resistance to EGFR inhibition is mediated through enhanced expression of VEGF (55). This suggests that blockade of both pathways (VEGF receptor 2 and EGFR) is important for demonstration of clinically important antitumor effects. SU11248, a novel tyrosine kinase inhibitor targeting VEGF and PDGF receptors, also has the ability to block Flt-3 and c-Kit receptors (54). These agents have largely completed phase I trials. Phase II and III trials have been completed with other cancers, whereas phase II and III trials with RCC are being planned or are underway. To date, the most promising results have been observed with anti-VEGF (Avastin) (56). A recently reported randomized phase II study that enrolled patients with metastatic RCC who had experienced failure of or were not eligible for cytokine therapy randomized the patients to receive either low-dose anti-VEGF (3 mg/kg), high-dose anti-VEGF (10 m/kg), or placebo treatment (56). The study was discontinued prematurely because of a significant delay in disease progression associated with high-dose anti-VEGF, compared with placebo. The trial involved a planned 150 patients, with 50 in each group (10 mg/kg, 3 mg/kg, and placebo). The end points were time to progression, major clinical response, survival time, and toxicity. Only 113 patients were randomized, with 100 able to be evaluated; the study was stopped prematurely because of large differences in the time to progression, as monitoring rules require. Four patients exhibited partial responses, and 30% were progression-free at 8 mo on high-dose anti-VEGF. Thirty-six of 38 placebo-treated patients exhibited progressive disease, whereas 29 of 37 patients treated with anti-VEGF (10 mg/kg) exhibited progressive disease (P = 0.001; hazard ratio, >2.5). Overall survival analysis at 6 mo indicated that 18 of 38 placebo-treated patients were dead as a result of disease and 12 of 37 patients treated with anti-VEGF (10 mg/kg) were dead as a result of disease (P = 0.20, crossover allowed). Phase III studies of anti-VEGF in RCC are planned and will be initiated in the near future. At the most recent American Society of Clinical Oncology meeting, the results of a randomized, placebo-controlled trial of anti-VEGF with a standard chemotherapy regimen (irinotecan and 5-fluorouracil plus leucovorin) for treatment of advanced colorectal cancer were presented (57). More than 800 patients were randomized and anti-VEGF was administered intravenously at 5 mg/m2 every 2 wk. With >400 patients in each treatment group, the results were remarkable, with very significant improvements in median survival time (20.3 versus 15.6 mo), median progression-free survival time (10.6 versus 6.2 mo), overall response rate (45 versus 35%), and duration of response (10.4 versus 7.1 mo). The P values indicated significance (P < 0.003) in each case. This was the first trial that conclusively demonstrated the benefit of an antiangiogenic agent.
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Overall, the future for the treatment of RCC looks far brighter than ever before. The targeted treatment discussed is firmly based on the biologic features of clear cell cancer of the kidney. However, trials must be carefully performed, must be well controlled, and must have realistic end points. We must carefully confirm that our results are not attributable to patient selection and prognostic factors, such as performance status, prior nephrectomy, serum calcium levels, anemia, and serum lactate dehydrogenase levels (41). If, as clinical investigators, we carefully select the correct molecular targets for inhibition in the tumors and the targets are present (clear cell histologic type, with loss of VHL expression), then we will likely begin to observe the results others have experienced with targeted therapy, such as the use of STI-571 (Gleevec) for treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors or anti-HER2/neu (Herceptin; Genentech) for treatment of breast cancer (60–62).
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References |
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TopAbstractIntroductionSystemic Therapy of RCCReferences |
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as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 20: 289–296, 20022a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 17: 2859–2867, 1999 and survival in metastatic renal carcinoma: Early results of a randomised controlled trial. Lancet 353: 14–17, 1999[CrossRef][Medline]
1b compared with placebo in metastatic renal-cell carcinoma: Canadian Urologic Oncology Group. N Engl J Med 338: 1265–1271, 1998-NL as adjuvant treatment for resectable renal cell carcinoma: An Eastern Cooperative Oncology Group/Intergroup trial. J Clin Oncol 21: 1214–1222, 20032b compared with interferon-2b alone for metastatic renal-cell cancer. N Engl J Med 345: 1655–1659, 2001-based immunotherapy compared with interferon- alone in metastatic renal-cell carcinoma: A randomised trial. Lancet 358: 966–970, 2001[CrossRef][Medline]
in von Hippel-Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: A possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci USA 98: 1387–1392, 2001 to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468–472, 2001 a valid therapeutic target? J Natl Cancer Inst 95: 498–499, 2003This article has been cited by other articles:
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  K. L. Wu, H. Miao, and S. Khan JAK kinases promote invasiveness in VHL-mediated renal cell carcinoma by a suppressor of cytokine signaling-regulated, HIF-independent mechanism Am J Physiol Renal Physiol, December 1, 2007; 293(6): F1836 - F1846. [Abstract] [Full Text] [PDF]
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 C. Morais, B. Pat, G. Gobe, D. W. Johnson, and H. Healy Pyrrolidine dithiocarbamate exerts anti-proliferative and pro-apoptotic effects in renal cell carcinoma cell lines Nephrol. Dial. Transplant., December 1, 2006; 21(12): 3377 - 3388. [Abstract] [Full Text] [PDF]
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 I. Talon, V. Lindner, C. Sourbier, E. Schordan, S. Rothhut, M. Barthelmebs, H. Lang, J.-J. Helwig, and T. Massfelder Antitumor effect of parathyroid hormone-related protein neutralizing antibody in human renal cell carcinoma in vitro and in vivo Carcinogenesis, January 1, 2006; 27(1): 73 - 83. [Abstract] [Full Text] [PDF]
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